Inborn errors of metabolism are a diverse group of inherited genetic disorders, typically presenting in the neonatal or early infantile period, in which a deficiency or dysfunction of a specific enzyme or transporter disrupts normal biochemical pathways, leading to accumulation of toxic substrates or deficiency of essential products.

Exam domain	One-glance essentials
Definition / diagnosis	Inherited enzyme, transporter or cofactor defects causing toxic accumulation or substrate deficiency ^[1] Presentations range from neonatal collapse to chronic neurodevelopmental disease ^[1]
Epidemiology / risks	Consanguinity, sibling deaths and maternal-line disease guide inheritance ^[1] Catabolic stress often precipitates decompensation ^[1]
Core mechanism	Blocked pathways cause intoxication, energy failure or storage disease ^[1] Fasting and infection increase toxic metabolites ^[1]
Clinical picture	Poor feeding, vomiting, encephalopathy, seizures or unusual odour ^[1] Hypoglycaemia, acidosis, hyperammonaemia and organomegaly are key patterns ^[1]
Investigations	During illness obtain glucose, gases, lactate, ammonia, ketones and electrolytes urgently ^[2] Save plasma/urine before treatment; confirm with metabolic and genetic testing ^[2]
Management	Stop catabolism with high-calorie glucose while treating airway, seizures and shock ^[3] Temporarily stop offending substrate and use disorder-specific detoxification ^[3]
Complications	Cerebral oedema, irreversible neurological injury and multiorgan failure ^[4] Recurrent crises impair growth and development ^[4]
Prevention / follow-up	Avoid fasting and provide written emergency regimens ^[3] Newborn screening, family testing and reproductive counselling prevent delayed diagnosis ^[3]
Exam traps	*Hyperammonaemia may occur without acidosis* ^[2] Never delay emergency treatment while awaiting a definitive metabolic diagnosis ^[3]

References

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section, slides on epidemiology, SSIEM classification, clinical presentation)

^[2] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — diagnosis, management, newborn screening)

^[3] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — management: dietary control, ERT, steroid treatment, transplantation, genetic counselling)

^[4] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — benefit from prompt recognition, diagnosis and treatment)

Inborn Errors of Metabolism (IEM) — Paediatrics

Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by defective enzymes or transporters in metabolic pathways, leading to disease due to metabolic malfunction and/or accumulation of toxic intermediate metabolites. ^[1]

Breaking this down from first principles:

"Inborn" = present from birth (genetic)
"Errors" = defects/mistakes
"Metabolism" = all chemical processes in cells including biosynthesis and breakdown of complex organic molecules ^[2]

In essence, a child inherits a mutation (usually autosomal recessive) that knocks out or reduces the activity of a specific enzyme or transporter. The consequence is predictable from basic biochemistry: the substrate before the blocked step accumulates (and may be toxic), the product after the blocked step is deficient (and may be essential), and alternative pathways may be activated producing abnormal secondary metabolites.

Metabolism = all chemical processes in cells including biosynthesis and breakdown of complex organic molecules. IEM = a group of > 500 diverse disorders of enzymatic reactions that degrade, synthesize, or interconvert molecules within cells. ^[2]

2. Epidemiology

Individually rare, but collectively common, contributing to a substantial patient burden and present in all ethnic groups. ^[1]

Parameter	Detail
Individual disease frequency	~1 in 50,000–100,000 ^[2]
Collective incidence (worldwide)	~1 in 4,000 newborns screened ^[1]
Local (HK) collective incidence	1 in 4,122 to 1 in 7,580 — comparable to worldwide figures ^[1]
Collective incidence (HK, Adrian Lui)	~1 in 4,000 children ^[2]
Total number of known IEMs	> 500 (and growing with genomic advances) ^[2]
Inheritance	Majority autosomal recessive (AR); occasionally mitochondrial or de novo ^[2]

High Yield — HK Figures

Local collective incidence of IEM ranges from 1 in 4,122 to 1 in 7,580 — this is a commonly tested figure for HKUMed exams. Remember: individually rare, collectively common. ^[1]

Usually presented at birth, early infancy and childhood (but some can present in adulthood). ^[1]
Neonatal onset IEMs are the most dramatic and life-threatening (e.g., urea cycle defects, maple syrup urine disease).
Late-onset forms exist — think of Wilson's disease (hepatolenticular degeneration) presenting in older children/adolescents, or some fatty acid oxidation defects presenting with the first fasting stress (e.g., intercurrent illness).

IEM is a significant health issue particularly in infants and young children. ^[3]
Early recognition and treatment is life-saving. ^[2]
Newborn screening becoming the gold standard worldwide. ^[1]

Risk Factor	Explanation
Consanguinity	AR inheritance means carrier parents have 25% risk per pregnancy; consanguineous marriages markedly increase the probability of homozygosity. In certain HK/Asian populations with smaller gene pools, specific IEMs may cluster.
Family history	Positive family history of neonatal/infant death of unknown cause, developmental regression, unexplained metabolic crises. A previously affected sibling gives 25% recurrence risk for AR conditions.
Ethnicity	Some IEMs are more prevalent in specific ethnic groups (e.g., Tay-Sachs in Ashkenazi Jewish populations; G6PD deficiency in Southern Chinese populations; CPT I deficiency in certain Inuit populations).
Parental carrier status	Known carrier parents (identified through cascade screening or newborn screening of a previous child).

4. Relevant Anatomy and Function (Metabolic Pathways)

IEMs affect virtually every organ system because metabolism is ubiquitous. However, understanding the key metabolic "hubs" helps you predict clinical features:

Amino acids are absorbed from dietary protein → transported to the liver → used for protein synthesis, gluconeogenesis, or converted to other metabolites.
Key enzymes: phenylalanine hydroxylase (PKU), branched-chain α-keto acid dehydrogenase (MSUD), urea cycle enzymes (OTC, ASS, ASL, arginase).
Blocked steps → accumulation of specific amino acids or their keto acids → neurotoxicity (brain is the most vulnerable organ in the developing child).

Organic acids are intermediates of amino acid catabolism (particularly branched-chain amino acids), fatty acid oxidation, and the TCA cycle.
Enzyme defects → accumulation of organic acids (e.g., methylmalonic acid, propionic acid) → metabolic acidosis with high anion gap.

During fasting, fatty acids are the primary energy source. β-oxidation in mitochondria generates acetyl-CoA → enters TCA cycle → ATP.
Also produces ketone bodies in liver for brain energy.
Blocked β-oxidation → hypoketotic hypoglycaemia (the hallmark: the child is fasting and hypoglycaemic but CANNOT make ketones), accumulation of acylcarnitines, and secondary carnitine deficiency.
Key disorders: MCAD deficiency (most common fatty acid oxidation defect), CPT I deficiency (more common in HK/Asian populations), VLCAD deficiency.

Glucose homeostasis via glycolysis, gluconeogenesis, glycogenolysis.
Galactose metabolism (galactose-1-phosphate uridylyltransferase in classic galactosemia).
Glycogen storage diseases (GSD): enzyme defects in glycogen synthesis or breakdown → hepatomegaly ± hypoglycaemia.

The only pathway for disposing of waste nitrogen from amino acid catabolism.
Located in hepatocyte mitochondria and cytoplasm.
Defects → hyperammonaemia → cerebral oedema, encephalopathy. This is a medical emergency in neonates.

Lysosomes contain acid hydrolases that break down macromolecules (glycosaminoglycans, sphingolipids, glycogen).
Defective enzyme → progressive accumulation of undigested substrate within lysosomes → organomegaly, neurodegenerative features, coarse facies, skeletal dysplasia.
Examples: Gaucher disease, Fabry disease, mucopolysaccharidoses (MPS), Pompe disease.

Peroxisomes handle very-long-chain fatty acid (VLCFA) oxidation, bile acid synthesis, plasmalogen synthesis.
Defects → accumulation of VLCFA → Zellweger spectrum disorders, X-linked adrenoleukodystrophy.

Oxidative phosphorylation via complexes I–V → ATP production.
Unique: can be maternally inherited (mitochondrial DNA) or nuclear-encoded (AR/AD).
Multi-system disease affecting high-energy-demand organs: brain, muscle, heart, liver.

5. Pathophysiology of IEM

The core pathophysiological mechanisms of IEM ^[2]:

Mechanism	Example	Clinical Consequence
↑ Primary substrate	↑ Leucine in MSUD ^[2]	Neurotoxicity, "maple syrup" odour
↓ Product	Hypoglycaemia (in GSD, fatty acid oxidation defects) ^[2]	Seizures, brain damage
↑ Secondary substrate	↑ Phenylpyruvic acid in PKU (phenylalanine shunted to alternative pathway)	"Musty" odour, intellectual disability
Secondary inhibition	Propionic acid inhibits N-acetylglutamate synthetase → secondary hyperammonaemia in organic acidaemias ^[2]	Encephalopathy

The developing neonatal/infant brain has high metabolic demands, incomplete myelination, and an immature blood–brain barrier.
Toxic metabolites (ammonia, leucine, phenylalanine) cross the BBB readily in neonates.
Energy failure (e.g., from fatty acid oxidation defects or mitochondrial disease) preferentially damages the basal ganglia and white matter.

Accumulated organic acids (methylmalonic acid, propionic acid, lactic acid) are "unmeasured anions."
They consume bicarbonate as buffers → metabolic acidosis with elevated anion gap.
Remember the mnemonic MUDPILES for high-anion-gap metabolic acidosis — the "I" includes Inborn errors of metabolism. ^[4]

High Yield — MUDPILES Mnemonic

M – Methanol; U – Uraemia; D – DKA; P – Paracetamol/Propylene glycol; I – Infection, Iron, Isoniazid, Inborn errors of metabolism; L – Lactic acidosis; E – Ethylene glycol; S – Salicylates. The "I" in MUDPILES is commonly tested and IEM is a cause of high anion gap metabolic acidosis in neonates/infants. ^[4]

6. Classification

IEM can be classified in multiple ways. The two most important frameworks for clinical practice:

Category	Description	Examples
Small molecule diseases	Accumulation of small, water-soluble molecules; typically acutely treatable	Amino acidopathies (PKU, MSUD), organic acidaemias, urea cycle defects, fatty acid oxidation defects, carbohydrate disorders
Organelle diseases	Defects in organelle function; typically progressive and harder to treat	Lysosomal storage diseases, peroxisomal disorders, mitochondrial diseases

This is the most clinically useful framework for the ward:

Category	Pathophysiology	Time Course	Key Features	Examples
Intoxication type	Accumulation of toxic metabolites proximal to the enzyme block	Acute, intermittent crises triggered by catabolic stress (fasting, illness, protein load)	Encephalopathy, vomiting, metabolic acidosis, hyperammonaemia; characteristically a symptom-free interval after birth before toxins accumulate	MSUD, organic acidaemias (PA, MMA), urea cycle defects, galactosaemia
Energy insufficiency type	Deficient energy production (ATP)	Can be acute (during fasting/stress) or chronic/progressive	Hypoglycaemia, lactic acidosis, myopathy, cardiomyopathy, failure to thrive; symptoms worsen with fasting or exercise	Fatty acid oxidation defects, glycogen storage diseases, mitochondrial respiratory chain defects, pyruvate metabolism defects
Complex molecule (making/breaking) type	Defective synthesis or degradation of complex molecules	Chronic, progressive, unrelated to dietary intake	Organomegaly, coarse facies, skeletal dysplasia, neurodegeneration; no symptom-free interval — symptoms accumulate progressively	Lysosomal storage diseases (Gaucher, MPS), peroxisomal disorders (Zellweger), CDG syndromes

High Yield — Symptom-Free Interval

Intoxication-type IEMs characteristically have a symptom-free interval after birth. The baby is born well (maternal enzymes cleared the toxins in utero) → feeds → toxins accumulate → becomes symptomatic hours to days later. This is KEY to distinguishing IEM from birth asphyxia or congenital malformations.

The Society for the Study of Inborn Errors of Metabolism (SSIEM) classifies IEM into 15 groups:

Disorders of amino acid and peptide metabolism
Disorders of carbohydrate metabolism
Disorders of fatty acid and ketone body metabolism
Disorders of energy metabolism
Disorders in the metabolism of purines, pyrimidines and nucleotides
Disorders of the metabolism of sterols
Disorders of porphyrin and haem metabolism
Disorders of lipid and lipoprotein metabolism
Congenital disorders of glycosylation and other disorders of protein modification
Lysosomal disorders
Peroxisomal disorders
Disorders of neurotransmitter metabolism
Disorders in the metabolism of vitamins and (non-protein) cofactors
Disorders in the metabolism of trace elements and metals
Disorders and variants in the metabolism of xenobiotics

^[1]

The most common types of IEM ^[3]:

IEM Category	Examples	Key Features
Organic acidaemias/acidurias	Maple syrup urine disease (MSUD)	Branched-chain amino acid accumulation; sweet-smelling urine
Amino acid metabolism disorders	Phenylketonuria (PKU)	Phenylalanine accumulation → intellectual disability if untreated
Urea cycle disorders	Citrullinaemia	Hyperammonaemia → encephalopathy
Fatty acid oxidation disorders	CPT I deficiency (more common in HK)	Hypoketotic hypoglycaemia during fasting
Carbohydrate metabolism disorders	Galactosaemia, GSD	Hypoglycaemia, hepatomegaly
Purine/pyrimidine metabolism	Lesch-Nyhan syndrome	Self-mutilation, hyperuricaemia
Transport and mineral disorders	Wilson's disease, haemochromatosis	Copper/iron accumulation
Mitochondrial diseases	MELAS, Leigh syndrome	Lactic acidosis, myopathy, encephalopathy
Peroxisomal disorders	Zellweger spectrum	Hypotonia, seizures, hepatomegaly
Lysosomal storage diseases	Gaucher, Fabry, MPS, Pompe	Organomegaly, skeletal dysplasia, neurodegeneration
Mucopolysaccharidosis	MPS I (Hurler), MPS II (Hunter)	Coarse facies, corneal clouding, skeletal deformity
Cholesterol/neutral lipid disorders	Smith-Lemli-Opitz syndrome	Dysmorphic features, intellectual disability

8. Clinical Features: Symptoms and Signs

In the neonatal period, IEM presents with nonspecific clinical symptoms such as poor appetite, vomiting, acute or chronic encephalopathy, myopathy, hypoglycaemia or hepatic syndromes — must rule out sepsis pattern. ^[1]

This is the crux of why IEM is so hard to diagnose: the presentation mimics sepsis. A sick neonate with poor feeding, lethargy, vomiting, and metabolic acidosis could be septic OR could have an IEM. The answer is: always consider both simultaneously.

8.2 Symptoms (with Pathophysiological Basis)

Symptom	Pathophysiological Basis
Lethargy → coma	Accumulation of neurotoxic metabolites (ammonia, leucine, organic acids) → cerebral oedema, impaired neurotransmission. Progressive energy failure in mitochondrial disease → neuronal death.
Seizures	Hypoglycaemia (→ inadequate glucose substrate for neuronal ATP); direct neurotoxicity of accumulated metabolites (e.g., glycine in non-ketotic hyperglycinaemia activates NMDA receptors → excitotoxicity); pyridoxine-dependent epilepsy (antiquitin deficiency → impaired GABA synthesis).
Developmental delay / intellectual disability	Chronic, low-grade accumulation of toxic metabolites during the critical period of brain development → impaired myelination, synaptogenesis, and neuronal migration. Classic example: untreated PKU — phenylalanine competitively inhibits transport of other large neutral amino acids across BBB → depleted tyrosine, tryptophan → impaired catecholamine and serotonin synthesis → intellectual disability.
Developmental regression	Progressive accumulation of storage material (lysosomal storage diseases) or ongoing energy failure (mitochondrial disease) → loss of previously acquired milestones. This is a RED FLAG — always consider IEM in a child who is losing skills.
Hypotonia (floppy infant)	Energy failure in muscle (mitochondrial myopathy, fatty acid oxidation defects); direct toxicity to anterior horn cells; Pompe disease (glycogen accumulation in muscle fibres disrupts contractile apparatus).
Movement disorders / dystonia	Basal ganglia injury from organic acid accumulation (e.g., glutaric aciduria type I → striatal necrosis); Wilson's disease (copper deposition in lenticular nucleus → extrapyramidal signs).

Symptom	Pathophysiological Basis
Poor feeding / food refusal	Encephalopathy from toxin accumulation; nausea; learned aversion in older children who feel unwell after protein-containing meals (organic acidaemias, urea cycle defects).
Vomiting	Toxic metabolites stimulate the chemoreceptor trigger zone in the area postrema; raised intracranial pressure from cerebral oedema (hyperammonaemia); pyloric spasm. Often cyclical and recurrent.
Hepatomegaly	Storage of glycogen (GSD), lipid (fatty acid oxidation defects, Niemann-Pick), sphingolipid (Gaucher), or copper (Wilson's).
Jaundice	Hepatocellular dysfunction (galactosaemia, tyrosinaemia type I, Wilson's disease); conjugation defects (Crigler-Najjar — deficiency of UGT1A1 → unconjugated hyperbilirubinaemia ^[7]); cholestasis from bile acid synthesis defects.
Diarrhoea	Carbohydrate malabsorption (disaccharidase deficiency); mucosal damage from toxin accumulation.

Symptom	Pathophysiological Basis
Metabolic acidosis (Kussmaul breathing in older children)	Accumulation of organic acids (propionic, methylmalonic, lactic) → consumes bicarbonate → high anion gap metabolic acidosis → compensatory hyperventilation.
Hypoglycaemia	Impaired gluconeogenesis (fructose-1,6-bisphosphatase deficiency); impaired glycogenolysis (GSD I); impaired fatty acid oxidation → inadequate acetyl-CoA for gluconeogenesis AND ketogenesis → hypoketotic hypoglycaemia (hallmark of fatty acid oxidation defects).
Hyperammonaemia	Direct block in urea cycle enzymes → cannot convert ammonia to urea; secondary hyperammonaemia in organic acidaemias (propionyl-CoA inhibits N-acetylglutamate synthetase, the cofactor activator of CPS I, the first step of the urea cycle).
Failure to thrive	Chronic energy deficit (mitochondrial disease, organic acidaemias); malabsorption; anorexia from chronic illness.
Peculiar body/urine odour	Volatile metabolites excreted in urine/sweat: MSUD → "maple syrup/burnt sugar" (branched-chain keto acids); PKU → "musty/mousy" (phenylacetic acid); isovaleric acidaemia → "sweaty feet" (isovaleric acid); trimethylaminuria → "fishy."

Symptom	Pathophysiological Basis
Cardiomyopathy (dilated or hypertrophic)	Energy failure in cardiomyocytes (fatty acid oxidation defects, mitochondrial disease); glycogen/lipid storage in myocardium (Pompe disease → HCM; Fabry disease → HCM). 5–10% of HCM is associated with metabolic disorders / inborn errors of metabolism. ^[5]
Arrhythmias	Fatty acid accumulation in conducting tissue; electrolyte derangements (hypocalcaemia, hyperkalaemia from metabolic acidosis).

Symptom	Pathophysiological Basis
Myopathy / exercise intolerance / rhabdomyolysis	Impaired mitochondrial β-oxidation or respiratory chain → cannot generate ATP during exercise → myoglobin release. GSD V (McArdle disease) → cannot break down muscle glycogen → cramps + rhabdomyolysis.
Skeletal dysplasia / dysostosis multiplex	Accumulation of glycosaminoglycans in bone and cartilage (MPS) → abnormal bone modelling → short stature, kyphosis, beaked vertebrae, broad ribs.

Symptom	Pathophysiological Basis
Fair skin/hair	PKU: ↓tyrosine (product of phenylalanine hydroxylase) → ↓melanin synthesis → fair complexion, light hair, blue eyes.
Eczema-like rashes	PKU (secondary to impaired immune modulation); acrodermatitis enteropathica (zinc transporter defect).
Angiokeratomas	Fabry disease: glycosphingolipid (Gb3) accumulation in vascular endothelium → dark-red papules in "bathing trunk" distribution.

Symptom	Pathophysiological Basis
Cataracts	Galactosaemia: galactitol (reduced by aldose reductase from galactose-1-phosphate) accumulates in the lens → osmotic swelling → cataract formation.
Cherry-red spot (macula)	Tay-Sachs, Niemann-Pick type A: GM2 ganglioside / sphingomyelin accumulation in retinal ganglion cells makes the surrounding retina pale; the fovea, which lacks ganglion cells, appears red by contrast.
Corneal clouding	MPS I (Hurler), MPS VI: GAG deposition in corneal stroma.
Kayser-Fleischer rings	Wilson's disease: copper deposition in Descemet's membrane of the cornea → golden-brown rings visible on slit-lamp examination.
Lens subluxation (ectopia lentis)	Homocystinuria: excess homocysteine interferes with fibrillin cross-linking in the zonular fibres → downward and inward lens dislocation (cf. Marfan's: upward and outward).

8.3 Signs (with Pathophysiological Basis)

This is the most common and most dangerous IEM presentation. The baby is born well (symptom-free interval) → becomes acutely unwell within hours to days.

Sign	Pathophysiological Basis
Encephalopathy (poor responsiveness, abnormal tone, absent reflexes)	Toxic metabolite accumulation → cerebral oedema, impaired neurotransmission
Tachypnoea without respiratory disease	Central respiratory stimulation by metabolic acidosis (Kussmaul-type compensation) OR direct CNS effect of hyperammonaemia stimulating the respiratory centre → respiratory alkalosis initially in urea cycle defects (ammonia directly stimulates brainstem respiratory centre → hyperventilation → primary respiratory alkalosis — this is a distinguishing feature of urea cycle defects vs organic acidaemias)
Apnoea / irregular breathing	Severe brainstem depression from massive hyperammonaemia or hypoglycaemia
Seizures	Hypoglycaemia, hypocalcaemia (secondary to metabolic derangement), direct neurotoxicity
Bulging fontanelle	Cerebral oedema from hyperammonaemia
Hepatomegaly	Storage diseases, galactosaemia (galactose-1-phosphate toxicity → hepatocyte injury)
Unusual odour	As above (MSUD, PKU, isovaleric acidaemia)
Dehydration	Vomiting, poor feeding, osmotic diuresis from organic aciduria

Must-Know — IEM vs Sepsis in the Neonate

A common exam pitfall: IEM and neonatal sepsis are clinically indistinguishable in the early stages. Both present with poor feeding, lethargy, vomiting, hypotonia, and metabolic acidosis. In real life, you must treat for BOTH simultaneously (give antibiotics AND send metabolic investigations). The clue to IEM: symptom-free interval after birth → followed by rapid deterioration; often no identifiable infectious source; metabolic acidosis with high anion gap + ↑ammonia + ↓glucose; and encephalopathy disproportionate to degree of sepsis. ^[1]

Sign	Pathophysiological Basis
Growth failure / failure to thrive	Chronic energy deficit, protein restriction (therapeutic diets), chronic acidosis inhibiting growth hormone action
Developmental delay	Chronic toxicity to developing brain
Coarse facies (MPS, mucolipidosis)	GAG deposition in skin, subcutaneous tissue → thick skin, broad nose, thick lips, prominent supraorbital ridges
Macrocephaly	Megalencephaly from storage material accumulation (Canavan disease, Alexander disease, glutaric aciduria type I) OR communicating hydrocephalus (MPS)
Microcephaly	Brain damage from metabolic insult (untreated PKU, mitochondrial disease)
Hepatosplenomegaly	Lysosomal storage in Kupffer cells and splenic macrophages (Gaucher: glucocerebroside; Niemann-Pick: sphingomyelin)
Splenomegaly alone	Gaucher disease (most common lysosomal storage disease)
Cardiomegaly	Pompe disease (glycogen storage in cardiomyocytes → massive HCM → HF in infantile form)
Skeletal abnormalities (dysostosis multiplex)	GAG in bone (MPS): anterior beaking of vertebral bodies, paddle-shaped ribs, J-shaped sella, claw-hand deformity
Joint stiffness (MPS) vs hypermobility (Ehlers-Danlos)	GAG deposition in periarticular tissues → contractures
Skin findings	As above + xanthomas in lipid metabolism disorders

Some IEMs present late because the enzyme has partial residual activity or the trigger (e.g., protein load, fasting) has not been encountered:

Sign	Pathophysiological Basis
Wilson's disease (> 3 years, typically 5–35 years)	Gradual hepatic copper accumulation → liver disease (hepatitis, cirrhosis, fulminant failure); copper spills into blood → deposits in brain (basal ganglia → movement disorders, behavioural changes) and cornea (Kayser-Fleischer rings). Can mimic Parkinson's, extrapyramidal deposition of the copper. ^[6]
Fabry disease (adolescent males)	X-linked, Gb3 accumulation → acroparaesthesia (burning pain in hands/feet), angiokeratomas, corneal verticillata, progressive renal failure
Homocystinuria	Tall, thin habitus (Marfanoid); lens subluxation (downward); thromboembolism; intellectual disability

This can occur at any age when a child with a known or unknown IEM encounters a catabolic trigger:

Trigger	Why It Precipitates a Crisis
Intercurrent illness (fever, infection)	Catabolism → increased breakdown of endogenous protein → flood of amino acids into blocked pathway; fever increases metabolic rate
Fasting	Dependence on fatty acid oxidation for energy → if FAO is defective, hypoglycaemia ± rhabdomyolysis
High protein intake	Increased substrate load into blocked amino acid/urea cycle pathway
Surgery / anaesthesia	Catabolic stress + fasting
Vaccination (rare)	Fever and mild catabolic stress

Signs of acute decompensation:

Rapid-onset encephalopathy (lethargy → coma)
Metabolic acidosis (high anion gap)
Hyperammonaemia
Hypoglycaemia ± ketosis (or inappropriately absent ketosis)
Multi-organ failure (liver failure, rhabdomyolysis, pancytopenia)

9. Important Specific IEMs — Clinical Details

Defect: Phenylalanine hydroxylase (PAH) deficiency → cannot convert phenylalanine to tyrosine
Inheritance: AR (chromosome 12q)
Pathophysiology: ↑Phe → neurotoxicity (competitive inhibition of amino acid transport across BBB → ↓tyrosine, tryptophan in brain → ↓dopamine, serotonin, melanin)
Clinical: Fair complexion, musty/mousy odour, intellectual disability, seizures, eczema, behavioural problems
Screening: Newborn screening (blood Phe level)
Treatment: Low-phenylalanine diet (lifelong); BH4-responsive PKU → sapropterin (BH4 supplementation); large neutral amino acid supplementation

Defect: Branched-chain α-keto acid dehydrogenase (BCKDH) complex deficiency
Substrates that accumulate: Leucine, isoleucine, valine (branched-chain amino acids) and their corresponding keto acids
Inheritance: AR
Clinical: Presents in first week of life with poor feeding, lethargy, "maple syrup" odour, encephalopathy, opisthotonus. ↑Leucine is the primary neurotoxic substrate. ^[2]
Investigation: ↑Branched-chain amino acids on plasma amino acid analysis; urine organic acids show branched-chain keto acids
Treatment: Dietary restriction of branched-chain amino acids; acute management with IV glucose + insulin to drive anabolism; thiamine trial (some forms are thiamine-responsive); liver transplantation in severe cases

Most common: Ornithine transcarbamylase (OTC) deficiency — X-linked (the exception to the AR rule for IEMs)
Pathophysiology: Cannot convert ammonia to urea → hyperammonaemia
Clinical: Neonatal presentation with encephalopathy, respiratory alkalosis (ammonia stimulates brainstem respiratory centre → hyperventilation), seizures, cerebral oedema
Key lab finding: ↑↑Ammonia, normal anion gap (no organic acid accumulation), respiratory alkalosis (distinguishes from organic acidaemias which have metabolic acidosis)
Treatment: Dietary protein restriction; nitrogen scavengers (sodium benzoate, sodium phenylbutyrate); IV arginine (replaces depleted arginine and primes the urea cycle); dialysis for acute severe hyperammonaemia; liver transplantation

Defect: Propionyl-CoA carboxylase (PA) or methylmalonyl-CoA mutase (MMA)
Pathophysiology: Accumulation of propionic acid or methylmalonic acid → metabolic acidosis with high anion gap; secondary inhibition of urea cycle (→ hyperammonaemia); bone marrow suppression (→ pancytopenia)
Clinical: Vomiting, dehydration, encephalopathy, metabolic acidosis + hyperammonaemia + hypoglycaemia + ketosis
Treatment: Dietary protein restriction (especially odd-chain amino acids); carnitine supplementation (conjugates with organic acids for renal excretion); B12 trial (some MMA is B12-responsive); metronidazole (reduces gut propionate production from bacteria); liver ± kidney transplantation

Most common fatty acid oxidation defect
Inheritance: AR
Pathophysiology: Cannot oxidise medium-chain fatty acids during fasting → hypoketotic hypoglycaemia + accumulation of medium-chain acylcarnitines
Clinical: Typically presents at 3–24 months with first prolonged fast (intercurrent illness); lethargy, vomiting, hypoketotic hypoglycaemia, hepatomegaly, Reye-like syndrome; can cause sudden infant death if unrecognised
Investigation: Acylcarnitine profile on tandem MS shows ↑C8 (octanoylcarnitine); urine organic acids show dicarboxylic aciduria
Treatment: Avoid fasting (regular feeds, especially during illness); IV dextrose during illness; medium-chain triglyceride (MCT) oil is CONTRAINDICATED (unlike in other conditions); L-carnitine supplementation

Defect: Galactose-1-phosphate uridylyltransferase (GALT) deficiency
Inheritance: AR
Pathophysiology: Galactose-1-phosphate accumulation → hepatotoxicity, renal tubular damage; galactitol (via aldose reductase) → cataracts
Clinical: Presents in first days of life when breast/formula feeding commences; vomiting, jaundice, hepatomegaly, lethargy, E. coli sepsis (galactose-1-phosphate impairs neutrophil function), cataracts
Treatment: Galactose-free diet (soya-based formula); long-term complications include ovarian failure, learning difficulties despite treatment

GSD I (von Gierke): Glucose-6-phosphatase deficiency → cannot release glucose from glycogen → severe fasting hypoglycaemia, lactic acidosis, hepatomegaly, "doll-like" facies, hyperuricaemia, hyperlipidaemia
GSD II (Pompe): Acid α-glucosidase deficiency (lysosomal) → glycogen accumulation in muscle → infantile: massive cardiomegaly + profound hypotonia ("floppy baby"); late-onset: progressive myopathy. Enzyme replacement therapy (alglucosidase alfa) available.
GSD III (Cori/Forbes): Debranching enzyme deficiency → hepatomegaly, hypoglycaemia (less severe than GSD I), myopathy
GSD V (McArdle): Muscle phosphorylase deficiency → exercise intolerance, cramps, rhabdomyolysis, second-wind phenomenon

Disease	Deficient Enzyme	Stored Material	Key Features
Gaucher (most common LSD)	β-Glucocerebrosidase	Glucocerebroside	Hepatosplenomegaly, bone crises, Erlenmeyer flask deformity, "crinkled paper" macrophages
Fabry	α-Galactosidase A	Gb3 (globotriaosylceramide)	X-linked; acroparaesthesia, angiokeratomas, renal failure, cardiomyopathy
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	Cherry-red spot, developmental regression, macrocephaly, death by age 3–5
Niemann-Pick A/B	Sphingomyelinase	Sphingomyelin	Hepatosplenomegaly, cherry-red spot (type A), interstitial lung disease
Pompe (GSD II)	Acid α-glucosidase	Glycogen	Infantile: massive HCM + hypotonia; late-onset: progressive myopathy
MPS I (Hurler)	α-L-Iduronidase	Dermatan sulfate, heparan sulfate	Coarse facies, corneal clouding, dysostosis multiplex, intellectual disability
MPS II (Hunter)	Iduronate-2-sulfatase	Dermatan sulfate, heparan sulfate	X-linked; similar to Hurler but NO corneal clouding

Defect: ATP7B mutation → impaired biliary copper excretion + impaired incorporation of copper into ceruloplasmin ^[6]^[8]
Inheritance: AR (chromosome 13)
Pathophysiology: Copper accumulates first in liver → hepatitis, cirrhosis; then overflows into blood → deposits in brain (basal ganglia → movement disorders), cornea (Kayser-Fleischer rings), kidneys (RTA), RBCs (Coombs-negative haemolytic anaemia)
Clinical in children: Usually hepatic presentation (chronic hepatitis, cirrhosis, acute liver failure); neuropsychiatric presentation more common in adolescents/young adults
Fulminant hepatic failure due to Wilson's has very specific features: young patient with no reason for fulminant liver failure, exclusion of all other common causes → only finding is low haemoglobin, Coombs-negative haemolytic anaemia ^[6]
Genetic test does not have to be positive to reach a diagnosis → with compatible clinical and history still can diagnose, since hereditary pathway of Wilson's is very heterogeneous → not just ATP7B ^[6]
Treatment: Penicillamine (copper chelator — causes worsened neurological symptoms in the first few days because the patient is used to copper in the brain, but once penicillamine is given, they lose copper, body is not used to it, may exacerbate the neuro symptoms ^[6]); trientine (alternative chelator with fewer side effects); zinc (blocks intestinal copper absorption); liver transplantation for fulminant failure or decompensated cirrhosis

Disorder	Defect	Bilirubin Type	Severity	Treatment
Gilbert syndrome	↓UGT1A1 expression (promoter mutation)	Unconjugated	Benign, intermittent mild jaundice triggered by fasting/stress	None required ^[8]
Crigler-Najjar type I	UGT1A1 activity essentially absent	Unconjugated	Severe; presents first 2–3 days of life; lifelong phototherapy required to avoid bilirubin-induced neurological disorders (BIND) unless liver transplant performed; AR inheritance ^[7]
Crigler-Najjar type II	UGT1A1 activity low but detectable	Unconjugated	Less severe; hyperbilirubinaemia often responds to phenobarbital treatment; usually AR ^[7]
Dubin-Johnson	Defective canalicular multispecific organic anion transporter (MRP2)	Conjugated	Benign; black liver on gross pathology	None required
Rotor	Defective hepatic uptake and storage of conjugated bilirubin	Conjugated	Benign	None required

A practical clinical framework:

Think IEM when you see:

Unexplained encephalopathy in an apparently well neonate who deteriorates
Metabolic acidosis with high anion gap ± ketonuria in a neonate
Hyperammonaemia (always check ammonia in a sick neonate!)
Hypoglycaemia — especially if hypoketotic (fatty acid oxidation defect) or refractory
Hepatomegaly / liver failure in neonate without obvious infectious cause
Unusual odour (MSUD, PKU, isovaleric acidaemia)
Family history of consanguinity, neonatal death, developmental regression
Cardiomyopathy in an infant (Pompe, fatty acid oxidation defects, mitochondrial disease)
Multi-system disease that doesn't fit a single organ diagnosis

Clinical Pearl — The Ammonia Level

Always check plasma ammonia in any sick neonate with unexplained encephalopathy. An ammonia > 100 µmol/L in a neonate is abnormal; > 200 µmol/L strongly suggests IEM (urea cycle defect or organic acidaemia). In urea cycle defects, ammonia can exceed 1000 µmol/L. This is a medical emergency requiring immediate treatment.

While formal investigations will be covered in the diagnostic workup section, understanding what to send is part of clinical features assessment:

Investigation	What It Detects	Relevance
Blood gas + electrolytes	Metabolic acidosis, anion gap	Organic acidaemias, mitochondrial disease
Plasma glucose	Hypoglycaemia	GSD, fatty acid oxidation defects
Plasma ammonia	Hyperammonaemia	Urea cycle defects, organic acidaemias
Plasma lactate	Lactic acidosis	Mitochondrial disease, GSD I, pyruvate metabolism defects
Urine ketones	Ketosis vs hypoketotic state	Hypoketotic hypoglycaemia → fatty acid oxidation defects
Plasma amino acids	↑Specific amino acids	PKU (↑Phe), MSUD (↑leucine), citrullinaemia (↑citrulline)
Urine organic acids	↑Specific organic acids	Organic acidaemias (↑MMA, ↑propionic acid)
Acylcarnitine profile (tandem MS)	Abnormal acylcarnitine species	Fatty acid oxidation defects (↑C8 in MCAD), organic acidaemias
Newborn screening (dried blood spot)	Multiple conditions	Newborn screening becoming the gold standard worldwide ^[1]

Newborn screening is becoming the gold standard worldwide. ^[1]

Hong Kong has implemented expanded newborn screening using tandem mass spectrometry (MS/MS) since 2015.
The programme screens for > 20 conditions including:
- Amino acid disorders (PKU, MSUD, homocystinuria)
- Organic acidaemias (PA, MMA, isovaleric acidaemia)
- Fatty acid oxidation defects (MCAD, VLCAD, CPT I, CPT II)
- Congenital hypothyroidism (TSH on dried blood spot)
- G6PD deficiency
- Congenital adrenal hyperplasia (17-OHP)
The four major IEMs screened for give a local collective incidence of ~1 in 4,100 ^[3]
False positive results are a significant issue → requires confirmatory testing

High Yield — Newborn Screening

Newborn screening detects both mild and severe cases. Not all IEMs are included in screening panels. Clinically detected cases represent only a fraction of those identifiable by screening (e.g., for MCAD deficiency, clinically detected cases are only ~1/3 of those identified by newborn screening). ^[3]

Inborn errors of metabolism are listed as an indication for allogeneic haematopoietic stem cell transplantation (HSCT). ^[9] This is because:

Some IEMs (e.g., MPS I Hurler, X-linked adrenoleukodystrophy) can be treated by providing enzyme-producing donor cells that engraft in the recipient.
Donor-derived macrophages (from transplanted haematopoietic stem cells) can cross the BBB and deliver enzyme to the CNS (cross-correction).
Must be done early before irreversible neurological damage.

High Yield Summary

Definition: IEM = phenotypically and genetically heterogeneous group of disorders caused by defective enzymes/transporters → metabolic malfunction ± toxic metabolite accumulation.

Epidemiology: Individually rare, collectively common (~1 in 4,000–7,580 in HK). Majority AR inherited. Present mainly in infancy/childhood but some in adulthood.

Pathophysiology — 4 mechanisms: ↑ primary substrate, ↓ product, ↑ secondary substrate, secondary inhibition of other pathways.

Classification by presentation:

Intoxication: Symptom-free interval → acute crisis (MSUD, urea cycle defects, organic acidaemias)
Energy insufficiency: Hypoglycaemia, lactic acidosis, cardiomyopathy (FAO defects, GSD, mitochondrial)
Complex molecule: Progressive, no free interval (LSD, MPS, peroxisomal)

Red flags for IEM in neonates: Unexplained encephalopathy after symptom-free interval; high-AG metabolic acidosis; hyperammonaemia; hypoglycaemia (especially hypoketotic); unusual odour; hepatomegaly; cardiomyopathy; family history.

Must-send labs: Blood gas, glucose, ammonia, lactate, urine ketones, plasma amino acids, urine organic acids, acylcarnitine profile.

IEM vs Sepsis: Clinically indistinguishable → treat both simultaneously.

Newborn screening: Gold standard worldwide; tandem MS/MS; HK screens > 20 conditions.

MUDPILES: IEM is the "I" in high-AG metabolic acidosis differential.

HCM: 5–10% associated with IEM.

Wilson's: ATP7B, AR; Coombs-negative haemolytic anaemia + liver failure; penicillamine may transiently worsen neuro symptoms.

Active Recall - Inborn Errors of Metabolism

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section, slides on epidemiology, SSIEM classification, clinical presentation) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (Chapter 14.1, Inborn Errors of Metabolism) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (Section 8.1, Inborn Errors of Metabolism) ^[4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Anion Gap section, MUDPILES mnemonic) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (Diverse etiologies of HCM, 5–10% associated with IEM) ^[6] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease section) ^[7] Paediatrics reference: Unconjugated hyperbilirubinemia in newborns ≥35 weeks of gestation: Etiology and pathogenesis - UpToDate.pdf (Crigler-Najjar sections) ^[8] Senior notes: Ryan Ho GI.pdf (Section 4.5, Gilbert syndrome and Wilson's disease) ^[9] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (Indications for HSCT)

The differential diagnosis of IEM is approached from two angles simultaneously:

Which IEM does this child have? — i.e., differentiating between the > 500 individual IEMs once you suspect the category.
Is this even an IEM, or is it something else that mimics an IEM? — i.e., distinguishing IEM from its clinical mimics (sepsis, non-accidental injury, cardiac disease, etc.).

Both perspectives are essential. A sick neonate with metabolic acidosis and encephalopathy could be septic, could have an IEM, or could have both simultaneously. The DDx must be systematically worked through.

1. Approach to the Differential: Presentation-Based Framework

The most practical way to build a differential for IEM is to start with the presenting clinical syndrome, because IEM presents with nonspecific clinical symptoms (esp. in neonatal period) such as appetite, vomiting, acute or chronic encephalopathy, myopathy, hypoglycaemia or hepatic syndromes, rule out sepsis pattern. ^[1]

Each presentation generates its own list of IEM differentials AND non-IEM mimics.

This is the highest-stakes scenario. The baby was born well (symptom-free interval), then deteriorates within hours to days.

Key discriminating investigations

Before launching into the DDx, you need a few critical lab results to narrow the field:

Lab Result	What It Tells You
Anion gap	High-AG metabolic acidosis → organic acidaemias, mitochondrial disease. Normal AG → urea cycle defects, RTA
Plasma ammonia	↑↑ → urea cycle defects, organic acidaemias. Normal → aminoacidopathies, mitochondrial disease (sometimes)
Blood glucose	↓ with appropriate ketosis → GSD, gluconeogenesis defects. ↓ with absent/low ketones (hypoketotic) → fatty acid oxidation defects
Plasma lactate	↑↑ → mitochondrial disease, pyruvate metabolism defects, GSD I
Urine ketones	Inappropriately absent in hypoglycaemia → fatty acid oxidation defects
Blood gas pH	Respiratory alkalosis with ↑ammonia → urea cycle defect (ammonia stimulates respiratory centre). Metabolic acidosis → organic acidaemias

High Yield — The IEM vs Sepsis Conundrum

Rule out sepsis pattern ^[1] — in practice, you treat for both simultaneously. Send blood cultures, start antibiotics, AND send metabolic investigations. The clues that favour IEM over pure sepsis: symptom-free interval → rapid deterioration; metabolic acidosis with very high anion gap; ↑↑ammonia > 200 µmol/L; hypoglycaemia; unusual odour; family history of neonatal death or consanguinity.

Metabolic Pattern	IEM Differential	Non-IEM Differential	How to Distinguish
↑AG metabolic acidosis + ↑ammonia + ↑ketones	Organic acidaemias (PA, MMA, isovaleric acidaemia)	Sepsis with lactic acidosis	Urine organic acids (specific organic acid peaks); acylcarnitine profile; IEM has disproportionately high ammonia for degree of illness
↑AG metabolic acidosis + normal ammonia + ↑↑lactate	Mitochondrial respiratory chain defects, pyruvate dehydrogenase deficiency, GSD type I	Sepsis-related lactic acidosis, tissue hypoperfusion	Lactate:pyruvate ratio (> 20 suggests respiratory chain defect); muscle biopsy; genetic testing
↑AG metabolic acidosis + normal ammonia + ↑branched-chain amino acids	MSUD	—	Plasma amino acids (↑leucine, isoleucine, valine); "maple syrup" odour; urine DNPH test positive
Respiratory alkalosis + ↑↑↑ammonia + no acidosis	Urea cycle defects — OTC deficiency is the most common form ^[10]	—	Plasma amino acids + urine orotic acid (↑ in OTC def, ↓ in CPS I def); genetic testing
Hypoglycaemia + ↓/absent ketones (hypoketotic)	Fatty acid oxidation defects (MCAD, VLCAD, CPT I/II, LCHAD) — most important treatment: avoid fasting ^[11]	Hyperinsulinism (congenital hyperinsulinaemia)	Acylcarnitine profile (specific pattern for each FAO defect, e.g. ↑C8 in MCAD); insulin level at time of hypoglycaemia (↑ in hyperinsulinism, ↓ in FAO defects); free fatty acids (↑ in FAO defects with inability to oxidise them)
Hypoglycaemia + appropriate ketosis	GSD (types I, III, VI, IX), gluconeogenesis defects (fructose-1,6-bisphosphatase deficiency)	Inadequate feeding, sepsis, adrenal insufficiency	Lactate (↑↑ in GSD I), hepatomegaly, response to glucagon (no glucose rise in GSD I), cortisol/ACTH (adrenal insufficiency)
Hepatomegaly + liver failure + coagulopathy	Galactosaemia, tyrosinaemia type I, neonatal haemochromatosis, mitochondrial DNA depletion syndromes	Neonatal hepatitis (viral — CMV, HSV, enterovirus), biliary atresia, haemophagocytic lymphohistiocytosis (HLH)	Galactosaemia: reducing substances in urine, GALT enzyme level; tyrosinaemia: succinylacetone in urine; biliary atresia: conjugated hyperbilirubinaemia, USG triangular cord sign ^[12]
Seizures refractory to conventional AEDs	Pyridoxine-dependent epilepsy (antiquitin deficiency), non-ketotic hyperglycinaemia (glycine encephalopathy), molybdenum cofactor deficiency, sulfite oxidase deficiency	HIE, CNS infection, cortical malformation	Pyridoxine trial (seizures stop with IV pyridoxine); CSF:plasma glycine ratio (↑ in NKH); urine sulfite test; uric acid (↓ in molybdenum cofactor deficiency)

1.3 DDx of the Infant / Young Child with Chronic / Subacute Presentation

When IEM presents beyond the neonatal period, the presentations are more varied. Here the DDx is broader and includes many non-metabolic conditions.

IEM Differential	Non-IEM Differential
PKU (if not screened), MSUD (intermittent form)	Cerebral palsy
Lysosomal storage diseases (Tay-Sachs, MPS, Gaucher type 2/3)	Chromosomal abnormalities (Down syndrome, Fragile X)
Mitochondrial encephalopathies (Leigh syndrome)	Autism spectrum disorder
Organic acidaemias (glutaric aciduria type I)	Hypothyroidism (congenital)
Metabolic disorders: GSD, MPS, organic acidaemia, urea cycle disorders, carbohydrate metabolism disorders, peroxisomal disorders, mitochondrial disorders, lipid storage disorders ^[13]	Brain tumour, spinal cord tumour ^[13]
Neurodegenerative disorders: Tay-Sachs, adrenoleukodystrophy, metachromatic leukodystrophy ^[13]	Rett syndrome ^[13]

If the motor impairment and abnormal tone have unusual accompanying symptoms, such as unexplained hypoglycaemia, recurrent vomiting, progressively worsening seizures or there is a family history of unexplained neurological symptoms or infant deaths, one would raise the possibility of an underlying metabolic disorder. ^[13]

High Yield — Red Flags for IEM in a Child with Developmental Problems

The key distinguishing features that point towards IEM rather than static causes (e.g., cerebral palsy, chromosomal abnormalities):

Developmental regression (loss of milestones) — CP does NOT regress
Episodic worsening with intercurrent illness or fasting
Unexplained metabolic derangements (hypoglycaemia, acidosis, hyperammonaemia)
Multi-system involvement (brain + liver + muscle + heart)
Consanguinity or family history of similar or unexplained deaths
Unusual odour

IEM Causes	Non-IEM Causes
Glycogen storage diseases (I, III, IV, VI, IX)	Congenital infections (TORCH)
Galactosaemia	Biliary atresia ^[12]
Tyrosinaemia type I	Choledochal cyst ^[12]
α1-antitrypsin deficiency (mutation in protease inhibitor gene on chr14, AR; abnormal folding → cannot export from liver → accumulation in hepatocytes → hepatocyte damage → prolonged NNJ or chronic liver disease; lack of circulating α1-AT → emphysema in adults) ^[14]	Hepatitis (viral — Hep B/C, CMV, EBV)
Wilson's disease	Autoimmune hepatitis
Niemann-Pick types A and C	Heart failure (congestive hepatomegaly)
Gaucher disease	Malignancy (neuroblastoma, hepatoblastoma, leukaemia)
Mucopolysaccharidoses	Haemophagocytic lymphohistiocytosis (HLH)
Fatty acid oxidation defects	—
CDG syndromes	—

IEM Causes	Non-IEM Causes
Pompe disease (GSD II) — massive HCM in infantile form	Myocarditis (viral — Coxsackie B, adenovirus)
Fatty acid oxidation defects (VLCAD, LCHAD) — DCM	Dilated cardiomyopathy (idiopathic, familial)
Mitochondrial cardiomyopathy	Kawasaki disease (coronary involvement)
Barth syndrome (X-linked; 3-methylglutaconic aciduria + DCM + neutropenia)	Anomalous left coronary artery from pulmonary artery (ALCAPA)
Propionic acidaemia (secondary cardiomyopathy)	—

IEM Causes (mostly unconjugated)	IEM Causes (conjugated)	Non-IEM Causes
Gilbert syndrome (benign, AD, ↓UGT1A1 expression) ^[15]	Galactosaemia	Physiological jaundice
Crigler-Najjar type I (UGT1A1 essentially absent; severe) ^[7]	Tyrosinaemia type I	Breast milk jaundice
Crigler-Najjar type II (UGT1A1 low but detectable; responds to phenobarbital) ^[7]	α1-antitrypsin deficiency ^[14]	ABO/Rh haemolytic disease
G6PD deficiency (↑haemolysis → ↑bilirubin production)	Bile acid synthesis defects	G6PD deficiency (also IEM)
Pyruvate kinase deficiency	Niemann-Pick C	Sepsis ^[7]
—	CDG syndromes	Biliary atresia, choledochal cyst ^[12]

IEM can present as cyanosis through two mechanisms ^[16]:

Mechanism	IEM Examples
Hypoventilation (from encephalopathy)	Hypoglycaemia, Inborn errors of metabolism — listed under "Endocrine" causes of central cyanosis ^[16]
Methemoglobinaemia	Haemoglobin M disease (haemoglobinopathy), cytochrome b5 reductase deficiency

When a child with a known IEM presents acutely unwell, the DDx includes:

Metabolic decompensation of the underlying IEM (triggered by fasting, illness, protein load)
Intercurrent illness (the infection itself causing the symptoms, not the IEM)
Both simultaneously (most common scenario — infection triggers metabolic decompensation)
Non-accidental injury (always consider in any acutely encephalopathic child)
Drug ingestion / poisoning (especially in toddlers)

Once you've identified that the child likely has an IEM, you need to narrow which specific IEM. The table below organises the major IEM categories by their characteristic biochemical "signature":

Biochemical Signature	IEM Category	Specific Conditions	Key Distinguishing Feature
↑Ammonia + respiratory alkalosis + NO acidosis	Urea cycle defects	OTC deficiency (most common, X-linked) ^[10], CPS I deficiency, ASS deficiency (citrullinaemia), ASL deficiency (argininosuccinic aciduria)	Plasma amino acids: ↑citrulline (ASS), ↑argininosuccinic acid (ASL), ↓citrulline + ↑orotic acid (OTC), ↓citrulline + normal orotic acid (CPS I)
↑Ammonia + high-AG metabolic acidosis + ketosis	Organic acidaemias	PA, MMA, isovaleric acidaemia, glutaric aciduria type I, multiple carboxylase deficiency	Urine organic acids: specific acid peaks; acylcarnitine profile: ↑C3 (PA/MMA), ↑C5 (isovaleric)
High-AG metabolic acidosis + ↑↑lactate	Energy metabolism defects	Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial respiratory chain defects, GSD I	Lactate:pyruvate ratio; muscle biopsy + respiratory chain enzyme analysis; genetic testing
↑Specific amino acid	Aminoacidopathies	PKU (↑Phe), MSUD (↑Leu/Ile/Val), homocystinuria (↑homocysteine + methionine), tyrosinaemia (↑tyrosine + succinylacetone)	Plasma amino acid quantification; urine organic acids for secondary metabolites
Hypoketotic hypoglycaemia + ↑acylcarnitines	Fatty acid oxidation defects	MCAD (↑C8), VLCAD (↑C14:1), CPT I (↑free carnitine, ↓acylcarnitines), CPT II/CACT (↑C16+C18), LCHAD (↑C16-OH)	NBS results suggested a form of fatty acid oxidation defect; findings confirmed from plasma acylcarnitine profile ^[11]
Hepatosplenomegaly + progressive neurodegeneration	Lysosomal storage diseases	Gaucher (↓β-glucocerebrosidase), Niemann-Pick (↓sphingomyelinase), Tay-Sachs (↓hexosaminidase A), MPS (specific GAG pattern)	Enzyme assay in leukocytes/fibroblasts; urine GAG quantification (MPS); genetic testing
Coarse facies + skeletal dysplasia + ± corneal clouding	Mucopolysaccharidoses	MPS I (Hurler — ↓α-L-iduronidase, corneal clouding), MPS II (Hunter — ↓iduronate-2-sulfatase, NO corneal clouding, X-linked), MPS III (Sanfilippo — behavioural), MPS IV (Morquio — skeletal)	Urine GAGs (dermatan/heparan sulfate pattern); specific enzyme assay
Liver disease + neuropsychiatric + KF rings	Wilson's disease	—	↓Ceruloplasmin, ↑24h urine copper, KF rings on slit-lamp, liver copper content on biopsy; genetic test does not have to be positive ^[6]
Prolonged NNJ + liver disease	α1-AT deficiency	—	α1-antitrypsin level in blood; phenotype PIZZ ^[14]

This is a critical section because the commonest exam trap is asking you to distinguish IEM from its mimics.

Non-IEM Mimic	Why It Looks Like IEM	How to Distinguish
Neonatal sepsis	Encephalopathy, metabolic acidosis, hypoglycaemia, poor feeding, vomiting	Positive blood culture; CRP/procalcitonin elevated; no symptom-free interval (or shorter); ammonia usually < 200; responds to antibiotics
Hypoxic-ischaemic encephalopathy (birth asphyxia)	Encephalopathy, seizures, metabolic acidosis (lactic)	History of perinatal distress (meconium, cord prolapse, abruption); Apgar scores; no symptom-free interval; acidosis is lactic, not from organic acids; ammonia may be mildly elevated from tissue injury
Congenital heart disease	Cyanosis, poor feeding, tachypnoea, metabolic acidosis (lactic from poor perfusion)	Hyperoxia test positive (PaO₂ does not rise with 100% O₂ in cyanotic CHD); 4-limb BP + saturations; echocardiography
Congenital adrenal hyperplasia (CAH)	Vomiting, dehydration, hyponatraemia, hyperkalaemia (mimics salt-wasting IEM)	Ambiguous genitalia (46,XX virilised); ↑17-OHP ^[17]; does not have ↑ammonia or organic acid peaks
Pyloric stenosis	Projectile vomiting, dehydration, metabolic alkalosis (not acidosis, but still metabolic derangement)	Metabolic alkalosis with ↓Cl (hypochloraemic), NOT acidosis; palpable "olive" mass; USG pylorus
Non-accidental injury (NAI)	Encephalopathy, seizures in an infant	Retinal haemorrhages, subdural haematoma on CT, inconsistent history, other injuries
Drug / toxin ingestion	Metabolic acidosis, encephalopathy (toddler age)	History of access to medications; specific drug levels (paracetamol, salicylate, ethylene glycol); osmolar gap
Hyperinsulinism (congenital)	Hypoglycaemia (can be severe and recurrent)	Insulin detectable at time of hypoglycaemia; ketones absent (similar to FAO defects, but ↑insulin distinguishes); C-peptide ↑; free fatty acids ↓ (suppressed by insulin, whereas in FAO defects FFAs are ↑ because they can't be oxidised)

Must-Know — Hyperinsulinism vs FAO Defects

Both present with hypoketotic hypoglycaemia. The discriminating feature: in hyperinsulinism, insulin is detectable and free fatty acids are SUPPRESSED (insulin drives FFAs into adipose). In FAO defects, insulin is appropriately LOW and free fatty acids are ELEVATED (released from fat stores but cannot be oxidised). Acylcarnitine profile will show characteristic acylcarnitine peaks in FAO defects.

4. DDx of Specific Metabolic Derangements

Category	Cause	Key Feature
Urea cycle defects	OTC, CPS I, ASS, ASL, arginase	Resp alkalosis, ↑↑↑ammonia, no acidosis
Organic acidaemias	PA, MMA	Metabolic acidosis + ↑ammonia (secondary inhibition of N-acetylglutamate synthetase)
FAO defects	Mild ↑ammonia possible	Hypoketotic hypoglycaemia dominates
Transient hyperammonaemia of the newborn	Preterm neonates	Self-limiting; ammonia normalises within days
Liver failure (any cause)	Viral hepatitis, galactosaemia, tyrosinaemia	Coagulopathy, ↑↑transaminases, jaundice
Valproate therapy	Drug-induced	History of valproate use; ↓carnitine
Infections (Herpes, UTI with urea-splitting organisms)	Urease-producing bacteria (Proteus)	Positive urine culture

Inborn errors of metabolism is the "I" in the MUDPILES mnemonic for increased anion gap metabolic acidosis ^[4]:

M – Methanol
U – Uraemia (chronic kidney failure)
D – Diabetic ketoacidosis
P – Paracetamol, Propylene glycol
I – Infection, Iron, Isoniazid, Inborn errors of metabolism ^[4]
L – Lactic acidosis
E – Ethylene glycol
S – Salicylates

In paediatrics, the most relevant causes of high-AG metabolic acidosis in a neonate/infant are:

IEM (organic acidaemias, mitochondrial disease) — always consider
Lactic acidosis from sepsis/shock — most common overall
DKA — rare in neonates, but important in older children with new-onset T1DM
Renal failure — CKD or AKI

Mechanism	Cause	Key Distinguishing Features
↑ Glucose utilisation	Congenital hyperinsulinism	↑Insulin + ↑C-peptide at time of hypo; ↓FFA; ↓ketones; macrosomia
	Beckwith-Wiedemann syndrome	Macrosomia, macroglossia, omphalocele, ear creases
↓ Glucose production	GSD I	Hepatomegaly, ↑lactate, ↑urate, ↑lipids
	GSD III	Hepatomegaly, ketotic hypoglycaemia, myopathy
	Gluconeogenesis defects	↑Lactate during fasting
↓ Fatty acid oxidation	MCAD, VLCAD, CPT I/II, LCHAD	Hypoketotic hypoglycaemia; specific acylcarnitine profile
Endocrine	Adrenal insufficiency, GH deficiency, cortisol deficiency	Electrolyte disturbances (hypoNa, hyperK in CAH ^[17]); cortisol/ACTH levels; GH stimulation test
Substrate limited	Ketotic hypoglycaemia of childhood	Most common cause of hypoglycaemia in children 18 months – 5 years; diagnosis of exclusion; normal between episodes
Exogenous	Accidental drug ingestion (sulfonylurea, insulin)	Drug screen; history

6. Key Points by Specific IEM for DDx Purposes

Most common form of urea cycle defect
X-linked condition: manifests in hemizygous males and heterozygous females
Can manifest as neonate, infants, adults
DDx clue: Respiratory alkalosis + ↑↑↑ammonia + NO metabolic acidosis + ↑urine orotic acid
Treatment: ammonia scavenger, protein restriction, liver transplant ^[10]

NBS results suggested a form of fatty acid oxidation defect → findings confirmed from plasma acylcarnitine profile ^[11]
Most important treatment: avoid fasting ^[11]
DDx clue: Hypoketotic hypoglycaemia; can present as Reye-like syndrome or sudden infant death

DDx clue: Onset when breast/formula feeding begins (galactose in milk); E. coli sepsis; reducing substances in urine; cataracts
Most commonly due to galactose-1-phosphate-uridyl transferase deficiency ^[14]

Prolonged NNJ is the most common presentation; phenotype PIZZ associated with liver disease
Diagnosis: α1-antitrypsin level in blood
DDx clue: Prolonged neonatal jaundice + liver disease without other obvious cause; ~50% have good prognosis

DDx clue: Liver disease in a child > 3 years + neuropsychiatric features + KF rings; can mimic Parkinson's; Coombs-negative haemolytic anaemia in fulminant presentation
Fulminant hepatic failure due to Wilson's: young patient, no reason for fulminant liver failure, exclusion of all other common causes → only finding is low Hb, Coombs-negative haemolytic anaemia ^[6]

Diagnosis and management: confirmatory test mainly through biochemical testing, supplemented with genetic testing. ^[1]

Once the differential is narrowed:

Biochemical testing (plasma amino acids, urine organic acids, acylcarnitine profile, enzyme assays) confirms the specific IEM
Genetic testing supplements and provides definitive molecular diagnosis
Management options: dietary control; enzyme replacement therapy; steroid treatment; surgical: liver & kidney transplantation; genetic counselling ^[1]

High Yield Summary — DDx of IEM

Always consider IEM AND sepsis simultaneously in a sick neonate — treat both.
Symptom-free interval → deterioration favours IEM over birth asphyxia.
Metabolic pattern discriminates:
- ↑AG acidosis + ↑ammonia → organic acidaemias
- ↑↑↑ammonia + resp alkalosis → urea cycle defects (OTC most common, X-linked)
- Hypoketotic hypoglycaemia → FAO defects (acylcarnitine profile confirms)
- ↑↑Lactate → mitochondrial / pyruvate defects
IEM is the "I" in MUDPILES for high-AG metabolic acidosis.
Non-IEM mimics: sepsis, HIE, CHD, CAH, NAI, hyperinsulinism, pyloric stenosis.
Hypoketotic hypoglycaemia DDx: FAO defects (↑FFA, ↓insulin) vs hyperinsulinism (↓FFA, ↑insulin).
Developmental regression + organomegaly → lysosomal storage diseases.
Confirmatory tests: biochemical first, supplemented by genetic testing.

Active Recall - DDx of Inborn Errors of Metabolism

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — clinical presentation, diagnosis and management) ^[4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Anion Gap section, MUDPILES mnemonic) ^[6] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease section) ^[7] Paediatrics reference: Unconjugated hyperbilirubinemia in newborns ≥35 weeks of gestation: Etiology and pathogenesis - UpToDate.pdf (Crigler-Najjar sections) ^[10] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Case of delirium — OTC deficiency) ^[11] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Case of neonatal cardiac arrest — FAO defect) ^[12] Senior notes: Maksim Surgery Notes.pdf (Biliary atresia, choledochal cyst) ^[13] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Differential diagnosis of developmental delay / cerebral palsy section) ^[14] Senior notes: Adrian Lui Pediatrics Notes.pdf (α1-antitrypsin deficiency, galactosaemia sections) ^[15] Senior notes: Ryan Ho GI.pdf (Gilbert syndrome section) ^[16] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Differential diagnosis of cyanosis — IEM under endocrine causes) ^[17] Senior notes: Ryan Ho Endocrine.pdf (Congenital adrenal hyperplasia section)

IEM does not have a single unified set of "diagnostic criteria" in the way that, say, rheumatic fever has the Jones criteria. Instead, the diagnosis of a specific IEM is confirmed through a stepwise approach combining clinical suspicion, biochemical testing, and genetic testing. This is because there are > 500 different IEMs, each with its own confirmatory test.

Confirmatory test: mainly through biochemical testing, supplemented with genetic testing. ^[1]

Difficult to diagnose unless specific investigations performed (usually require genetic testing). Early recognition and treatment is life-saving! ^[2]

The general diagnostic framework for any IEM mirrors endocrine workup principles ^[18]:

History and physical examination — clinical suspicion
Baseline blood tests — CBC, LRFT, blood gas, glucose, electrolytes
Screening biochemistry — ammonia, lactate, urine ketones, newborn screening results
Confirmatory tests — plasma amino acids, urine organic acids, acylcarnitine profile, enzyme assays
Genetic testing — molecular confirmation (increasingly used as first-line with next-generation sequencing)
Functional / imaging tests — as needed for complications or specific diagnoses

High Yield — The Diagnosis of IEM is Biochemical First, Then Genetic

Confirmatory test mainly through biochemical testing, supplemented with genetic testing. ^[1] Unlike many genetic conditions where you go straight to DNA, in IEM the biochemical phenotype (accumulated metabolites, deficient products) is often faster and more immediately actionable. Genetic testing provides definitive molecular diagnosis, enables carrier testing and prenatal diagnosis, but takes longer to return. In an acutely sick neonate, you cannot wait for genetic results — you must act on biochemistry.

When Can You "Diagnose" an IEM?

A specific IEM is diagnosed when:

Level of Certainty	Basis	Example
Presumptive	Abnormal newborn screen (NBS) result	Elevated C8 acylcarnitine on tandem MS → suspected MCAD deficiency
Biochemically confirmed	Characteristic metabolic profile on confirmatory biochemical testing	Elevated plasma phenylalanine > 360 µmol/L with normal tyrosine → PKU
Enzymatically confirmed	Deficient enzyme activity measured in leukocytes, fibroblasts, or tissue	↓β-glucocerebrosidase activity in leukocytes → Gaucher disease
Genetically confirmed (definitive)	Biallelic pathogenic variants identified in the causative gene	Homozygous or compound heterozygous pathogenic variants in PAH gene → PKU confirmed

2. Diagnostic Algorithm

High Yield — NBS False Positives

Incidence of IEM estimated by: newborn screening programs — not all IEMs are included; detect both mild and severe cases. ^[3] Conversely, NBS has a significant false-positive rate. For every true positive, there may be 10–50 false positives requiring recall and confirmatory testing. This causes parental anxiety — communicate sensitively. The NBS result is a SCREEN, not a diagnosis.

3. Investigation Modalities — Detailed

These are investigations you send on any sick neonate/infant where IEM is in the differential. They should be done urgently in the acute setting.

Investigation	What You're Looking For	Interpretation	Why / Pathophysiology
Arterial / capillary blood gas	pH, pCO₂, HCO₃⁻, base excess	Metabolic acidosis (↓pH, ↓HCO₃⁻) → organic acidaemias, mitochondrial disease. Respiratory alkalosis (↑pH, ↓pCO₂) → urea cycle defects (ammonia stimulates respiratory centre)	Accumulated organic acids consume bicarbonate → high-AG metabolic acidosis. Ammonia crosses BBB → stimulates brainstem → hyperventilation → resp alkalosis
Serum electrolytes + anion gap	Na⁺, K⁺, Cl⁻, HCO₃⁻ → calculate AG = Na⁺ − Cl⁻ − HCO₃⁻ (normal 8–14)	High AG → unmeasured anions → organic acids, lactate. Normal AG → consider urea cycle defect, RTA ^[4]	MUDPILES — "I" = Inborn errors of metabolism ^[4]
Plasma glucose	Hypoglycaemia (< 2.6 mmol/L in neonates; < 3.3 mmol/L in children)	With ketones → GSD, gluconeogenesis defects. Without ketones (hypoketotic) → FAO defects, hyperinsulinism	Blocked β-oxidation → cannot generate ketone bodies during fasting; blocked glycogenolysis → cannot release glucose from glycogen stores
Plasma ammonia	> 100 µmol/L abnormal in neonates; > 200 strongly suggests IEM	↑↑↑ (> 500–1000) + resp alkalosis → urea cycle defect. ↑↑ + metabolic acidosis → organic acidaemia. Mild ↑ → liver failure, transient hyperammonaemia of newborn, valproate	Urea cycle defects: cannot detoxify ammonia to urea. Organic acidaemias: secondary inhibition of CPS I via ↓N-acetylglutamate
Plasma lactate	> 2.5 mmol/L elevated; > 5 mmol/L significantly elevated	↑↑ with normal pyruvate (L:P ratio > 25) → respiratory chain defect. ↑↑ with ↑ pyruvate (L:P ratio < 25) → pyruvate dehydrogenase deficiency. ↑ with hepatomegaly → GSD I	Mitochondrial respiratory chain block → pyruvate cannot enter TCA cycle → shunted to lactate by LDH (↑L:P ratio). PDH deficiency → pyruvate accumulates AND lactate (normal ratio)
Urine ketones (dipstick)	Positive = ketosis; Negative despite hypoglycaemia = hypoketotic	Hypoketotic hypoglycaemia → FAO defects, hyperinsulinism. Ketotic hypoglycaemia → GSD, organic acidaemias, ketotic hypoglycaemia of childhood	In FAO defects, cannot oxidise fatty acids → cannot generate acetyl-CoA for ketogenesis
CBC	Pancytopenia, neutropenia, thrombocytopenia	Pancytopenia → organic acidaemias (bone marrow suppression by toxic metabolites), Gaucher disease (hypersplenism)	Propionic acid directly suppresses myeloid progenitors in bone marrow
LFT	Transaminases, bilirubin, albumin, coagulation (PT/INR)	↑↑ALT/AST + coagulopathy → liver failure (galactosaemia, tyrosinaemia, Wilson's). ↑Unconjugated bilirubin → Crigler-Najjar, Gilbert. ↑Conjugated bilirubin → bile acid synthesis defects	Galactose-1-phosphate toxicity → hepatocyte necrosis; Wilson's copper → hepatocyte damage
Blood glucose (confirm with lab glucose, not just bedside glucometer)	Accurate glucose	Glucometers can be inaccurate in sick neonates (haematocrit effects, interference)	Lab glucose is confirmatory; glucometer is screening
CRP / Blood culture	Infection markers	To exclude or confirm concurrent sepsis — remember, rule out sepsis pattern ^[1]	IEM and sepsis are clinically indistinguishable; treat both simultaneously

Critical — Ammonia Sample Handling

Plasma ammonia is notoriously prone to pre-analytical error. The sample must be:

Collected in a lithium heparin tube (NOT EDTA)
Placed on ice immediately after collection
Transported to the lab within 15–30 minutes
Analysed promptly (ammonia rises artifactually in blood left at room temperature due to amino acid deamination)

A falsely elevated ammonia from poor handling can trigger unnecessary panic and invasive treatment. If in doubt, repeat with proper handling before acting on a borderline result.

These are the specific metabolic investigations that narrow down which IEM is present. They should be sent as soon as IEM is suspected — ideally at the same time as first-line investigations in the acute setting.

Investigation	Method	What It Detects	Key Findings and Interpretation
Plasma amino acids	Quantitative amino acid analysis (ion-exchange chromatography or tandem MS)	Aminoacidopathies, urea cycle defects	↑Phenylalanine → PKU. ↑Leucine/isoleucine/valine → MSUD. ↑Citrulline → citrullinaemia (ASS deficiency). ↓Citrulline + ↑orotic acid → OTC deficiency. ↑Argininosuccinic acid → ASL deficiency. ↑Glycine (plasma + CSF) → non-ketotic hyperglycinaemia
Urine organic acids	Gas chromatography–mass spectrometry (GC-MS)	Organic acidaemias, FAO defects, aminoacidopathies	↑Methylmalonic acid → MMA. ↑Propionic acid / 3-OH-propionic / methylcitrate → PA. ↑Isovalerylglycine → isovaleric acidaemia. ↑Glutaric acid + 3-OH-glutaric acid → glutaric aciduria type I. Dicarboxylic aciduria → FAO defects. ↑Succinylacetone → tyrosinaemia type I
Acylcarnitine profile	Tandem mass spectrometry (MS/MS) — same platform as NBS	FAO defects, organic acidaemias	Pattern suggestive of a form of fatty acid oxidation defect; findings confirmed from plasma acylcarnitine profile ^[11]. ↑C8 (octanoylcarnitine) → MCAD. ↑C14:1 → VLCAD. ↑C16 + C18 → CPT II / CACT. ↑C3 → PA / MMA. ↑C5 → isovaleric acidaemia. ↑Free carnitine with ↓acylcarnitines → CPT I deficiency
Total and free carnitine	Plasma	Secondary carnitine deficiency	↓ in organic acidaemias (consumed conjugating with organic acids), FAO defects, valproate use
Urine reducing substances	Clinitest tablet (non-specific)	Galactosaemia	Positive reducing substances with negative glucose dipstick (reducing substance is galactose, not glucose) → galactosaemia. Note: Clinitest is non-specific; glucose, fructose also positive
Urine orotic acid	Quantitative	Urea cycle defects (specifically OTC vs CPS I differentiation)	↑ Orotic acid → OTC deficiency (carbamyl phosphate diverted to pyrimidine pathway). Normal orotic acid → CPS I deficiency
CSF amino acids	Lumbar puncture + amino acid analysis	Non-ketotic hyperglycinaemia (NKH)	↑CSF glycine and ↑CSF:plasma glycine ratio (> 0.08) → NKH. In NKH, glycine cleavage system is defective → glycine accumulates preferentially in CSF
Lactate:pyruvate ratio	Simultaneous plasma lactate and pyruvate	Mitochondrial respiratory chain vs pyruvate metabolism	L:P > 25 (sometimes > 30) → mitochondrial respiratory chain defect. L:P normal (< 25) → pyruvate dehydrogenase deficiency
Urine DNPH test (2,4-dinitrophenylhydrazine)	Bedside qualitative test	MSUD screening	Positive (precipitate forms) → branched-chain keto acids present → MSUD. Quick bedside test but not confirmatory

High Yield — Acylcarnitine Profile as Diagnostic Cornerstone

The acylcarnitine profile by tandem MS/MS is arguably the single most important metabolic investigation in the acute setting. It is the same technology used for newborn screening and can simultaneously detect fatty acid oxidation defects AND organic acidaemias from a single dried blood spot or plasma sample. NBS results suggested a form of fatty acid oxidation defect → findings confirmed from plasma acylcarnitine profile → subsequent genetic analysis confirmed the diagnosis. ^[11]

Investigation	When Used	What It Confirms
Enzyme assay (in leukocytes, fibroblasts, liver tissue, muscle)	When biochemical screen is abnormal and specific enzyme deficiency is suspected	Definitive demonstration of enzyme deficiency: e.g., ↓galactose-1-phosphate uridylyltransferase activity → classic galactosaemia; ↓β-glucocerebrosidase → Gaucher; ↓acid α-glucosidase → Pompe. Gold standard for many lysosomal storage diseases
Genetic testing	Supplementary to biochemistry; increasingly used as primary test with NGS panels or WES/WGS	Confirmatory test mainly through biochemical testing, supplemented with genetic testing ^[1]. Identifies specific pathogenic variants; enables carrier testing for family members; enables prenatal diagnosis in future pregnancies; essential for genetic counselling
Fibroblast culture	From skin biopsy (punch biopsy)	Provides living cells for enzyme assays, β-oxidation studies, respiratory chain enzyme studies. Cells can be stored for future testing
Muscle biopsy	Suspected mitochondrial disease	Histology: ragged red fibres (Gomori trichrome stain — abnormal mitochondrial proliferation), COX-negative fibres. Electron microscopy: abnormal mitochondrial morphology (paracrystalline inclusions). Respiratory chain enzyme complex I–V activity measurement
Liver biopsy	Specific situations (GSD, Wilson's, α1-AT deficiency)	Liver copper content (Wilson's); glycogen quantification and enzyme assays (GSD); PAS-positive, diastase-resistant globules (α1-AT deficiency, PIZZ phenotype)
Urine GAGs (glycosaminoglycans)	Suspected mucopolysaccharidosis	↑ Total urine GAGs + specific GAG pattern (dermatan + heparan sulfate → MPS I/II; heparan sulfate alone → MPS III; keratan sulfate → MPS IV)
Lysosomal enzyme panel	Suspected lysosomal storage disease	Multiplex enzyme assay on dried blood spot or leukocytes can screen for multiple LSDs simultaneously (Gaucher, Fabry, Pompe, MPS I, Niemann-Pick, Krabbe)

Modality	Description	When to Use
Targeted single-gene Sanger sequencing	Sequences a specific gene	When biochemistry points clearly to a single gene (e.g., PAH in PKU, ATP7B in Wilson's)
NGS gene panel	Sequences a curated panel of genes associated with a disease group	When the IEM category is known but the specific gene is uncertain (e.g., "urea cycle panel," "fatty acid oxidation panel")
Whole-exome sequencing (WES)	Sequences all protein-coding regions (~2% of genome)	When biochemistry is inconclusive or unusual; increasingly used as first-line in difficult cases
Whole-genome sequencing (WGS)	Sequences entire genome including intronic/regulatory regions	Research setting; may detect deep intronic variants or structural variants missed by WES
Chromosomal microarray (CMA)	Detects copy number variants (deletions/duplications)	When a deletion/duplication syndrome is suspected (e.g., contiguous gene deletion involving IEM gene)

Genetic test does not have to be positive to reach a diagnosis → with compatible clinical and history still can diagnose, since the hereditary pathway can be very heterogeneous. ^[6] This is an important point — some patients with clinically and biochemically confirmed Wilson's disease, for example, may not have detectable variants on standard genetic testing because > 200 different mutations exist and not all are covered by all panels.

3.5 Specific Investigations for Key IEMs

Investigation	Finding	Interpretation
Serum ceruloplasmin	< 0.2 g/L (usually < 0.1)	↓ Because mutated ATP7B cannot incorporate copper into apoceruloplasmin → shorter half-life → ↓ circulating ceruloplasmin. But ~5% of Wilson's patients have normal ceruloplasmin (hence not sufficient alone)
24-hour urine copper	> 100 µg/day (> 1.6 µmol/day) in symptomatic patients; > 40 µg/day suspicious in children	Copper "overflows" from saturated liver into blood → filtered and excreted by kidneys
Serum copper	Paradoxically ↓ total copper (bound to ceruloplasmin which is low) but ↑ free (non-ceruloplasmin-bound) copper	Free copper is the toxic fraction → correlates with tissue damage
Slit-lamp examination	Kayser-Fleischer (KF) rings	Copper deposition in Descemet's membrane; present in ~95% of neurological Wilson's but only ~50% of hepatic Wilson's in children
Liver biopsy copper	> 250 µg/g dry weight	Gold standard for hepatic copper quantification
Genetic testing	Biallelic pathogenic variants in ATP7B	Genetic test does not have to be positive to reach a diagnosis ^[6] — > 200 mutations; compound heterozygosity common

Diagnosis: α1-antitrypsin level in blood ^[14]
α1-AT phenotyping (Pi typing by isoelectric focusing): identifies PIZZ, PIMZ, PISZ, etc.
Liver biopsy: PAS-positive, diastase-resistant globules in hepatocytes (accumulated misfolded α1-AT protein)

Diagnosis: galactose-1-phosphate-uridyl transferase level in blood ^[14]
Urine reducing substances positive (Clinitest), urine glucose dipstick negative
Confirmatory: GALT enzyme activity in erythrocytes
Genetic testing: GALT gene mutations

Newborn screening becoming the gold standard worldwide. ^[1]

Incidence of IEM estimated by newborn screening programs — not all IEMs are included; detect both mild and severe cases. Retrospective data from registries or lab records — only clinical cases are included; only cases with clinically detectable phenotypes included. ^[3]

Aspect	Detail
Sample	Dried blood spot (DBS) collected by heel prick at 24–72 hours of life
Method	Tandem mass spectrometry (MS/MS) for amino acids, acylcarnitines; immunoassay for hormones (TSH, 17-OHP); fluorometric assay (for G6PD in HK)
Conditions screened in HK	> 20 conditions including amino acid disorders (PKU, MSUD, homocystinuria), organic acidaemias (PA, MMA, IVA), fatty acid oxidation defects (MCAD, VLCAD, CPT I/II), congenital hypothyroidism, G6PD deficiency, congenital adrenal hyperplasia
Sensitivity	High for conditions included in the panel (> 95% for most)
Specificity	Variable; false positives common (especially for low birth weight, premature, or sick neonates)
Limitations	Not all IEMs screened; lysosomal storage diseases, urea cycle defects, mitochondrial diseases are NOT included in most standard NBS panels (though some programmes are expanding to include these)

High Yield — For MCAD Deficiency

For medium-chain acyl-CoA dehydrogenase deficiency (MCAD), a fatty acid oxidation disorder, the number of clinically detected cases is only ~1/3 of those identified by newborn screening. ^[3] This illustrates the power of NBS — many affected individuals would never have been diagnosed clinically (either because they never encountered a sufficient fasting stress or because they died suddenly — MCAD is a cause of sudden infant death).

IEM Category	Key Investigations	Characteristic Findings
Aminoacidopathies (PKU, MSUD, homocystinuria, tyrosinaemia)	Plasma amino acids; urine organic acids (for secondary metabolites); specific enzyme assay; genetic testing	↑ Specific amino acid: Phe (PKU), Leu/Ile/Val (MSUD), Met + homocysteine (homocystinuria), Tyr + succinylacetone in urine (tyrosinaemia I)
Organic acidaemias (PA, MMA, IVA, glutaric aciduria)	Urine organic acids (GC-MS); acylcarnitine profile; plasma amino acids (glycine often ↑); ammonia; blood gas	Specific organic acid peaks; ↑C3 (PA/MMA), ↑C5 (IVA); secondary hyperammonaemia; high-AG metabolic acidosis
Urea cycle defects (OTC, CPS I, ASS, ASL)	Plasma amino acids; urine orotic acid; ammonia; blood gas	↑↑↑ Ammonia; respiratory alkalosis; specific amino acid pattern (↑citrulline in ASS; ↓citrulline + ↑orotic acid in OTC; ↑argininosuccinic acid in ASL)
Fatty acid oxidation defects (MCAD, VLCAD, CPT I/II, LCHAD)	Acylcarnitine profile (tandem MS); urine organic acids; free fatty acids; total/free carnitine; glucose + ketones at time of crisis; genetic testing	Findings confirmed from plasma acylcarnitine profile ^[11]; ↑ specific acylcarnitine species; hypoketotic hypoglycaemia; dicarboxylic aciduria
Glycogen storage diseases	Glucose + lactate (fasting and post-prandial); urate; lipid profile; glucagon stimulation test (no glucose rise in GSD I); liver/muscle biopsy + enzyme assay; genetic testing	GSD I: ↑lactate, ↑urate, ↑TG, ↑cholesterol, hepatomegaly, NO glucose response to glucagon. GSD II (Pompe): ↓acid α-glucosidase on DBS or fibroblasts
Lysosomal storage diseases	Urine GAGs (MPS); enzyme assay in leukocytes/fibroblasts/DBS; genetic testing	↑ Specific GAGs (MPS); ↓ specific enzyme activity; characteristic cells on bone marrow aspirate (Gaucher cells in Gaucher disease)
Mitochondrial diseases	Plasma lactate + pyruvate (L:P ratio); CSF lactate; CK; muscle biopsy (ragged red fibres, respiratory chain enzyme assay); mtDNA analysis + nuclear gene panel; MRI brain (basal ganglia lesions in Leigh syndrome); cardiac echo (cardiomyopathy)	L:P ratio > 25; ↑CSF lactate; ragged red fibres; specific MRI patterns; respiratory chain complex deficiency on biochemistry
Peroxisomal disorders	Very-long-chain fatty acids (VLCFA) in plasma; plasmalogens in RBCs; phytanic acid; bile acid intermediates; genetic testing	↑↑ C26:0 and ↑ C26:0/C22:0 ratio → X-ALD or Zellweger spectrum; ↓ plasmalogens

Pitfall	Explanation	How to Avoid
Ammonia sample error	Left at room temperature → falsely ↑	Collect on ice, analyse within 30 min; repeat if result unexpected
NBS timing	Sample too early (< 24 hours) → false negatives for PKU (phenylalanine hasn't accumulated sufficiently)	Collect NBS at 24–72 hours; if collected < 24 hours, repeat at 48–72 hours
NBS in premature / sick neonates	Abnormal acylcarnitines or amino acids due to prematurity, TPN, illness → false positives	Always do confirmatory testing; correlate with clinical context
Ketone interpretation	Trace ketonuria is normal in neonates and young children during brief fasting; significant ketonuria without hypoglycaemia may be physiological	Interpret ketones in context of glucose level and fasting duration
Normal results in between crises	Many IEMs (especially intoxication type) have NORMAL metabolites between crises	Collect samples DURING the acute illness; "critical samples" at time of hypoglycaemia are essential
Enzyme assays after blood transfusion	Transfused RBCs contribute donor enzyme → false-normal GALT or G6PD results	Wait 3 months post-transfusion before measuring RBC-based enzyme assays; use genetic testing instead

Critical — 'Critical Samples'

In a child presenting with unexplained hypoglycaemia, seizures, or metabolic decompensation, always collect "critical samples" at the time of the event — BEFORE giving glucose or other treatment if safe to do so. These include: plasma glucose, insulin, C-peptide, cortisol, GH, free fatty acids, β-hydroxybutyrate, acylcarnitine profile, plasma amino acids, and urine organic acids + ketones. Once glucose is given, the metabolic window closes and you may never be able to make the diagnosis.

Take-home message from the Chemical Pathology Seminar 2025: ^[19]

Inherited metabolic diseases: heterogeneous group of genetic diseases involving disorders of human metabolism
Accumulation of precursors/by-products and/or deficiency of downstream metabolites cause the pathology
Widely variable manifestations
Can manifest in utero and even till late adulthood
Perform baseline and special investigations if suspecting these diseases
Consult metabolic specialists and pathologists for patient care and investigations

High Yield Summary — Diagnosis of IEM

Diagnostic approach: Clinical suspicion → first-line bloods (gas, glucose, ammonia, lactate, ketones, CBC, LFT) → second-line metabolic screen (plasma amino acids, urine organic acids, acylcarnitine profile) → confirmatory enzyme assay/genetic testing.

Confirmatory test is mainly biochemical, supplemented by genetic testing ^[1].

Key discriminating tests:

High-AG metabolic acidosis + ↑ammonia → organic acidaemias (urine organic acids, acylcarnitine ↑C3/C5)
↑↑↑Ammonia + resp alkalosis → urea cycle defect (plasma amino acids + urine orotic acid)
Hypoketotic hypoglycaemia → FAO defect (acylcarnitine profile is diagnostic)
↑↑Lactate → mitochondrial disease (L:P ratio, muscle biopsy)

Newborn screening = gold standard for early detection; uses tandem MS/MS; not all IEMs included; false positives common.

Critical samples must be taken AT THE TIME of metabolic crisis — before treatment.

Ammonia sample must be collected on ice and analysed within 30 minutes — pre-analytical error is common and dangerous.

Active Recall - Diagnostic Criteria, Algorithm and Investigations of IEM

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — diagnosis, management, newborn screening) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (Chapter 14.1, Inborn Errors of Metabolism) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (Section 8.1–8.4, Inborn Errors of Metabolism, incidence estimation) ^[4] Senior notes: Block A - Electrolyte and Acid-Base Disorders.pdf (Anion Gap section, MUDPILES mnemonic) ^[6] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease — genetic testing caveat) ^[11] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Case of neonatal cardiac arrest — FAO defect, acylcarnitine confirmation) ^[14] Senior notes: Adrian Lui Pediatrics Notes.pdf (α1-antitrypsin deficiency and galactosaemia diagnostic tests) ^[18] Senior notes: Block A - Introduction to Endocrine investigations.pdf (Principle 1 — sequence of investigations) ^[19] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Take-home message slide)

The management of IEM rests on a simple but powerful conceptual framework derived directly from the pathophysiology. If you understand why the disease causes harm, you understand how to treat it.

Recall the four pathophysiological mechanisms ^[2]:

↑ Primary substrate → Reduce substrate intake (dietary restriction) or block substrate formation
↓ Product → Supplement the deficient product
↑ Secondary substrate → Provide alternative excretion pathways (nitrogen scavengers, carnitine conjugation)
Secondary inhibition → Remove the inhibiting metabolite (dialysis, scavengers)

Additionally, for organelle diseases where the enzyme itself is missing:

Replace the enzyme (enzyme replacement therapy)
Replace the organ that makes the enzyme (transplantation — liver, HSCT)
Stabilise the mutant enzyme (molecular chaperone therapy)
Reduce the substrate that the enzyme should break down (substrate reduction therapy)

High Yield — GC Lecture Management Framework

Management of IEM ^[1]:

Dietary control
Enzyme replacement therapy
Steroid treatment
Surgical: liver and kidney transplantation
Genetic counselling

3. Acute Emergency Management ("The Sick Neonate / Child in Metabolic Crisis")

This is the most critical scenario — a child (often a neonate) presenting with acute metabolic decompensation. The principles are the same regardless of the specific IEM, because in the acute phase you often don't know the exact diagnosis yet.

Step	Action	Rationale
A — Airway	Secure airway; intubate if GCS ≤ 8 or respiratory failure	Severe encephalopathy → loss of protective airway reflexes
B — Breathing	Monitor SpO₂; provide O₂ as needed; ventilate if apnoeas	Hyperammonaemia / organic acid accumulation → central respiratory depression
C — Circulation	IV access (×2 if possible); fluid bolus 10–20 mL/kg 0.9% NaCl if shocked; commence IV dextrose 10%	Correct dehydration from vomiting/poor feeding; provide glucose to suppress catabolism
D — Disability	Assess GCS / AVPU; treat seizures (lorazepam / midazolam); monitor blood glucose hourly	Hypoglycaemia and metabolic toxins cause seizures; need tight glucose monitoring
E — Exposure	Check temperature; look for rash, hepatomegaly, unusual odour	Fever → catabolic stress; hepatomegaly → storage or liver failure; odour → specific IEM

The overarching goal in acute management is to halt endogenous protein and fat catabolism and provide exogenous energy. Why? Because catabolism floods the blocked metabolic pathway with substrate (amino acids from muscle breakdown, fatty acids from adipose), worsening the metabolic crisis exponentially.

Intervention	How to Do It	Paediatric Dosing	Contraindications / Cautions
IV Dextrose	10% dextrose (D10) as continuous infusion; ± insulin if hyperglycaemic	Neonates: D10 at 5–8 mg/kg/min glucose infusion rate (GIR). Infants/children: D10 at 6–10 mg/kg/min. Titrate to maintain blood glucose 4–8 mmol/L	Higher concentrations (D20, D25) require central venous access (risk of peripheral vein phlebitis/extravasation). Avoid fluid overload in neonates (cerebral oedema)
NPO protein (temporarily)	Stop all oral/enteral protein intake for 24–48 hours maximum	—	Must not exceed 48 hours of protein-free state → prolonged protein restriction causes endogenous protein catabolism (the opposite of what you want) and is itself harmful. Restart protein gradually once metabolically stable
IV Intralipid	Lipid emulsion to provide non-protein calories	1–3 g/kg/day IV lipid	CONTRAINDICATED in fatty acid oxidation defects (giving fat to a child who cannot oxidise fat is dangerous → worsens lipid accumulation); use in organic acidaemias and urea cycle defects where fat oxidation is intact
Insulin ± glucose	IV insulin infusion to drive anabolism (promote cellular glucose and amino acid uptake)	0.05–0.1 units/kg/hr with concurrent D10/D20; monitor glucose Q30min initially	Risk of hypoglycaemia if glucose infusion inadequate; requires ICU-level monitoring

Critical — The 48-Hour Rule for Protein Restriction

In acute metabolic crisis, we temporarily stop protein to reduce substrate load. But protein-free status must NOT exceed 24–48 hours because:

The child still needs essential amino acids for basic cellular function
Prolonged protein deprivation → endogenous muscle proteolysis → paradoxically floods the blocked pathway with more substrate
In neonates, protein is essential for growth — even 48 hours of zero protein can be harmful

Always restart protein (usually at 50% of normal intake) as soon as metabolic stability is achieved, and increase to full intake under metabolic specialist guidance.

3.3 Specific Acute Interventions by Metabolic Derangement

Intervention	Mechanism	Dosing (Paediatric)	When to Use
Nitrogen scavengers	Provide alternative pathways for nitrogen excretion, bypassing the blocked urea cycle
— Sodium benzoate	Conjugates with glycine → hippuric acid → excreted in urine (removes 1 mol nitrogen per mol benzoate)	250 mg/kg IV loading dose over 90 min → 250 mg/kg/day maintenance infusion	Ammonia > 150–200 µmol/L in neonates
— Sodium phenylbutyrate (converted to phenylacetate in vivo)	Conjugates with glutamine → phenylacetylglutamine → excreted in urine (removes 2 mol nitrogen per mol phenylacetate)	250 mg/kg IV loading dose → 250 mg/kg/day maintenance	Same; often used in combination with benzoate
IV Arginine	Replaces arginine (which is depleted when the urea cycle is blocked); primes the urea cycle; facilitates excretion of citrulline (ASS) or argininosuccinic acid (ASL) as "nitrogen waste carriers"	200–600 mg/kg IV loading dose → 200–600 mg/kg/day maintenance (dose depends on specific enzyme deficiency)	All urea cycle defects EXCEPT arginase deficiency (where arginine is already elevated)
Dialysis (haemodialysis or continuous venovenous haemodiafiltration, CVVHDF)	Directly removes ammonia from blood	—	Ammonia > 500 µmol/L; or ammonia > 300 and rising despite nitrogen scavengers; or clinical deterioration (deepening coma, cerebral oedema)
Carnitine	NOT primary treatment for urea cycle defects; but useful in organic acidaemias to conjugate with accumulated organic acids → acylcarnitine excretion in urine	100–200 mg/kg/day IV (acute) → 50–100 mg/kg/day PO (chronic)	Organic acidaemias (PA, MMA, IVA); secondary carnitine deficiency

High Yield — Dialysis for Hyperammonaemia

Peritoneal dialysis is often the most readily available modality in paediatric centres but is the LEAST efficient at removing ammonia. Haemodialysis or CVVHDF is far superior. In neonates, CVVHDF with neonatal-sized circuits is preferred because it provides continuous clearance without the haemodynamic instability of intermittent HD. Exchange transfusion is NOT effective for ammonia removal.

Intervention	Mechanism	Notes
IV sodium bicarbonate	Directly buffers H⁺ ions; raises serum HCO₃⁻	Use cautiously — only if pH < 7.1 or HCO₃⁻ < 10 mmol/L. Risk of paradoxical intracellular acidosis, hyperosmolality, and hypernatraemia. Give slowly (1–2 mmol/kg over 30–60 min)
IV carnitine	Conjugates with accumulated organic acids (propionyl-CoA, methylmalonyl-CoA) → acylcarnitines excreted in urine; replenishes depleted carnitine stores	L-carnitine 100–200 mg/kg/day IV in acute setting
Cofactor trials	Some organic acidaemias are cofactor-responsive	B12 (hydroxocobalamin) 1 mg IM → for B12-responsive MMA. Biotin 10–20 mg/day PO/IV → for multiple carboxylase deficiency. Thiamine 100–300 mg/day → for thiamine-responsive MSUD

Intervention	Mechanism	Cautions
IV dextrose 10%	2 mL/kg bolus (= 200 mg/kg glucose) then maintenance infusion at GIR 6–10 mg/kg/min	In hyperinsulinism, may need GIR up to 15–20 mg/kg/min
Avoid fasting	Most important treatment ^[11] for FAO defects — the fundamental problem is inability to mobilise energy from fat during fasting	Educate family about regular feeding schedules, maximum fasting duration for age
Avoidance of MCT oil	MCT oil is CONTRAINDICATED in MCAD deficiency (medium-chain triglycerides are exactly what cannot be oxidised)	MCT is actually therapeutic in LCHAD/VLCAD (provides an alternative energy source that bypasses the blocked long-chain step) — so the contraindication is specific to MCAD

Trial	Dose	IEM Being Tested For
IV Pyridoxine (B6)	100 mg IV (single dose, can repeat ×3)	Pyridoxine-dependent epilepsy (antiquitin / ALDH7A1 deficiency) — seizures stop within minutes if responsive
Pyridoxal phosphate	30–60 mg/kg/day PO divided TDS	PNPO deficiency (pyridox(am)ine 5'-phosphate oxidase deficiency) — these patients do NOT respond to pyridoxine
Folinic acid	2.5 mg BD PO/IV	Cerebral folate deficiency / folinic acid-responsive seizures

4. Chronic (Long-Term) Management

This is the cornerstone of treatment for most small-molecule IEMs. The principle is simple: restrict the substrate that cannot be metabolised, while ensuring adequate nutrition for growth and development.

IEM	Dietary Modification	Mechanism	Key Points (Paediatric)
PKU	Phenylalanine-restricted diet ^[3]	Restricts Phe intake to prevent neurotoxic accumulation; supplements tyrosine (the product that cannot be made)	Lifelong diet; special medical formulas providing all amino acids except Phe; target blood Phe 120–360 µmol/L. In pregnancy, strict Phe control essential (maternal PKU → fetal teratogenicity). Phenylalanine-restricted diet can prevent neurological damage ^[3]
MSUD	Branched-chain amino acid (BCAA)-restricted diet	Restricts leucine, isoleucine, valine intake	Special BCAA-free formula; monitor plasma leucine closely (target < 200 µmol/L); thiamine trial for thiamine-responsive MSUD
Galactosaemia	Galactose-free diet ^[14]	Removes the substrate (galactose) that cannot be metabolised	Soy-based formula (breast milk and standard formula contain lactose → galactose). Infants with galactosaemia: breast feeding is contraindicated ^[20]
GSD type I	Uncooked cornstarch ^[3] + frequent feeds	Uncooked cornstarch is slowly digested, providing a sustained glucose release that prevents fasting hypoglycaemia	1.5–2.5 g/kg every 4–6 hours (including overnight in young children); avoid fructose and galactose (cannot be converted to glucose in GSD Ia); night-time continuous gastric drip-feeds in infants
Urea cycle defects	Protein-restricted diet	Reduces nitrogen load on the blocked urea cycle	Protein restricted to 1.0–1.5 g/kg/day (much lower than normal requirements of ~2.5 g/kg/day in infants); supplement with essential amino acid mixtures; requires close monitoring of growth and nutritional status
Organic acidaemias (PA, MMA)	Protein restriction (specifically restrict odd-chain amino acids — isoleucine, valine, methionine, threonine)	Reduces substrate load into the blocked propionate/methylmalonate pathway	Special medical formulas; metronidazole can reduce gut propionate production from anaerobic bacteria
FAO defects	Avoid fasting ^[11]; frequent high-carbohydrate feeds; MCT oil supplementation (LCHAD/VLCAD only, NOT MCAD)	Carbohydrates provide alternative energy source; MCT bypasses the long-chain oxidation block in LCHAD/VLCAD	Age-specific maximum safe fasting duration: neonates 3–4 hours; infants 4–6 hours; children 6–8 hours; always give a carbohydrate-rich snack before bed
Homocystinuria	Methionine-restricted diet; betaine supplementation	Restricts methionine (upstream of the block); betaine provides alternative remethylation pathway for homocysteine	Pyridoxine trial first — ~50% of patients are B6-responsive (pyridoxine is cofactor for cystathionine β-synthase)

High Yield — Breast Feeding Contraindication

Infants with galactosaemia and newborn screening-detected inborn errors of metabolism (depending on the specific IEM) are listed as contraindications to breast feeding ^[20]. This is because breast milk contains lactose (which is hydrolysed to glucose + galactose in the gut). In galactosaemia, the galactose cannot be metabolised → accumulates → liver failure, cataracts, E. coli sepsis. The infant must be switched to a galactose-free soy-based formula immediately.

Some IEMs are partially or fully responsive to supraphysiological doses of the vitamin cofactor of the defective enzyme. A cofactor trial should always be attempted because responsive patients have dramatically better outcomes.

Cofactor	IEM it Treats	Mechanism	Dose (Paediatric)
Tetrahydrobiopterin (BH4 / sapropterin) ^[3]	BH4-responsive PKU (~25–50% of PKU patients)	BH4 is the cofactor for PAH; supraphysiological doses stabilise the mutant enzyme → ↑ residual activity → ↓ blood Phe	5–20 mg/kg/day PO
Biotin ^[3]	Biotinidase deficiency; holocarboxylase synthetase deficiency (multiple carboxylase deficiency)	Biotin is the cofactor for carboxylase enzymes (pyruvate carboxylase, propionyl-CoA carboxylase, etc.)	5–20 mg/day PO (lifelong)
Hydroxocobalamin (B12) ^[3]	B12-responsive methylmalonic acidaemia (cblA, cblB complementation groups)	B12 is converted to adenosylcobalamin, the cofactor for methylmalonyl-CoA mutase	1 mg IM daily initially → taper to 1 mg IM weekly/monthly
Pyridoxine (B6) ^[3]	Pyridoxine-dependent epilepsy; homocystinuria (B6-responsive)	B6 → pyridoxal phosphate, cofactor for antiquitin (epilepsy) and CBS (homocystinuria)	50–200 mg/day PO (seizures); 200–1000 mg/day (homocystinuria)
Riboflavin (B2) ^[3]	Multiple acyl-CoA dehydrogenase deficiency (MADD / glutaric aciduria type II); some FAO defects	Riboflavin → FAD, cofactor for acyl-CoA dehydrogenases	100–300 mg/day PO
Thiamine (B1) ^[3]	Thiamine-responsive MSUD; pyruvate dehydrogenase deficiency (some forms)	Thiamine pyrophosphate is cofactor for BCKDH (MSUD) and PDH	50–300 mg/day PO
L-Carnitine	Organic acidaemias (secondary carnitine deficiency); primary carnitine deficiency; some FAO defects	Carnitine conjugates with accumulated acyl-CoA species → acylcarnitines excreted renally; replenishes depleted free carnitine	50–100 mg/kg/day PO divided TDS–QDS

ERT involves IV infusion of recombinant human enzyme to replace the deficient enzyme. This is primarily used for lysosomal storage diseases, because the infused enzyme is taken up into cells via mannose-6-phosphate receptors on the cell surface → delivered to lysosomes.

Disease	Enzyme Replaced	Drug Name	Frequency	Key Points (Paediatric)
Gaucher disease ^[3]	β-Glucocerebrosidase	Imiglucerase, velaglucerase alfa, taliglucerase alfa	IV every 2 weeks	Very effective for visceral and haematological manifestations; does NOT cross BBB → cannot treat neuronopathic forms (type 2/3)
Fabry disease ^[3]	α-Galactosidase A	Agalsidase alfa, agalsidase beta	IV every 2 weeks	Slows progression of renal and cardiac disease; start early for best outcomes; lifelong treatment
Pompe disease ^[3]	Acid α-glucosidase	Alglucosidase alfa, avalglucosidase alfa	IV every 2 weeks	Infantile form: dramatically improves survival (from fatal by age 1–2 years to survival into childhood); late-onset: stabilises respiratory and motor function
MPS I (Hurler-Scheie) ^[3]	α-L-Iduronidase	Laronidase	IV weekly	Improves hepatosplenomegaly, joint mobility, respiratory function; does NOT adequately cross BBB → does NOT prevent CNS deterioration in severe Hurler phenotype (→ HSCT preferred)
MPS II (Hunter)	Iduronate-2-sulfatase	Idursulfase	IV weekly	Similar limitations as MPS I ERT; intrathecal ERT being investigated
MPS VI (Maroteaux-Lamy) ^[3]	N-Acetylgalactosamine-4-sulfatase	Galsulfase	IV weekly	Improves endurance and pulmonary function

Key Limitation of ERT

Standard IV ERT does NOT cross the blood–brain barrier effectively. Therefore, for IEMs with significant CNS involvement (e.g., severe MPS I Hurler, neuronopathic Gaucher type 2), ERT alone is insufficient to prevent neurodegeneration. For these patients, HSCT or intrathecal ERT may be needed.

Therapy	Drug	IEM	Mechanism	Notes
Substrate reduction therapy	Miglustat ^[3]	Gaucher disease type 1 (mild–moderate); Niemann-Pick type C	Inhibits glucosylceramide synthase → ↓ synthesis of glucocerebroside (the substrate that accumulates)	Oral medication; alternative to ERT for mild Gaucher; crosses BBB → used for NPC (stabilises neurological decline). Side effects: GI (osmotic diarrhoea), tremor, peripheral neuropathy
	Eliglustat	Gaucher disease type 1	Same mechanism, better tolerated	First-line oral SRT for Gaucher type 1; requires CYP2D6 metaboliser status testing
Molecular chaperone therapy	Migalastat ^[3]	Fabry disease (only amenable mutations)	Binds to and stabilises misfolded α-galactosidase A → facilitates correct folding in ER → ↑ enzyme trafficking to lysosome → ↑ residual activity	Oral; only works for specific "amenable" mutations (must be tested by in vitro assay); not suitable for all Fabry patients

Drug	IEM	Mechanism	Dosing	Key Points
Nitisinone (NTBC) ^[3]	Tyrosinaemia type I	Inhibits 4-hydroxyphenylpyruvate dioxygenase (the enzyme UPSTREAM of the block) → prevents formation of toxic metabolites fumarylacetoacetate and succinylacetone, which cause liver damage and HCC risk	1–2 mg/kg/day PO divided BD	Must be combined with tyrosine and phenylalanine-restricted diet (because nitisinone ↑↑ tyrosine levels by blocking its degradation pathway upstream). Has transformed the natural history of tyrosinaemia type I from fatal liver failure to manageable disease

4.6 Organ Transplantation [1][3]

Transplantation can be curative for specific IEMs because it provides a permanent source of the missing enzyme.

IEM	Why Liver Transplant Works	When Indicated
Urea cycle defects ^[3]	Liver is the only organ expressing the full urea cycle → donor liver provides functional enzymes → normalises ammonia	Recurrent severe hyperammonaemic crises despite medical management; neonatal-onset OTC deficiency with recurrent decompensation
MSUD	Liver is the major site of BCAA catabolism → donor liver provides functional BCKDH → normalises leucine	Severe classic MSUD with recurrent crises; allows unrestricted diet post-transplant
Tyrosinaemia type I	Removes the diseased liver (which is the organ producing the toxic metabolites AND the organ at risk for HCC)	Liver failure despite nitisinone; HCC; non-responders
Wilson's disease	Removes the liver with the defective ATP7B gene → restores copper metabolism	Fulminant liver failure; decompensated cirrhosis
Galactosaemia	Rarely done; diet is mainstay	Only if fulminant liver failure at presentation
Organic acidaemias (PA, MMA)	Liver contributes ~50% of propionate/methylmalonate metabolism → transplant reduces (but does not eliminate) metabolite levels	Severe recurrent decompensation; cardiomyopathy from PA; renal failure from MMA (combined liver-kidney transplant)
GSD type I	Provides glucose-6-phosphatase → corrects fasting hypoglycaemia	Severe disease with hepatic adenomas at risk of malignant transformation; poor metabolic control

Inborn errors of metabolism are listed as an indication for allogeneic HSCT ^[9].

IEM	Why HSCT Works	When to Transplant
MPS I (Hurler)	Donor-derived monocytes/macrophages engraft in tissues (including microglia crossing BBB) → produce α-L-iduronidase → "cross-correct" surrounding enzyme-deficient cells via mannose-6-phosphate uptake	Before age 2.5 years (before irreversible CNS damage); DQ > 70 at time of transplant
X-linked adrenoleukodystrophy (cerebral form) ^[3]	Same cross-correction principle; donor microglia provide functional ABCD1 protein in CNS	Early stage cerebral disease (Loes score ≤ 9 on MRI); once advanced neurological decline has occurred, HSCT is contraindicated
MPS II (Hunter) — selected cases	Cross-correction; but results less reliable than MPS I	Controversial; under investigation
Metachromatic leukodystrophy (MLD)	Donor cells produce arylsulfatase A	Pre-symptomatic or early symptomatic stage
Krabbe disease (globoid cell leukodystrophy)	Donor cells produce galactocerebroside β-galactosidase	Pre-symptomatic (ideally diagnosed by NBS or family screening)

High Yield — HSCT Timing is Everything

For HSCT in IEM, the window of opportunity is narrow. Once significant neurological damage has occurred, it is irreversible and transplant will not reverse it. This is why newborn screening and early diagnosis are so critical — they allow HSCT to be performed before the disease destroys the brain.

IEM	Why Kidney Transplant	Notes
Fabry disease	Progressive renal failure from Gb3 accumulation in glomeruli/tubules	Kidney transplant for ESRF; continue ERT post-transplant (donor kidney does not produce enough enzyme for whole-body needs)
Cystinosis	Cystine accumulation in renal tubular cells → Fanconi syndrome → progressive CKD	Kidney transplant for ESRF; continue cysteamine post-transplant (cystine accumulates in other organs)
Primary hyperoxaluria type 1	Liver produces excess oxalate → calcium oxalate deposits in kidneys → ESRF	Combined liver-kidney transplant (liver transplant corrects the metabolic defect; kidney transplant replaces damaged kidneys)
MMA	Renal failure from chronic methylmalonic acid toxicity to kidneys	Often combined liver-kidney transplant

Steroid treatment is listed among management modalities on the GC lecture slide ^[1]. In the context of IEM, steroids are used specifically for:

Indication	Steroid	Mechanism
Congenital adrenal hyperplasia (CAH)	Hydrocortisone (glucocorticoid) + Fludrocortisone (mineralocorticoid)	CAH (21-hydroxylase deficiency) is technically an IEM of steroid biosynthesis. Hydrocortisone replaces deficient cortisol AND suppresses ACTH-driven androgen excess. Fludrocortisone replaces aldosterone in salt-wasting forms
Adrenal crisis in IEM	IV hydrocortisone stress dose	Some IEM patients may have concurrent adrenal insufficiency or need stress-dose steroids during acute illness

Gene therapy represents the frontier of IEM treatment. While not yet standard of care for most IEMs, several are in advanced clinical trials:

IEM	Gene Therapy Approach	Status
SMA (spinal muscular atrophy)	Onasemnogene abeparvovec (Zolgensma) — AAV9 vector delivering SMN1 gene	Approved and in clinical use; transforms outcomes
Aromatic L-amino acid decarboxylase (AADC) deficiency	Eladocagene exuparvovec — AAV2 vector delivering DDC gene to putamen	Approved (2022); dramatic improvement in motor function
MPS I, II	AAV-based gene therapy (investigational)	Phase I/II trials
PKU	Liver-directed AAV gene therapy (investigational)	Phase I/II trials
OTC deficiency	Liver-directed AAV gene therapy (investigational)	Phase I/II trials

Genetic counselling is a core component of IEM management ^[1]. In paediatrics, this involves:

Aspect	Details
Inheritance counselling	Explain AR inheritance (most IEMs): 25% recurrence risk per pregnancy; carrier parents are unaffected
Carrier testing	Test siblings and parents; identify carrier status using enzyme assays or genetic testing
Prenatal diagnosis	Chorionic villus sampling (CVS) at 10–12 weeks or amniocentesis at 15–17 weeks; enzyme assay or molecular testing on fetal cells
Pre-implantation genetic diagnosis (PGD)	Available for families who wish to avoid affected pregnancies; IVF with genetic testing of embryos before transfer
Psychosocial support	Family-centred care; address guilt, anxiety, impact on siblings; connect with patient support groups

Every child with a known IEM must have a written sick day management plan that the family keeps at home and brings to every healthcare encounter. This is the single most important preventive measure.

Component	Details
When to activate	Fever, vomiting, diarrhoea, poor oral intake, refusal to feed
Increase energy intake	Switch to emergency regimen: high-calorie, low/no protein drinks (e.g., Maxijul, Polycal) or specific emergency formula
Increase frequency of feeds	Every 2–3 hours; if vomiting, small frequent sips; if unable to tolerate oral, go to hospital for IV dextrose
When to go to hospital	Persistent vomiting (> 2–3 episodes), drowsiness/lethargy, inability to tolerate oral intake for > 4–6 hours (age-dependent), seizure
Emergency letter	Written protocol from metabolic team detailing: diagnosis, emergency IV dextrose concentration and rate, medications to give/avoid, metabolic team contact numbers
Medic-Alert bracelet	All children with IEM should wear one, listing the diagnosis and emergency instructions

Family-Centred Care in IEM

IEM management is lifelong and demanding. The burden on families is enormous — restrictive diets, medication schedules, constant vigilance for metabolic crises, hospital admissions. A multidisciplinary team (metabolic paediatrician, dietitian, genetic counsellor, psychologist, social worker, specialist nurse) is essential. Engage the child in their own care as they grow older — age-appropriate education about their condition, assent for procedures, transition planning to adult metabolic services.

IEM	Acute Management	Chronic Management	Definitive Treatment
PKU	N/A (usually detected by NBS)	Phe-restricted diet; BH4 trial ^[3]; large neutral amino acid supplementation	Gene therapy (investigational)
MSUD	IV dextrose ± insulin; stop protein; thiamine trial	BCAA-restricted diet	Liver transplant (curative)
Urea cycle defects	Nitrogen scavengers; IV arginine; dialysis if needed	Protein restriction; oral nitrogen scavengers; arginine/citrulline supplementation	Liver transplant ^[3]
Organic acidaemias	IV dextrose; carnitine; B12/biotin trial; correct acidosis; dialysis if severe	Protein restriction; carnitine; metronidazole; cofactor supplementation	Liver ± kidney transplant
FAO defects	IV dextrose; avoid fasting ^[11]; AVOID intralipid with MCT in MCAD	Avoid fasting; frequent feeds; MCT oil (LCHAD/VLCAD only)	Supportive (no curative Tx)
Galactosaemia	Supportive; switch to soy formula	Galactose-free diet ^[14]; breast feeding contraindicated ^[20]	Supportive (no curative Tx)
GSD I	IV dextrose for hypoglycaemia	Uncooked cornstarch; frequent feeds; avoid fructose/galactose ^[3]	Liver transplant (selected cases)
Pompe disease	Supportive; cardiac management	ERT (alglucosidase alfa) ^[3]; physiotherapy	ERT (lifelong) ± gene therapy (investigational)
Gaucher	N/A	ERT or SRT (miglustat/eliglustat) ^[3]	ERT/SRT (lifelong)
MPS I (Hurler)	N/A	HSCT (before age 2.5) ^[3]^[9]; ERT (for attenuated forms)	HSCT (curative for CNS)
Fabry	N/A	ERT or migalastat ^[3]; ACEi for nephroprotection	ERT/chaperone (lifelong)
Wilson's disease	D-penicillamine or trientine (chelation); zinc; liver transplant if fulminant	Chelation therapy; zinc; avoid copper-rich foods	Liver transplant (fulminant/decompensated)
Tyrosinaemia I	Supportive; nitisinone	Nitisinone + Tyr/Phe-restricted diet ^[3]	Liver transplant (if HCC or non-response)

High Yield Summary — Management of IEM

GC Lecture Slide Management Framework ^[1]:

Dietary control — substrate restriction (Phe in PKU, galactose in galactosaemia, protein in UCD/OA)
Enzyme replacement therapy — for lysosomal storage diseases (Gaucher, Fabry, Pompe, MPS)
Steroid treatment — specifically for CAH (IEM of steroid biosynthesis)
Surgical: liver and kidney transplantation — curative for UCD, MSUD, Wilson's, etc.
Genetic counselling — AR inheritance, prenatal diagnosis, carrier testing

Emergency principles:

Stop catabolism → IV dextrose, stop protein (max 48 hours)
Remove toxic metabolites → nitrogen scavengers (benzoate + phenylbutyrate), carnitine, dialysis
Cofactor trials → B12, biotin, thiamine, pyridoxine (always try — responsive patients have dramatically better outcomes)
Treat concurrently for sepsis

Avoid fasting = single most important long-term intervention for FAO defects ^[11]

HSCT for IEM = must be done early, before irreversible CNS damage (MPS I Hurler before age 2.5) ^[9]

ERT does NOT cross BBB → cannot prevent CNS disease in neuronopathic forms

Breast feeding contraindicated in galactosaemia and some NBS-detected IEM ^[20]

Active Recall - Management of Inborn Errors of Metabolism

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — management: dietary control, ERT, steroid treatment, transplantation, genetic counselling) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (Chapter 14.1, Inborn Errors of Metabolism — pathophysiology) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (Section 8.3, Treatment of IEM; Section 8.4, Prevention by Newborn Screening) ^[9] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (Indications for HSCT including IEM) ^[11] Lecture slides: Chemical Pathology Seminar_Inherited metabolic disease 2025.pdf (Case of neonatal cardiac arrest — FAO defect: most important treatment is avoid fasting) ^[14] Senior notes: Adrian Lui Pediatrics Notes.pdf (Galactosaemia — galactose-free diet) ^[20] Lecture slides: CFB (OGPAE02-1) Physiology of Lactation, Breast Feeding and Infant Feeding (Part I).pdf (Contraindications to breast feeding — galactosaemia, NBS-detected IEM)

Complications of IEM can be understood as the downstream consequences of two fundamental problems: (1) chronic accumulation of toxic metabolites in developing organs, and (2) chronic deficiency of essential products. Because the developing child's organs are immature and highly metabolically active, they are disproportionately vulnerable compared to adult organs. Complications can be divided into those arising from the disease itself (disease-related), those from acute metabolic crises, and those from treatment (iatrogenic).

The brain is the organ most devastatingly affected by IEM, for several reasons explained from first principles:

The neonatal/infant brain has the highest metabolic rate of any organ (consuming ~60% of total body glucose in neonates vs ~20% in adults)
The blood–brain barrier (BBB) is immature in neonates, allowing toxic metabolites to cross more freely
Critical windows of myelination, synaptogenesis, and neuronal migration occur in the first 2–3 years — damage during these windows is irreversible
The brain has essentially no regenerative capacity — once neurons are lost, they are lost forever

Complication	Pathophysiology	Associated IEMs	Clinical Manifestation
Intellectual disability	Chronic neurotoxicity from accumulated metabolites (e.g., phenylalanine competitively inhibits transport of other large neutral amino acids across BBB → ↓tyrosine and tryptophan in brain → ↓dopamine and serotonin synthesis → impaired neuronal development)	PKU (untreated), MSUD, organic acidaemias, galactosaemia	Progressive irreversible mental retardation and movement disorders ^[3] — the hallmark of untreated PKU. This is the entire reason newborn screening exists
Seizure disorders / Epilepsy	Direct neurotoxicity; energy failure; excitotoxicity (e.g., glycine activates NMDA receptors in non-ketotic hyperglycinaemia); structural brain injury from recurrent crises	Virtually all intoxication-type IEMs, mitochondrial disease, pyridoxine-dependent epilepsy, non-ketotic hyperglycinaemia	Neonatal seizures (may be refractory to conventional AEDs); infantile spasms; Lennox-Gastaut syndrome. Epilepsy may persist even after metabolic control is achieved
Cerebral oedema	Hyperammonaemia → astrocyte glutamine accumulation → osmotic swelling → raised ICP. This is the mechanism by which acute hyperammonaemia kills	Urea cycle defects, organic acidaemias (severe crises)	Bulging fontanelle in neonates; altered consciousness → coma → brainstem herniation → death. This is a medical emergency
Basal ganglia necrosis / Leigh-like lesions	Energy failure in basal ganglia (high metabolic demand); toxic metabolite deposition (glutaric acid → striatal necrosis)	Mitochondrial disease (Leigh syndrome), glutaric aciduria type I, methylmalonic acidaemia, propionic acidaemia	Dystonia, choreoathetosis, movement disorders. MRI shows bilateral symmetric T2 hyperintensity in basal ganglia/brainstem. In glutaric aciduria type I, the acute basal ganglia crisis typically occurs between 6–36 months during an intercurrent illness
White matter disease / Leukodystrophy	Demyelination from accumulated storage material (e.g., sulfatides in metachromatic leukodystrophy; very-long-chain fatty acids in X-linked ALD)	Metachromatic leukodystrophy, Krabbe disease, X-linked adrenoleukodystrophy, Canavan disease	Progressive spasticity, ataxia, visual loss, cognitive decline. MRI shows symmetric white matter abnormalities
Developmental regression	Progressive accumulation of storage material in neurons → neuronal death; ongoing energy failure	Lysosomal storage diseases (Tay-Sachs, Sanfilippo, Niemann-Pick C), mitochondrial diseases	Loss of previously acquired milestones — this is a RED FLAG that should always prompt IEM investigation. Regression distinguishes IEM from static causes like cerebral palsy
Stroke (metabolic)	Homocysteine → endothelial damage and thrombophilia; organic acids → vasculopathy; mitochondrial disease → MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)	Homocystinuria, MELAS, organic acidaemias, Fabry disease	Acute hemiplegia, aphasia. In homocystinuria, stroke can occur in childhood/adolescence. In MELAS, "stroke-like episodes" do not follow typical vascular territories

High Yield — Why Early Treatment Prevents Neurological Complications

Benefit from prompt recognition, diagnosis and treatment ^[1]. Phenylalanine-restricted diet can prevent neurological damage ^[3]. The entire rationale for newborn screening programmes is that early treatment prevents irreversible brain damage. Once neurotoxic metabolites have damaged the developing brain, the damage is permanent. This is why NBS at 24–72 hours of life, before symptoms appear, is the gold standard.

The liver is the metabolic powerhouse of the body — it performs gluconeogenesis, glycogenolysis, ureagenesis, bile acid synthesis, protein synthesis, and detoxification. Many IEMs directly affect hepatic metabolic pathways, and the liver is often the first organ to fail.

Complication	Pathophysiology	Associated IEMs	Clinical Features
Acute liver failure	Direct hepatocyte toxicity from accumulated metabolites (galactose-1-phosphate → hepatocyte necrosis; tyrosine metabolites → hepatocyte apoptosis; copper → oxidative hepatocyte damage)	Galactosaemia, tyrosinaemia type I, Wilson's disease, neonatal haemochromatosis, mitochondrial DNA depletion syndromes	Coagulopathy (↑INR — because liver cannot synthesise clotting factors), jaundice, encephalopathy, hypoglycaemia, ↑↑transaminases. Fulminant hepatic failure due to Wilson's: young patient with no reason for fulminant liver failure → only finding is low Hb, Coombs-negative haemolytic anaemia ^[6]
Chronic liver disease / Cirrhosis	Chronic hepatocyte injury → fibrosis → cirrhosis. In α1-antitrypsin deficiency: misfolded protein accumulates in hepatocyte ER → chronic hepatocyte stress → fibrosis. In Wilson's: chronic copper toxicity	α1-AT deficiency, Wilson's disease, GSD IV, tyrosinaemia type I, galactosaemia (long-term), Niemann-Pick C	Hepatomegaly → eventually shrunken liver; portal hypertension (varices, ascites, splenomegaly); synthetic dysfunction (hypoalbuminaemia, coagulopathy)
Hepatocellular carcinoma (HCC)	Chronic hepatocyte injury and regeneration → accumulation of mutations → malignant transformation. Tyrosinaemia type I has the highest HCC risk among IEMs (fumarylacetoacetate is directly mutagenic — it alkylates DNA)	Tyrosinaemia type I (30–40% develop HCC if untreated), GSD I (hepatic adenomas → malignant transformation), Wilson's disease (rare), haemochromatosis	Rising AFP (monitor serially); hepatic mass on imaging. In tyrosinaemia type I, nitisinone has dramatically reduced HCC risk, but monitoring with AFP and imaging is still required lifelong
Hepatic adenomas	Chronic metabolic stress on hepatocytes; glycogen/lipid accumulation → benign neoplastic proliferation	GSD I (adenomas develop in ~75% by age 25), GSD III	Multiple hepatic masses on imaging; risk of haemorrhage; risk of malignant transformation to HCC
Cholestasis	Impaired bile acid synthesis or secretion; hepatocyte damage disrupting bile flow	Bile acid synthesis defects, Niemann-Pick C, CDG syndromes, Zellweger spectrum (peroxisomal — cannot synthesise bile acids because peroxisomes are required for bile acid side-chain shortening)	Conjugated hyperbilirubinaemia, pale stools, dark urine, pruritus, fat-soluble vitamin deficiency (A, D, E, K)

Complication	Pathophysiology	Associated IEMs	Clinical Features
Hypertrophic cardiomyopathy (HCM)	Glycogen or lipid accumulation within cardiomyocytes → ↑wall thickness → diastolic dysfunction → outflow obstruction. 5–10% of HCM is associated with metabolic disorders / inborn errors of metabolism ^[5]	Pompe disease (infantile — massive HCM, often fatal by 1–2 years without ERT), Fabry disease, fatty acid oxidation defects, Friedreich ataxia (mitochondrial iron overload), Danon disease	Infantile Pompe: massive cardiomegaly on CXR, short PR interval on ECG, thick LV walls on echo. Fabry: progressive HCM in adolescence/adulthood
Dilated cardiomyopathy (DCM)	Energy failure in cardiomyocytes → ↓contractility → ventricular dilatation	Fatty acid oxidation defects (VLCAD, LCHAD), mitochondrial cardiomyopathy, Barth syndrome (X-linked: 3-methylglutaconic aciduria + DCM + neutropenia + 3-methylglutaric aciduria), propionic acidaemia (secondary DCM from chronic propionate toxicity)	Heart failure symptoms: tachycardia, tachypnoea, hepatomegaly, poor feeding in infants; ↓ejection fraction on echo
Arrhythmias	Metabolite deposition in conduction system; electrolyte derangements (hyperkalaemia from metabolic acidosis, hypocalcaemia); fatty acid accumulation in conducting fibres	Fatty acid oxidation defects, GSD (particularly cardiac GSD — type III), mitochondrial disease	Sudden death (particularly in FAO defects during metabolic crisis — this is a mechanism of sudden infant death syndrome); prolonged QTc; ventricular tachycardia
Coronary artery disease (premature)	Endothelial damage from homocysteine or from chronic dyslipidaemia	Homocystinuria, familial hypercholesterolaemia	Premature atherosclerosis; angina/MI in adolescence or young adulthood. Homocysteine is directly toxic to vascular endothelium and promotes thrombosis

High Yield — Pompe Disease Cardiac Outcome

Infantile Pompe disease is one of the most dramatic cardiac complications of IEM. Without treatment, these infants develop massive HCM with LV wall thickness sometimes exceeding 20 mm (normal < 5 mm in neonates), leading to heart failure and death by 1–2 years. ERT (alglucosidase alfa) ^[3] has transformed the natural history, allowing survival into childhood and beyond — but must be started early before irreversible cardiac remodelling occurs.

Complication	Pathophysiology	Associated IEMs	Clinical Features
Chronic kidney disease / Renal failure	Chronic metabolite deposition in renal parenchyma (methylmalonic acid → tubulointerstitial nephritis in MMA; Gb3 → glomerulosclerosis in Fabry; oxalate → nephrocalcinosis in primary hyperoxaluria)	Methylmalonic acidaemia, Fabry disease, primary hyperoxaluria, cystinosis	Progressive decline in GFR; proteinuria; hypertension. MMA patients may progress to ESRF requiring combined liver-kidney transplant
Renal Fanconi syndrome	Toxic metabolites or storage material damage proximal tubular cells → generalised proximal tubular dysfunction → loss of glucose, amino acids, phosphate, bicarbonate, uric acid in urine ^[21]	Cystinosis (most common inherited cause of Fanconi syndrome in children), galactosaemia, tyrosinaemia type I, Wilson's disease, GSD I, mitochondrial disease	Polyuria, polydipsia, dehydration; hypophosphataemic rickets (in children); growth failure; acidosis; hypokalaemia; hyperchloraemia. Also glycosuria, proteinuria/aminoaciduria, hyperuricosuria ^[21]
Nephrocalcinosis / Nephrolithiasis	Excessive excretion of calcium, oxalate, cystine, or uric acid → crystal precipitation in renal medulla/collecting system	Primary hyperoxaluria (calcium oxalate), cystinuria (cystine stones), Lesch-Nyhan syndrome (uric acid stones), Dent disease	Haematuria, renal colic (older children), UTIs. USG kidneys shows medullary echogenicity
Renal tubular acidosis (RTA)	Impaired tubular acid excretion (type I, distal) or bicarbonate reabsorption (type II, proximal) secondary to metabolite toxicity or as part of Fanconi syndrome	Galactosaemia (proximal RTA), Wilson's disease (proximal or distal RTA from copper tubular toxicity), GSD I	Normal anion gap metabolic acidosis; hypo or hyperkalaemia depending on type

Complication	Pathophysiology	Associated IEMs
Cataracts	Galactitol accumulation in lens (reduced from galactose-1-phosphate by aldose reductase) → osmotic lens swelling → cataract	Galactosaemia (may present within first weeks of life); also Zellweger spectrum, Lowe syndrome
Cherry-red spot	Storage material (GM2 ganglioside, sphingomyelin) in perifoveal retinal ganglion cells makes surrounding retina pale; the fovea (which lacks ganglion cells) appears red by contrast	Tay-Sachs, Niemann-Pick type A, GM1 gangliosidosis, Sandhoff disease
Corneal clouding	GAG deposition in corneal stroma	MPS I (Hurler), MPS VI (Maroteaux-Lamy), MPS VII. Note: MPS II (Hunter) does NOT have corneal clouding — this is a classic distinguishing feature
Kayser-Fleischer rings	Copper deposition in Descemet's membrane of cornea → golden-brown rings on slit-lamp	Wilson's disease (present in ~95% neurological, ~50% hepatic)
Lens subluxation (ectopia lentis)	Homocysteine disrupts fibrillin cross-links in zonular fibres → lens dislocation (downward and inward, cf. Marfan's: upward and outward)	Homocystinuria; also sulfite oxidase deficiency
Corneal verticillata	Gb3 deposition in corneal epithelium → whorl-like opacities	Fabry disease
Retinitis pigmentosa	Mitochondrial dysfunction in photoreceptors → progressive degeneration	Mitochondrial diseases (Kearns-Sayre syndrome, NARP)
Optic atrophy	Demyelination of optic nerve; neuronal degeneration	Krabbe disease, metachromatic leukodystrophy, LHON (Leber hereditary optic neuropathy — mitochondrial)

Complication	Pathophysiology	Associated IEMs
Dysostosis multiplex	GAG accumulation in bone and cartilage → abnormal bone modelling → characteristic radiographic changes: anterior beaking of vertebral bodies, paddle-shaped ribs, J-shaped sella turcica, thickened calvarium, claw-hand deformity	Mucopolysaccharidoses (MPS I, II, VI), mucolipidoses
Short stature	Chronic metabolic acidosis → GH resistance; chronic energy deficit; restrictive diet limiting protein for growth; skeletal dysplasia; hypothyroidism (secondary to metabolic disease)	Virtually all chronic IEMs; particularly organic acidaemias, RTA, MPS
Rickets	Renal phosphate wasting (Fanconi syndrome) → hypophosphataemia → impaired bone mineralisation; or vitamin D metabolism defects	Cystinosis, tyrosinaemia type I, GSD I (renal Fanconi); also vitamin D-dependent rickets (type I: 1α-hydroxylase deficiency; type II: VDR defect)
Osteoporosis / Pathological fractures	Chronic acidosis mobilises calcium from bone as buffer; Gaucher disease → bone marrow infiltration by Gaucher cells → bone infarction, avascular necrosis	Gaucher disease (Erlenmeyer flask deformity of distal femur, bone crises mimicking osteomyelitis), chronic metabolic acidosis states

Complication	Pathophysiology	Impact
Failure to thrive / Growth failure	Chronic energy deficit (can't use fat for energy in FAO defects, can't maintain glucose in GSD); protein restriction limiting growth substrate; chronic acidosis → GH resistance; chronic illness → ↑metabolic demand	A child with an undiagnosed IEM may present primarily as failure to thrive — always consider IEM in the differential of FTT, especially if there are associated features (hepatomegaly, developmental delay, metabolic acidosis)
Developmental delay (global)	Chronic low-grade neurotoxicity during critical brain development periods; inadequate energy supply to the brain; recurrent metabolic crises causing cumulative brain injury	Even with treatment, many children with IEM have some degree of developmental delay — particularly those diagnosed late or who experienced severe neonatal crises. Early intervention services (physiotherapy, occupational therapy, speech therapy) are essential
Learning difficulties	Even in "well-treated" IEM, subtle cognitive deficits are common	Galactosaemia: despite galactose-free diet from birth, > 50% of patients have learning difficulties, speech dyspraxia, and reduced IQ — the galactose-1-phosphate causes endogenous damage (the body produces some galactose internally via the epimerase pathway, so dietary restriction cannot completely prevent toxicity)

Complication	Pathophysiology	Associated IEMs
Premature ovarian insufficiency (POI)	Galactose-1-phosphate toxicity to ovarian follicles → accelerated follicular atresia	Galactosaemia (~80% of females develop POI despite treatment — this is NOT prevented by galactose-free diet, because endogenous galactose production is sufficient to cause ovarian damage)
Hypothyroidism	Iron deposition in thyroid (haemochromatosis); copper toxicity (Wilson's); storage material in thyroid cells	Haemochromatosis (transfusional iron overload in thalassaemia), cystinosis
Hypogonadism	Iron deposition in pituitary gonadotrophs → hypogonadotrophic hypogonadism	Haemochromatosis
Diabetes mellitus	Iron deposition in pancreatic β-cells → β-cell destruction → insulin-dependent DM ("bronze diabetes")	Haemochromatosis
Adrenal insufficiency	Very-long-chain fatty acid accumulation in adrenal cortex → adrenal destruction	X-linked adrenoleukodystrophy (adrenal insufficiency may precede neurological symptoms by years — always screen for ALD in a boy with unexplained Addison's disease)

These are the life-threatening complications that can occur during any acute decompensation:

Complication	Pathophysiology	Prevention / Management
Cerebral oedema / Brain herniation	Hyperammonaemia → astrocyte glutamine accumulation → osmotic swelling → raised ICP	Aggressive ammonia lowering (nitrogen scavengers, dialysis); ICP monitoring; mannitol/hypertonic saline if herniation imminent; avoid over-hydration
Cardiac arrest	Severe hypoglycaemia → myocardial energy failure; severe hyperkalaemia (from acidosis) → arrhythmia; long-chain acylcarnitine accumulation → arrhythmogenesis (FAO defects)	Rapid glucose correction; continuous cardiac monitoring; correct electrolytes
Multi-organ failure	Severe metabolic crisis → systemic energy failure + direct metabolite toxicity to multiple organs simultaneously	ICU level care; organ support (ventilation, inotropes, RRT)
Acute pancreatitis	Organic acid toxicity to pancreatic acinar cells; hypertriglyceridaemia (in some IEMs)	Organic acidaemia patients (especially PA, MMA) may develop recurrent pancreatitis; supportive management
Bone marrow suppression / Pancytopenia	Direct toxicity of organic acids (propionic acid, methylmalonic acid) to myeloid progenitor cells	Pancytopenia during organic acidaemia crisis; resolves with metabolic stabilisation. Important: do NOT mistake for leukaemia
Rhabdomyolysis	Energy failure in skeletal muscle (FAO defects, mitochondrial myopathy, GSD V) → myocyte necrosis → release of myoglobin, CK, potassium	↑↑CK, myoglobinuria (dark urine), risk of AKI from myoglobin cast nephropathy; aggressive IV hydration; avoid nephrotoxins
Sudden infant death	Unrecognised FAO defect → fasting during overnight sleep → hypoketotic hypoglycaemia → cardiac arrhythmia → death	This is why NBS for MCAD is so important — MCAD deficiency is a recognised cause of SIDS. For MCAD, clinically detected cases are only ~1/3 of those identified by newborn screening ^[3] — many of the "missed" cases likely died before diagnosis

High Yield — MCAD and Sudden Infant Death

MCAD deficiency is a cause of sudden infant death syndrome (SIDS). The infant goes through a normal overnight fast → cannot oxidise medium-chain fatty acids → hypoketotic hypoglycaemia → cardiac arrhythmia → death. This was only recognised after newborn screening was introduced and the incidence of "SIDS" in screened populations decreased. Clinically detected cases of MCAD are only ~1/3 of those identified by newborn screening ^[3] — many of the undetected cases likely presented as SIDS.

Complication	Cause	Details
Nutritional deficiencies from restrictive diets	Protein-restricted or amino acid-restricted diets	Children on PKU or MSUD diets may develop deficiencies in essential amino acids, vitamins (especially B12 in vegan-like diets), minerals (iron, zinc, selenium), and total protein → growth failure, anaemia, osteoporosis. Requires close dietitian monitoring
Trace element / micronutrient deficiencies	GSD I diet (avoiding fructose, galactose, sucrose) severely limits fruit and dairy	Calcium, vitamin D, iron deficiency. These children need targeted supplementation
Psychological / Social complications of dietary therapy	Lifelong restrictive diet in a child/adolescent	Social isolation (cannot eat the same foods as peers); body image concerns; diet fatigue and non-compliance (especially in adolescence); eating disorders; parental stress and anxiety
Infusion-related reactions to ERT	Immune response to recombinant enzyme protein	Anaphylaxis, urticaria, fever, rigors during or after infusion. More common in Pompe disease (cross-reactive immunologic material-negative patients who have zero native enzyme — the immune system sees the recombinant enzyme as entirely foreign). Pre-medication with antihistamines and steroids; desensitisation protocols
Anti-drug antibodies	Immune response to ERT	Neutralising antibodies → ↓ERT efficacy over time. Particularly problematic in infantile Pompe disease and MPS I
GVHD post-HSCT	Donor T-cells attack recipient tissues	Acute GVHD (skin rash, diarrhoea, liver dysfunction) and chronic GVHD (sclerodermatous skin, dry eyes/mouth, bronchiolitis obliterans). Managed with immunosuppression (ciclosporin, tacrolimus, steroids) ^[9]
Graft failure / Rejection	Inadequate engraftment of donor stem cells	Requires repeat transplant or alternative donor. Risk of fatal infections during the cytopenic phase ^[9]
Post-transplant complications (liver)	Surgical complications, rejection, immunosuppression side effects	Bile leak, hepatic artery thrombosis, rejection episodes; long-term immunosuppression → infection risk, lymphoproliferative disease
Penicillamine side effects (Wilson's disease)	Copper chelation	Penicillamine causes worsened neurological symptoms in the first few days — patient is used to copper in brain, but once penicillamine is given, they lose copper, body is not used to it, may exacerbate the neuro symptoms ^[6]. Also: nephrotoxicity, bone marrow suppression, lupus-like syndrome, skin changes

Complication	Details
Impact on quality of life	Frequent hospital admissions; daily medications; dietary restrictions; need for medic-alert bracelet; anxiety about metabolic crises. Children may feel "different" from peers
Family burden	Parents carry enormous burden of daily care; guilt about genetic transmission; impact on siblings (both genetic risk and reduced parental attention); financial burden of specialised formulas and supplements
Transition to adult care	Many IEMs were historically fatal in childhood. With improved treatment, patients survive to adulthood → need transition to adult metabolic services. Adolescence is a particularly high-risk period for non-compliance with diet/medications
Reproductive complications	Maternal PKU: if a woman with PKU becomes pregnant with poorly controlled blood Phe → teratogenic effects on the fetus (microcephaly, congenital heart disease, growth restriction) — even though the fetus does NOT have PKU. Strict Phe control pre-conception and throughout pregnancy is essential

Organ System	Key Complications	Most Relevant IEMs
CNS	Intellectual disability, seizures, cerebral oedema, developmental regression, stroke, leukodystrophy, basal ganglia necrosis	PKU, MSUD, urea cycle defects, organic acidaemias, LSDs, mitochondrial, homocystinuria
Liver	Acute liver failure, cirrhosis, HCC, hepatic adenomas, cholestasis	Galactosaemia, tyrosinaemia I, Wilson's, α1-AT deficiency, GSD I/IV
Heart	HCM, DCM, arrhythmias, sudden death	Pompe, FAO defects, Fabry, Barth, PA, mitochondrial
Kidney	CKD, Fanconi syndrome, nephrocalcinosis, RTA	MMA, Fabry, cystinosis, primary hyperoxaluria, galactosaemia
Eye	Cataracts, cherry-red spot, corneal clouding, KF rings, lens subluxation	Galactosaemia, Tay-Sachs, MPS, Wilson's, homocystinuria
Skeleton	Dysostosis multiplex, rickets, osteoporosis, short stature	MPS, Gaucher, chronic acidosis, cystinosis
Endocrine	POI, hypothyroidism, adrenal insufficiency, DM	Galactosaemia, haemochromatosis, X-ALD
Growth/Development	FTT, global developmental delay, learning difficulties	All chronic IEMs

High Yield Summary — Complications of IEM

Brain is the most vulnerable organ — intellectual disability, seizures, regression, cerebral oedema. Early treatment prevents irreversible brain damage (entire rationale for NBS).

Liver complications span a spectrum from acute liver failure (galactosaemia, tyrosinaemia, Wilson's) to chronic cirrhosis and HCC (tyrosinaemia I has highest HCC risk among IEMs).

Cardiac: HCM (5–10% associated with IEM ^[5] — Pompe, Fabry); DCM (FAO defects, Barth); sudden death (FAO defects = cause of SIDS).

Renal: Fanconi syndrome (cystinosis, galactosaemia); CKD (MMA, Fabry); nephrocalcinosis.

Galactosaemia paradox: Despite galactose-free diet, > 80% females develop premature ovarian insufficiency and > 50% have learning difficulties — endogenous galactose production causes ongoing damage.

MCAD and SIDS: Unrecognised MCAD → overnight fast → hypoketotic hypoglycaemia → cardiac arrest → sudden infant death. NBS has reduced this.

Maternal PKU: Uncontrolled Phe during pregnancy → teratogenic to fetus (microcephaly, CHD) even if fetus does NOT have PKU.

Treatment complications: Nutritional deficiencies from restrictive diets; ERT infusion reactions/anti-drug antibodies; GVHD post-HSCT; penicillamine neurological worsening in Wilson's.

Active Recall - Complications of Inborn Errors of Metabolism

^[1] Lecture slides: GC 157. Paediatric Chemical Pathology.pdf (IEM section — benefit from prompt recognition, diagnosis and treatment) ^[3] Senior notes: Ryan Ho Chemical Path.pdf (Section 8.3–8.4, Treatment of IEM; PKU — progressive irreversible mental retardation; prevention by newborn screening; clinically detected MCAD cases only ~1/3 of NBS-detected) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (Diverse etiologies of HCM — 5–10% associated with IEM) ^[6] Senior notes: Block A - Patients with non-viral chronic liver diseases.pdf (Wilson's disease — fulminant hepatic failure, Coombs-negative haemolytic anaemia; penicillamine neurological worsening) ^[9] Senior notes: Block A - High white cell count: acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (HSCT procedure and complications including GVHD) ^[21] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Fanconi syndrome features — polyuria, polydipsia, rickets, glycosuria, aminoaciduria)

High Yield Summary

Definition: IEM = phenotypically and genetically heterogeneous group of disorders caused by defective enzymes/transporters → metabolic malfunction ± toxic metabolite accumulation.

Epidemiology: Individually rare, collectively common (~1 in 4,000–7,580 in HK). Majority AR inherited. Present mainly in infancy/childhood but some in adulthood.

Pathophysiology — 4 mechanisms: ↑ primary substrate, ↓ product, ↑ secondary substrate, secondary inhibition of other pathways.

Classification by presentation:

Intoxication: Symptom-free interval → acute crisis (MSUD, urea cycle defects, organic acidaemias)
Energy insufficiency: Hypoglycaemia, lactic acidosis, cardiomyopathy (FAO defects, GSD, mitochondrial)
Complex molecule: Progressive, no free interval (LSD, MPS, peroxisomal)

Must-send labs: Blood gas, glucose, ammonia, lactate, urine ketones, plasma amino acids, urine organic acids, acylcarnitine profile.

IEM vs Sepsis: Clinically indistinguishable → treat both simultaneously.

Newborn screening: Gold standard worldwide; tandem MS/MS; HK screens > 20 conditions.

MUDPILES: IEM is the "I" in high-AG metabolic acidosis differential.

HCM: 5–10% associated with IEM.

Wilson's: ATP7B, AR; Coombs-negative haemolytic anaemia + liver failure; penicillamine may transiently worsen neuro symptoms.

High Yield Summary — DDx of IEM

Always consider IEM AND sepsis simultaneously in a sick neonate — treat both.
Symptom-free interval → deterioration favours IEM over birth asphyxia.
Metabolic pattern discriminates:
- ↑AG acidosis + ↑ammonia → organic acidaemias
- ↑↑↑ammonia + resp alkalosis → urea cycle defects (OTC most common, X-linked)
- Hypoketotic hypoglycaemia → FAO defects (acylcarnitine profile confirms)
- ↑↑Lactate → mitochondrial / pyruvate defects
IEM is the "I" in MUDPILES for high-AG metabolic acidosis.
Non-IEM mimics: sepsis, HIE, CHD, CAH, NAI, hyperinsulinism, pyloric stenosis.
Hypoketotic hypoglycaemia DDx: FAO defects (↑FFA, ↓insulin) vs hyperinsulinism (↓FFA, ↑insulin).
Developmental regression + organomegaly → lysosomal storage diseases.
Confirmatory tests: biochemical first, supplemented by genetic testing.

High Yield Summary — Diagnosis of IEM

Confirmatory test is mainly biochemical, supplemented by genetic testing ^[1].

Key discriminating tests:

High-AG metabolic acidosis + ↑ammonia → organic acidaemias (urine organic acids, acylcarnitine ↑C3/C5)
↑↑↑Ammonia + resp alkalosis → urea cycle defect (plasma amino acids + urine orotic acid)
Hypoketotic hypoglycaemia → FAO defect (acylcarnitine profile is diagnostic)
↑↑Lactate → mitochondrial disease (L:P ratio, muscle biopsy)

Newborn screening = gold standard for early detection; uses tandem MS/MS; not all IEMs included; false positives common.

Critical samples must be taken AT THE TIME of metabolic crisis — before treatment.

Ammonia sample must be collected on ice and analysed within 30 minutes — pre-analytical error is common and dangerous.

High Yield Summary — Management of IEM

GC Lecture Slide Management Framework ^[1]:

Dietary control — substrate restriction (Phe in PKU, galactose in galactosaemia, protein in UCD/OA)
Enzyme replacement therapy — for lysosomal storage diseases (Gaucher, Fabry, Pompe, MPS)
Steroid treatment — specifically for CAH (IEM of steroid biosynthesis)
Surgical: liver and kidney transplantation — curative for UCD, MSUD, Wilson's, etc.
Genetic counselling — AR inheritance, prenatal diagnosis, carrier testing

Emergency principles:

Stop catabolism → IV dextrose, stop protein (max 48 hours)
Remove toxic metabolites → nitrogen scavengers (benzoate + phenylbutyrate), carnitine, dialysis
Cofactor trials → B12, biotin, thiamine, pyridoxine (always try — responsive patients have dramatically better outcomes)
Treat concurrently for sepsis

Avoid fasting = single most important long-term intervention for FAO defects ^[11]

HSCT for IEM = must be done early, before irreversible CNS damage (MPS I Hurler before age 2.5) ^[9]

ERT does NOT cross BBB → cannot prevent CNS disease in neuronopathic forms

Breast feeding contraindicated in galactosaemia and some NBS-detected IEM ^[20]

High Yield Summary — Complications of IEM

Brain is the most vulnerable organ — intellectual disability, seizures, regression, cerebral oedema. Early treatment prevents irreversible brain damage (entire rationale for NBS).

Liver complications span a spectrum from acute liver failure (galactosaemia, tyrosinaemia, Wilson's) to chronic cirrhosis and HCC (tyrosinaemia I has highest HCC risk among IEMs).

Cardiac: HCM (5–10% associated with IEM ^[5] — Pompe, Fabry); DCM (FAO defects, Barth); sudden death (FAO defects = cause of SIDS).

Renal: Fanconi syndrome (cystinosis, galactosaemia); CKD (MMA, Fabry); nephrocalcinosis.

MCAD and SIDS: Unrecognised MCAD → overnight fast → hypoketotic hypoglycaemia → cardiac arrest → sudden infant death. NBS has reduced this.

Maternal PKU: Uncontrolled Phe during pregnancy → teratogenic to fetus (microcephaly, CHD) even if fetus does NOT have PKU.

Treatment complications: Nutritional deficiencies from restrictive diets; ERT infusion reactions/anti-drug antibodies; GVHD post-HSCT; penicillamine neurological worsening in Wilson's.

Inborn Error of Metabolism

References

Inborn Errors of Metabolism (IEM) — Paediatrics

2. Epidemiology

4. Relevant Anatomy and Function (Metabolic Pathways)

5. Pathophysiology of IEM

6. Classification

8. Clinical Features: Symptoms and Signs

8.2 Symptoms (with Pathophysiological Basis)

8.3 Signs (with Pathophysiological Basis)

9. Important Specific IEMs — Clinical Details

Think IEM when you see:

Active Recall - Inborn Errors of Metabolism

1. Approach to the Differential: Presentation-Based Framework

Key discriminating investigations

1.3 DDx of the Infant / Young Child with Chronic / Subacute Presentation

4. DDx of Specific Metabolic Derangements

6. Key Points by Specific IEM for DDx Purposes

Active Recall - DDx of Inborn Errors of Metabolism

When Can You "Diagnose" an IEM?

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed

3.5 Specific Investigations for Key IEMs

Active Recall - Diagnostic Criteria, Algorithm and Investigations of IEM

3. Acute Emergency Management ("The Sick Neonate / Child in Metabolic Crisis")

3.3 Specific Acute Interventions by Metabolic Derangement

4. Chronic (Long-Term) Management

4.6 Organ Transplantation [1][3]

Active Recall - Management of Inborn Errors of Metabolism

Active Recall - Complications of Inborn Errors of Metabolism

On this page

Inborn Error of Metabolism

References

Inborn Errors of Metabolism (IEM) — Paediatrics

1. Definition

2. Epidemiology

Age of Presentation

Significance in Paediatrics

3. Risk Factors

4. Relevant Anatomy and Function (Metabolic Pathways)

4.1 Amino Acid Metabolism

4.2 Organic Acid Metabolism

4.3 Fatty Acid Oxidation

4.4 Carbohydrate Metabolism

4.5 Urea Cycle

4.6 Lysosomal Pathway

4.7 Peroxisomal Pathway

4.8 Mitochondrial Respiratory Chain

5. Pathophysiology of IEM

Why the brain is so vulnerable

Why IEM causes metabolic acidosis with high anion gap

6. Classification

6.1 Classification by Molecule Type [2]

6.2 Classification by Clinical Presentation [2]

6.3 SSIEM Classification (15 Groups) [1]

7. Most Common / Important IEM Types

8. Clinical Features: Symptoms and Signs

8.1 General Principles

8.2 Symptoms (with Pathophysiological Basis)

A. Neurological Symptoms

B. Gastrointestinal Symptoms

C. Metabolic / Systemic Symptoms

D. Cardiac Symptoms

E. Musculoskeletal Symptoms

F. Dermatological Symptoms

G. Ophthalmological Symptoms

8.3 Signs (with Pathophysiological Basis)

A. Neonatal Presentation — "The Sick Neonate"

B. Infantile / Childhood Presentation — "The Failure-to-Thrive Child"

C. Adolescent / Late Presentation

D. Acute Metabolic Decompensation / Crisis

9. Important Specific IEMs — Clinical Details

9.1 Phenylketonuria (PKU)

9.2 Maple Syrup Urine Disease (MSUD)

9.3 Urea Cycle Defects

9.4 Organic Acidaemias (Propionic Acidaemia, Methylmalonic Acidaemia)

9.5 Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency

9.6 Galactosaemia (Classic)

9.7 Glycogen Storage Diseases (GSD)

9.8 Lysosomal Storage Diseases

9.9 Wilson's Disease

9.10 Congenital Disorders of Bilirubin Metabolism (A Special Subset)

10. The Approach to a Sick Neonate — When to Suspect IEM

Think IEM when you see:

11. Key Metabolic Investigations (First-Line)

12. Newborn Screening in Hong Kong

13. Indications for HSCT in IEM

Active Recall - Inborn Errors of Metabolism

References

Differential Diagnosis of Inborn Errors of Metabolism (IEM) — Paediatrics

1. Approach to the Differential: Presentation-Based Framework

1.1 The Sick Neonate (Acute Encephalopathy ± Metabolic Crisis)

Key discriminating investigations

1.2 DDx of the Sick Neonate by Metabolic Pattern

1.3 DDx of the Infant / Young Child with Chronic / Subacute Presentation

A. Developmental Delay / Regression

B. Hepatomegaly / Liver Disease in Infancy and Childhood

C. Cardiomyopathy in Infancy

D. Neonatal / Infantile Jaundice

E. Cyanosis of Metabolic / Endocrine Origin

1.4 DDx of Acute Metabolic Decompensation in a Known or Unknown IEM Child

2. Differential Diagnosis Within IEM Categories

3. Non-IEM Conditions That Mimic IEM

4. DDx of Specific Metabolic Derangements

4.1 Hyperammonaemia DDx (Paediatric Focus)

4.2 High Anion Gap Metabolic Acidosis DDx in Paediatrics (MUDPILES)

4.3 Hypoglycaemia DDx in Paediatrics

5. DDx Summary Algorithm

6. Key Points by Specific IEM for DDx Purposes

OTC Deficiency [10]

FAO Defects [11]