Duchenne muscular dystrophy is a severe X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene, leading to progressive skeletal muscle degeneration and weakness, typically presenting in early childhood.

Duchenne Muscular Dystrophy (DMD)

2. Epidemiology

Milestone	Typical Age
Symptom onset	2–5 years
Diagnosis (average)	~4.5 years
Loss of independent ambulation	9–12 years
Scoliosis development	After loss of ambulation
Need for ventilatory support	Mid-late teens
Death (untreated)	Late teens to early 20s
Death (with current care)	Late 20s to 30s+

3. Anatomy and Function of Dystrophin

Understanding DMD requires understanding what dystrophin does and why its absence is catastrophic.

Dystrophin has four functional domains — think of it as a molecular shock absorber that links the internal cytoskeleton of the muscle fibre to the extracellular matrix:

[N-terminal] ——— [Central rod domain] ——— [Cysteine-rich domain] ——— [C-terminal]
     |                    |                          |                        |
Binds F-actin       24 spectrin-like repeats    Binds β-dystroglycan      Binds syntrophins
(intracellular      (acts as spring/shock       (connects to              and dystrobrevins
 cytoskeleton)       absorber)                   extracellular matrix      (signalling)
                                                 via DGC)

Domain	Function
N-terminal (actin-binding)	Anchors to intracellular F-actin (cytoskeleton)
Central rod domain	24 spectrin-like repeats + 4 hinge regions — provides flexibility and mechanical resilience during contraction
Cysteine-rich domain	Binds β-dystroglycan → connects to the dystrophin-associated glycoprotein complex (DGC)
C-terminal domain	Binds syntrophins and dystrobrevins → involved in cell signalling (e.g., nNOS recruitment)

The DMD gene has multiple promoters producing tissue-specific isoforms:

Isoform	Tissue	Molecular Weight	Clinical Relevance
Dp427m	Skeletal and cardiac muscle	427 kDa	The "main" full-length dystrophin; absent in DMD
Dp427c	Cortical neurons	427 kDa	Explains cognitive/behavioural features
Dp427p	Purkinje cells	427 kDa	May contribute to cerebellar dysfunction
Dp260	Retina	260 kDa	Explains abnormal electroretinogram
Dp140	Brain, kidney	140 kDa	Cognitive involvement
Dp116	Schwann cells	116 kDa	Peripheral nerve function
Dp71	Most non-muscle tissues	71 kDa	Ubiquitous; important in brain

This explains why DMD is not purely a muscle disease — cognitive impairment and behavioural issues occur because dystrophin isoforms are expressed in the CNS.

4. Aetiology and Genetics

Mutation Type	Frequency	Effect
Deletions	~60–70%	Single or multi-exon deletions
Duplications	~10–15%	Single or multi-exon duplications
Point mutations / small indels	~20–25%	Nonsense, missense, splice-site mutations

Two deletion hotspots: exons 2–20 and exons 44–55
~30–60% of mutations are deletions ^[2]

5. Pathophysiology

Understanding the pathophysiology explains every clinical feature. The cascade flows logically from the molecular defect:

6. Classification

Feature	DMD	BMD
Inheritance	X-linked recessive	X-linked recessive
Gene	DMD (Xp21.2)	DMD (Xp21.2)
Mutation type	Out-of-frame	In-frame
Dystrophin	Absent	Reduced / truncated but partially functional
Onset	2–5 years	5–15 years (later)
Loss of ambulation	~9–12 years (before age 13)	After age 16 (continue to ambulate beyond 15) ^[2]
CK elevation	50–100× ULN	5–20× ULN
Cardiomyopathy	Universal by late teens	Common (may dominate clinical picture)
Cognition	IQ ~85 (mean)	Usually normal
Death (untreated)	Late teens–early 20s	40–60 years ^[2]
Severity	Severe	Milder

From the lecture slides and senior notes, DMD must be differentiated from other causes of weakness ^[6]^[7]:

Category	Conditions
Congenital / Muscular	DMD, BMD, FSHD, LGMD, congenital myopathies
Anterior horn cell	Spinal muscular atrophy (SMA), poliomyelitis
NMJ	Congenital myasthenia gravis, transient neonatal myasthenia
Peripheral nerve	Charcot-Marie-Tooth, GBS
CNS	Cerebral palsy, Down syndrome, Prader-Willi
Inflammatory	Dermatomyositis, polymyositis
Endocrine	Thyroid disorders, Cushing's, electrolyte imbalance
Drug-induced	Statins, steroids

7. Clinical Features

The clinical features of DMD can be systematically understood by linking each feature back to the underlying pathophysiology.

7.1 Symptoms

Symptom	Typical Age	Pathophysiological Basis
Delayed motor milestones	< 18 months	Dystrophin is absent from birth, but maternal-derived satellite cells and small muscle mass partially compensate initially. Walking may be delayed (mean 18 months vs. normal 12 months)
Difficulty running, climbing stairs, rising from floor	2–5 years	Progressive weakness begins in girdles and paraspinal muscles ^[2]. Proximal muscles are affected first because they generate higher forces → more contraction-induced damage
Gower's sign	3–5 years	Attempt to "climb up oneself" when trying to get up from ground due to pelvic muscle weakness ^[2]. The child uses hands to push off thighs and "walk" up their own body because hip extensors and knee extensors are too weak to stand from a squatting position
Waddling gait	3–6 years	Hip abductor weakness → inability to stabilise the pelvis during single-leg stance → the pelvis drops on the unsupported side (positive Trendelenburg sign) → compensatory trunk sway = waddling gait ^[3]
Tip-toe gait (toe-walking)	4–7 years	Tight Achilles tendon ^[3] — progressive contracture of the gastrocnemius-soleus complex due to fibrosis; the child compensates by walking on toes as dorsiflexion is restricted
Frequent falls	3–6 years	Proximal weakness and impaired balance
Progressive weakness → loss of ambulation	~9–12 years	Cumulative muscle destruction overwhelms regeneration; once quadriceps strength falls below antigravity function, independent walking becomes impossible
Upper limb weakness	After loss of ambulation	Shoulder girdle weakness follows hip girdle; eventually affects all voluntary muscles

Symptom	Typical Age	Pathophysiological Basis
Weak cough, recurrent chest infections	Early-mid teens	Diaphragm and intercostal muscle weakness → reduced vital capacity → ineffective cough → mucus retention → atelectasis and pneumonia
Sleep-disordered breathing, morning headaches	Mid-late teens	Nocturnal hypoventilation due to diaphragmatic weakness (worse in supine position as abdominal contents push against weak diaphragm) → CO₂ retention → morning headache
Progressive respiratory failure	Late teens–20s	FVC declines by ~6–10% per year after loss of ambulation; restrictive lung disease worsens with scoliosis (chest wall deformity further limits expansion)

Symptom	Typical Age	Pathophysiological Basis
Often asymptomatic initially	< 10 years	Cardiac dystrophin is absent but cardiac reserve compensates initially; children are also increasingly sedentary due to skeletal muscle weakness, masking exertional cardiac symptoms
Palpitations, fatigue	Teens	Fibrosis-related conduction abnormalities and early DCM
Symptoms of heart failure	Late teens–20s	Dilated cardiomyopathy ^[5] — progressive cardiomyocyte loss and fibrosis → LV dilation → reduced ejection fraction → systolic heart failure

Symptom	Prevalence	Pathophysiological Basis
Learning difficulties	~30%	Absence of brain dystrophin isoforms (Dp427c, Dp140, Dp71) disrupts synaptic function and neuronal circuitry
Mild mental impairment	Mean IQ ~85	^[2] Non-progressive — present from birth, does not worsen over time. Full-scale IQ averages ~1 SD below mean with verbal IQ more affected than performance IQ
ADHD, ASD, OCD features	20–30%	Dystrophin's role in GABAergic neurotransmission in the cerebral cortex and cerebellum
Emotional difficulties	Common	Combination of neurobiological factors and psychosocial impact of progressive disability

Symptom	Pathophysiological Basis
Constipation	Smooth muscle involvement + immobility + weak abdominal wall muscles → reduced bowel motility
Gastroparesis, pseudo-obstruction	Smooth muscle dystrophin deficiency affecting GI motility (rare but recognised in advanced disease)
Dysphagia	Pharyngeal and oesophageal muscle weakness in advanced disease → aspiration risk

7.2 Signs

Sign	Description	Pathophysiological Basis
Calf pseudohypertrophy	^[3] Calves appear enlarged and firm to palpation	Muscle fibres are replaced by fat and fibrotic tissue → increased bulk without increased strength. The term "pseudo" is used because it is not true muscle hypertrophy (which would imply increased contractile protein)
Gower's sign	^[2]^[3] Child turns prone, pushes up to hands-and-knees, then "walks" hands up legs to stand	Pelvic girdle and proximal lower limb weakness — the child cannot generate enough hip extensor torque to stand directly; uses upper limbs and trunk as a mechanical lever
Lordotic posture	Exaggerated lumbar lordosis when standing	Trunk and hip weakness ^[3] → the child hyperextends the lumbar spine to shift the centre of gravity behind the hip joint, allowing gravity to passively extend the hip and maintain upright posture
Positive Trendelenburg sign	Pelvis drops on the unsupported side when standing on one leg	Hip abductor (gluteus medius/minimus) weakness → cannot stabilise the pelvis
Muscle contractures	Progressive flexion contractures of hips, knees, ankles (equinovarus)	Fibrosis and fatty replacement shorten the muscle-tendon unit; postural compensations and reduced mobility accelerate contractures
Scoliosis	Progressive thoracolumbar scoliosis (develops after loss of ambulation)	Paraspinal muscle weakness + gravity + asymmetric muscle involvement → spinal curvature. Worsens restrictive lung disease
Global muscle wasting	Progressive loss of muscle bulk, initially masked by pseudohypertrophy and subcutaneous fat	Progressive fibrosis and fatty replacement of muscle tissue

Sign	Description	Pathophysiological Basis
Proximal > distal weakness	MRC grading shows weakness greatest in hip flexors, extensors, and shoulder girdle	Proximal muscles generate higher forces → more contraction damage. Symmetrical proximal muscle weakness is the hallmark of myopathy ^[3]
Normal or reduced reflexes (early = normal; late = reduced/absent)	Normal reflex, no fatigability (DDx: myasthenia gravis) ^[3]	Reflexes are preserved initially because the reflex arc (sensory nerve → spinal cord → motor nerve → NMJ) is intact; they diminish only when muscle mass is so depleted that it cannot contract in response to the stretch
No sensory loss	^[3] Sensation is entirely normal	Dystrophin is not expressed in sensory neurons; the pathology is purely in muscle (and partially in CNS for cognition, but not sensory pathways)
No fatigability	Unlike myasthenia gravis, strength does not fluctuate with repetition	The NMJ is normal in DMD; the problem is the muscle fibre itself, not neuromuscular transmission

Sign	Pathophysiological Basis
Resting tachycardia	Early compensatory response to declining cardiac output
S3 gallop	Reflects volume overload in the dilated, poorly contracting LV
Displaced apex beat	LV dilation shifts the apex laterally and inferiorly
Signs of heart failure (elevated JVP, peripheral oedema, hepatomegaly)	Dilated cardiomyopathy → systolic dysfunction → backward failure (congestion) + forward failure (reduced output) ^[5]

Sign	Pathophysiological Basis
Reduced chest expansion	Intercostal and diaphragm weakness + chest wall deformity (scoliosis)
Paradoxical abdominal breathing	Diaphragm weakness → during inspiration, the weak diaphragm is "sucked up" by negative intrathoracic pressure → abdomen moves inward (opposite of normal)
Weak cough	Expiratory muscle weakness → cannot generate sufficient intrathoracic pressure for effective cough

Stage	Age Range	Key Features
Pre-symptomatic	Birth–2 years	Elevated CK from birth; may have delayed walking
Early ambulatory	2–6 years	Gower's sign, toe-walking, waddling gait, frequent falls
Late ambulatory	6–12 years	Increasing difficulty walking, contractures developing
Early non-ambulatory	12–16 years	Wheelchair-dependent; upper limb function preserved; scoliosis develops
Late non-ambulatory	> 16 years	Progressive loss of upper limb function; cardiorespiratory decline; requires ventilatory support

Key Clinical Pearl

The "classic triad" that should make you think DMD in a young boy:

Calf pseudohypertrophy ^[3]
Gower's sign ^[2]^[3]
Tip-toe gait (tight Achilles) ^[3]

All three are mentioned in the GC lecture slides and senior notes as hallmark features of DMD/BMD dystrophinopathy.

DMD is a multi-system disease, not just a muscle disease:

System	Manifestation	Mechanism
Musculoskeletal	Weakness, contractures, scoliosis, osteoporosis, fractures	Muscle degeneration + immobility + steroid therapy
Cardiac	Dilated cardiomyopathy, arrhythmias, heart failure ^[5]	Cardiomyocyte dystrophin deficiency + fibrosis
Respiratory	Restrictive lung disease, respiratory failure	Respiratory muscle weakness + chest wall deformity
CNS	Intellectual disability, learning difficulties, ASD, ADHD	Brain dystrophin isoform deficiency
GI	Constipation, gastroparesis, dysphagia	Smooth muscle involvement + immobility
Bone	Osteoporosis, pathological fractures	Immobility + steroid use + muscle-bone crosstalk loss
Nutrition	Obesity (early) or malnutrition (late)	Reduced mobility + steroid appetite effects (early); dysphagia + catabolism (late)
Psychosocial	Depression, anxiety, social isolation	Progressive disability + dependency

High Yield Summary

Definition: DMD is an X-linked recessive progressive muscular dystrophy caused by out-of-frame mutations in the DMD gene (Xp21.2) → absent dystrophin → sarcolemma fragility → muscle fibre necrosis → fibrosis and fatty replacement
Epidemiology: ~1 in 3,500 live male births; most common lethal genetic disorder in childhood; 1/3 are de novo mutations
Key Gene: DMD gene — largest known human gene (2.4 Mb, 79 exons); ~60–70% deletions, ~10–15% duplications, ~20–25% point mutations
Pathophysiology: Absent dystrophin → DGC disassembly → sarcolemma tears with contraction → Ca²⁺ influx → calpain activation → necrosis → inflammation → satellite cell exhaustion → fibrosis + fat → progressive weakness
Reading Frame Rule: Out-of-frame = DMD (absent dystrophin); In-frame = BMD (reduced dystrophin) — ~90–95% predictive accuracy
Clinical triad: Calf pseudohypertrophy + Gower's sign + Tip-toe gait in a young boy
Motor progression: Onset ~2–5y → loss of ambulation ~9–12y → respiratory failure late teens → death late 20s–30s (with current care)
Key non-motor features: Dilated cardiomyopathy (universal), mild intellectual impairment (mean IQ ~85), scoliosis, osteoporosis
Investigations: Markedly elevated CK (50–100× ULN); genetic testing (dystrophin gene at Xp21.2); ECG/echo for dilated cardiomyopathy ^[3]^[5]
DMD vs. BMD: Same gene, different reading frame → DMD is severe (loss of ambulation < 13y, death 20s–30s); BMD is milder (ambulation beyond 15y, death 40–60y)

Active Recall - Duchenne Muscular Dystrophy (Overview, Pathophysiology, Clinical Features)

Differential Diagnosis of Duchenne Muscular Dystrophy

The differential diagnosis of DMD is essentially the differential of a young boy presenting with progressive proximal muscle weakness, elevated CK, and ± pseudohypertrophy. The key clinical task is to localise the lesion anatomically and then narrow the pathological differential.

Before diving into specific diagnoses, you must first determine where along the motor pathway the problem lies. This is the single most important step — it narrows your differential from hundreds of conditions to a manageable handful.

GC Lecture Slide — High Yield Anatomical Localisation

Anatomical differentials for weakness ^[8]:

Cerebrum (primary motor cortex, corona radiata, internal capsule)
Brainstem (cerebral peduncle, anterior pons, medulla oblongata)
Extrapyramidal system
Spinal cord / Anterior horn cells / Nerve root
Brachial plexus / Peripheral nerve
Neuromuscular junction
Muscle
Bone and joints / Metabolic / Functional

DMD is a muscle-level lesion — a primary myopathy. The clinical features that point to the muscle as the site of pathology are: symmetrical proximal weakness, no sensory loss, normal reflexes (early), no fatigability, pseudohypertrophy ^[3]^[8].

The table below summarises how to distinguish the anatomical level clinically:

Feature	UMN Lesion	Anterior Horn Cell	Peripheral Nerve	NMJ	Myopathy (DMD)
Distribution	Pyramidal pattern	Segmental / diffuse	Distal > proximal	Ocular, bulbar, proximal	Proximal > distal
Tone	↑ (spastic)	↓	↓	Normal	Normal or ↓
Reflexes	↑ (brisk)	↓ or absent	↓ or absent	Normal	Normal (early) → ↓ (late)
Fasciculations	No	Yes	Possible	No	No
Sensory loss	±	No	Yes (glove-stocking)	No	No
Fatigability	No	No	No	Yes	No
CK	Normal	Normal–mildly ↑	Normal	Normal	Markedly ↑

2. The Differential Diagnosis — Structured by Category

Once you have localised the lesion to the muscle, the differential is that of a myopathy in a child (or rarely young adult). The lecture slides and senior notes provide comprehensive frameworks:

GC Lecture Slide — Pathological Differentials for Lower Limb Weakness (High Yield)

Pathological differentials ^[7]^[8]:

Vascular
Infection (encephalitis, myelitis, old polio)
Neoplasm (brain tumour, paraneoplastic syndromes)
Degenerative (neurodegenerative disorders)
Inflammatory (GBS, vasculitic neuropathy, dermatomyositis)
Congenital (cerebral palsy, muscular dystrophy)
Autoimmune (myasthenia gravis, encephalitis, NMO)
Trauma / Toxins (neuropathy secondary to chemotherapy; myopathy secondary to statins)
Endocrine (B12 deficiency, diabetic neuropathy, myopathy secondary to endocrine causes — hyper/hypothyroidism, Cushing's)

2.1 Other Muscular Dystrophies (Genetic Myopathies — Most Important DDx)

These are the closest mimics of DMD because they share the hallmark of progressive, inherited muscle weakness with degeneration and regeneration on histology.

Feature	Distinguishing Point
Gene	Same DMD gene (Xp21.2) — this is the closest differential
Mutation	In-frame mutation → partial expression of dystrophin ^[2]
Inheritance	X-linked recessive (same)
Onset	Later (5–15 years vs. 2–5 years in DMD)
Severity	Milder — continue to ambulate beyond age 15 ^[2]
CK	Elevated but less so (5–20× ULN vs. 50–100× ULN)
Pseudohypertrophy	Present (same as DMD)
Cardiomyopathy	Present — may actually dominate the clinical picture in BMD (cardiac symptoms out of proportion to skeletal weakness)
Cognition	Usually normal (dystrophin isoform is partially present in brain too)
Death	Between 40–60 years ^[2]
Why this matters	The reading frame rule distinguishes DMD from BMD with ~90–95% accuracy. Genetic testing (MLPA or sequencing) confirms the diagnosis.

Clinical pearl: If a boy with suspected DMD is still walking independently beyond age 13, think BMD. If cardiomyopathy is disproportionately severe compared to limb weakness, think BMD.

Feature	Distinguishing Point
Inheritance	AD or AR ^[3] (not X-linked → can affect females)
Protein defect	Sarcoglycans, calpain, dysferlin, or other DGC-associated proteins
Distribution	Predominantly shoulder and hip muscles ^[9] — very similar to DMD
Pseudohypertrophy	May be present in some subtypes (especially sarcoglycanopathies)
CK	Moderately–markedly elevated
Key distinguishing feature	Can affect females; genetic testing shows normal dystrophin gene but mutations in other genes (e.g., SGCA, SGCB, CAPN3, DYSF). Some AR sarcoglycanopathies can be clinically indistinguishable from DMD

Feature	Distinguishing Point
Inheritance	AD ^[3]^[9]
Gene	D4Z4 repeat contraction on chromosome 4q35
Distribution	Predominantly facial, periscapular and humeral ^[1]^[9] — not hip girdle first
Key features	Facial weakness (can't whistle, can't bury eyelashes), scapular winging, foot drop. No pseudohypertrophy, no cardiomyopathy
CK	Normal or mildly elevated
Why it's different	The facial involvement and AD inheritance pattern immediately distinguish it from DMD

Feature	Distinguishing Point
Inheritance	XR or AD ^[3]
Proteins	Emerin (X-linked) or Lamin A/C (AD)
Key features	Early contractures (elbow flexion, Achilles, posterior neck) + humero-peroneal weakness + cardiac conduction defects (heart block, risk of sudden death). The contractures precede weakness, which is atypical for DMD

Feature	Distinguishing Point
Inheritance	AD ^[3]^[9]
Gene	Type 1: CTG trinucleotide repeat in DMPK gene; Type 2: CCTG tetranucleotide repeat in CNBP gene ^[3]
Distribution	Distal muscle weakness (unlike DMD which is proximal) ^[3]
Key features	Myotonia (hand grip, close eyes, percussion myotonia), myopathic facies (tented open mouth, elongated face, expressionless), frontal baldness, temporalis wasting, bilateral ptosis, cataract, cardiomyopathy ^[3]
Why it's different	Distal (not proximal) weakness + myotonia + multisystem features. No pseudohypertrophy.

GC Lecture Slide Classification — High Yield

Clinical classification of muscular dystrophies ^[1]:

Duchenne (DMD), Becker (BMD)
Facioscapulohumeral (FSHD)
Limb-girdle (LGMD)
Myotonic dystrophy (MyoD)

A. Spinal Muscular Atrophy (SMA)

This is the second most important differential in a floppy/weak child ^[4].

Feature	SMA	DMD
Inheritance	AR (SMN1 gene, chromosome 5q13) ^[4]	X-linked recessive
Lesion site	Anterior horn cells (LMN degeneration) ^[4]	Muscle
Onset	SMA Type I: < 6 months; Type II: 6–18 months; Type III: > 18 months	2–5 years
Weakness pattern	Generalised, proximal > distal, symmetrical	Proximal, symmetrical
Tone	Markedly hypotonic ("floppy baby")	Hypotonic but less severe
Reflexes	Absent (LMN lesion)	Normal early, decreased late
Fasciculations	Present (especially tongue)	Absent
CK	Normal or mildly elevated	Massively elevated
Pseudohypertrophy	Absent	Present
Cognition	Normal (bright, alert)	Mean IQ ~85

Key distinguishing point: Absent reflexes + fasciculations + normal CK → anterior horn cell disease (SMA). Preserved reflexes + no fasciculations + massively elevated CK + pseudohypertrophy → myopathy (DMD).

A. Myasthenia Gravis (Congenital or Juvenile)

Feature	Myasthenia Gravis	DMD
Mechanism	Antibodies to AChR (autoimmune) or congenital NMJ defect	Absent dystrophin
Key feature	Fatigability — weakness worsens with repetitive use and improves with rest ^[3]^[10]	No fatigability — weakness is constant
Distribution	Ocular (ptosis, diplopia) → bulbar → proximal limb	Proximal limb
CK	Normal	Massively elevated
Reflexes	Normal	Normal (early)
EMG	Decremental response on repetitive stimulation	Myopathic pattern
Response to anticholinesterase	Dramatic improvement	No improvement

Distinguished from myositis by presence of facial muscle weakness, normal muscle enzymes, characteristic EMG changes and AChR antibodies ^[10]

These are acquired — usually present later, with subacute onset, and often have systemic features.

A. Juvenile Dermatomyositis (JDM) / Polymyositis (PM)

Feature	JDM/PM	DMD
Onset	Subacute (weeks–months)	Insidious (years)
Inheritance	Not inherited (autoimmune)	X-linked recessive
Skin findings	Heliotrope rash (periorbital), Gottron's papules (knuckles) in DM	None
Pain/tenderness	Present ^[9]^[2] — tenderness/pain indicates inflammatory or metabolic muscle diseases ^[2]	Absent (painless)
CK	Elevated, usually > 10× ULN, may be > 50–100× ULN ^[11]	50–100× ULN (higher at baseline)
Autoantibodies	Anti-Jo-1 (myositis-specific), anti-Mi2, anti-MDA5 ^[11]	Negative
Muscle biopsy	Endomysial lymphocytic infiltrates (PM), perimysial/perivascular infiltrates (DM), perifascicular atrophy (DM) ^[11]	Dystrophic changes — necrosis, regeneration, fibrosis, fatty replacement. No inflammation
Response to steroids	Yes (this is a major diagnostic clue)	No

Important Distinction

A common exam trap: both DMD and inflammatory myopathies cause markedly elevated CK and proximal weakness. The key distinguishers are: (1) age and time course — DMD is a boy aged 2–5 with gradual onset over years; JDM is subacute over weeks–months; (2) skin rash in DM; (3) family history and sex in DMD; (4) response to steroids in inflammatory myopathy; (5) autoantibodies and biopsy pattern.

2.5 Metabolic and Endocrine Myopathies

Feature	Metabolic Myopathy	DMD
Examples	Pompe disease (acid maltase deficiency), McArdle disease (myophosphorylase deficiency), CPT II deficiency	—
Key features	Exercise intolerance, myoglobinuria (dark urine after exercise), cramps, +/- resting weakness	Progressive weakness regardless of exercise
CK	Normal at rest, elevated after exercise (McArdle) or persistently elevated (Pompe)	Persistently elevated
Special tests	Ischemic lactate test for glycolytic enzyme deficiency; exercise lactate for mitochondrial myopathy ^[9]	Genetic testing

Feature	Congenital Myopathies	DMD
Examples	Central core disease, nemaline myopathy, myotubular myopathy	—
Onset	Birth or early infancy	2–5 years
Progression	Non-progressive or very slowly progressive ^[2]	Progressive ^[1]
CK	Normal or mildly elevated	Massively elevated
Biopsy	Characteristic structural abnormalities (central cores, nemaline rods, central nuclei)	Dystrophic changes

These are upper motor neuron or chromosomal causes — they produce truncal hypotonia but not true weakness in the way DMD does ^[4]:

Condition	Key Distinguishing Features
Cerebral palsy	UMN signs (spasticity, hyperreflexia, Babinski), often asymmetric, history of perinatal insult
Down syndrome (Trisomy 21)	Hypotonia without progressive weakness, dysmorphic features, normal CK
Prader-Willi syndrome	Severe neonatal hypotonia, feeding difficulties → obesity, hypogonadism, intellectual disability, small hands/feet

A. Charcot-Marie-Tooth Disease (CMT / Hereditary Motor and Sensory Neuropathy)

Feature	CMT	DMD
Lesion	Peripheral nerve (demyelinating or axonal)	Muscle
Distribution	Distal — peroneal muscle atrophy → "inverted champagne bottle" legs, pes cavus	Proximal
Sensory loss	Present (glove-stocking)	Absent
Reflexes	Absent	Normal (early)
CK	Normal	Massively elevated
NCS	Slow conduction velocity (demyelinating type)	Normal

Condition	Why It's in the DDx	Key Distinguishing Feature
Mitochondrial myopathy (e.g., CPEO, Kearns-Sayre)	Progressive weakness + multi-organ involvement	External ophthalmoplegia, ptosis, retinitis pigmentosa, cardiac conduction block; ragged red fibres on biopsy; maternal inheritance
Rhabdomyolysis ^[6]	Massively elevated CK	Acute onset, myoglobinuria (dark urine), renal failure; not progressive
Periodic paralysis ^[6]	Episodic weakness	Episodic (not progressive), associated with potassium shifts, normal between attacks
Channelopathies ^[6]	Episodic weakness, myotonia	Sodium/chloride/potassium channel mutations; episodic, not progressive

Diagnosis	Inheritance	Onset	Distribution	CK	Reflexes	Sensory	Unique Feature
DMD	XR	2–5y	Proximal	50–100×	Normal→↓	No	Pseudohypertrophy, Gower's
BMD	XR	5–15y	Proximal	5–20×	Normal→↓	No	Milder, ambulate > 15y
SMA	AR	0–18m	Proximal	Normal–mild ↑	Absent	No	Fasciculations, tongue
LGMD	AD/AR	Variable	Proximal	Moderate–high	Normal→↓	No	Can affect females
FSHD	AD	10–30y	Face, scapula	Normal–mild ↑	Normal	No	Facial weakness
MyD	AD	15–40y	Distal	Normal–mild ↑	Normal	No	Myotonia, cataracts
JDM/PM	Acquired	Variable	Proximal	High (> 10×)	Normal	No	Rash, pain, autoAb
MG	Acquired	Variable	Ocular→proximal	Normal	Normal	No	Fatigability
CMT	AD/AR/XR	Childhood	Distal	Normal	Absent	Yes	Pes cavus
Metabolic	AR	Variable	Proximal	Variable	Normal	No	Exercise intolerance

High Yield Summary — Differential Diagnosis of DMD

First step: Localise the lesion — DMD is a muscle-level problem (proximal weakness, no sensory loss, no fasciculations, markedly elevated CK, no fatigability)
Closest differential: BMD — same gene, same protein, but in-frame mutation → partial dystrophin → milder course (ambulate > 15y, death 40–60y). Distinguished by genetic testing
Most important non-muscle DDx in a floppy child: SMA — anterior horn cell disease, AR inheritance, absent reflexes, fasciculations, normal CK
Most important NMJ DDx: Myasthenia gravis — distinguished by fatigability, normal CK, response to anticholinesterase, AChR antibodies
Most important acquired myopathy DDx: Inflammatory myopathy (JDM/PM) — subacute onset, pain/tenderness, rash (DM), autoantibodies, responds to steroids
Always exclude: Endocrine myopathy (thyroid, Cushing's), drug-induced myopathy (especially steroids in treated DMD patients), metabolic myopathy, electrolyte disturbance
Clinical features of myopathy: motor involvement only, no sensory and rarely affects sphincters ^[2]^[9]
CK levels guide DDx: 200–1000 IU/L for most myopathies; > 1000 for inflammatory myopathies, rhabdomyolysis, DMD/BMD ^[9]

Active Recall - Differential Diagnosis of DMD

References

^[1] Lecture slides: GC 056. Generalized muscle weakness.pdf (p24 — Muscular dystrophies classification) ^[2] Senior notes: Ryan Ho Neurology.pdf (p191–192 — Diseases of Muscles, X-linked Dystrophinopathies) ^[3] Senior notes: Maksim Medicine Notes.pdf (p276 — Myopathy section, muscular dystrophy features and DDx table) ^[4] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p535 — SMA and floppy infant DDx) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (p5 — Familial DCM, neuromuscular causes) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p706 — Differential diagnosis of myopathies table) ^[7] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (p38 — Differential Diagnosis of Myopathy) ^[8] Lecture slides: CFB_Neuro clinical skills demonstration_01.08.22_file to students.pdf (p7–8 — Anatomical and pathological differentials) ^[9] Senior notes: Adrian Lui Pediatrics Notes.pdf (p143–145 — Myopathy approach, CK levels, muscular dystrophies) ^[10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1757 — DDx of inflammatory myopathy vs MG vs muscular dystrophy) ^[11] Senior notes: Ryan Ho Rheumatology.pdf (p92 — Inflammatory myopathy diagnosis and biopsy)

Diagnostic Criteria, Algorithm, and Investigations for Duchenne Muscular Dystrophy

1. Diagnostic Criteria

Unlike many rheumatological or neurological conditions, DMD does not have a formal "points-based" diagnostic criteria set (like ACR/EULAR criteria for SLE or the McDonald criteria for MS). Instead, the diagnosis is established through a combination of clinical suspicion and confirmatory genetic testing. The diagnostic approach is best understood as a stepwise algorithm.

A diagnosis of DMD is established when ALL of the following are met:

Criterion	Detail
1. Clinical phenotype	Progressive proximal muscle weakness in a male child, onset before age 5, with characteristic features (Gower's sign, calf pseudohypertrophy, tip-toe gait)
2. Markedly elevated CK	Serum CK typically 50–100× ULN (often > 10,000 IU/L)
3. Genetic confirmation	Identification of a pathogenic mutation in the DMD gene (Xp21.2) that is predicted to abolish functional dystrophin production (out-of-frame deletion/duplication or nonsense/frameshift point mutation)
4. OR Muscle biopsy confirmation	If genetic testing is inconclusive: absent or < 3% dystrophin on immunohistochemistry / Western blot of skeletal muscle biopsy

Key Principle

Diagnosis is usually based on genetics ^[9]. In the modern era, genetic testing has largely replaced muscle biopsy as the primary confirmatory test. Biopsy is now reserved for cases where genetic testing is inconclusive or where the clinical phenotype is atypical.

3. Investigation Modalities — Detailed Breakdown

The investigations for DMD serve three purposes:

Confirm the diagnosis (CK, genetic testing, ± biopsy)
Assess multi-system involvement (cardiac, respiratory, skeletal, cognitive)
Exclude differentials (NCS/EMG, autoantibodies, endocrine tests)

3.1 Blood Tests

GC & Medicine Lecture Slides — CK in Myopathy (High Yield)

CK: released from damaged muscle membrane ^[2]^[9]

200–1000 IU/L: most myopathies, SMA/MND, rigorous exercise, IM injection, after EMG/muscle biopsy, tonic-clonic seizures, acute MI, statin/neuroleptic-induced ^[2]^[9]
1000–10,000 IU/L: inflammatory myopathies, acute rhabdomyolysis, DMD/BMD ^[2]^[9]

Parameter	Detail
What is CK?	Creatine kinase (CK, also called creatine phosphokinase/CPK) catalyses the conversion of creatine + ATP → phosphocreatine + ADP. It is abundant in skeletal muscle (CK-MM isoform), cardiac muscle (CK-MB), and brain (CK-BB)
Why is it elevated in DMD?	The sarcolemma is inherently leaky due to absent dystrophin → CK continuously leaks from damaged myofibres into the bloodstream. This occurs even at rest, unlike exercise-induced CK elevation in normal individuals
Typical level in DMD	50–100× ULN, often 10,000–20,000+ IU/L. Can exceed 30,000 IU/L in early disease
Timing	Elevated from birth — even in the pre-symptomatic phase. This is why CK-based newborn screening is feasible
Trend over time	CK peaks in early childhood (age 2–5) then gradually declines as muscle mass is replaced by fat and fibrosis (less muscle = less CK to leak). By the wheelchair-bound stage, CK may be only mildly elevated
Isoform	Predominantly CK-MM (skeletal muscle). CK-MB may also be mildly elevated (from regenerating muscle fibres that re-express embryonic isoforms — not necessarily indicating cardiac damage)

Clinical pearl: A "normal" CK in a boy with progressive proximal weakness makes DMD extremely unlikely. Conversely, a markedly elevated CK in the absence of rhabdomyolysis or vigorous exercise in a young boy should prompt genetic testing for DMD.

Enzyme	Relevance to DMD
ALT (alanine aminotransferase)	ALT is present in both liver AND skeletal muscle. In DMD, ALT is elevated due to muscle damage — this is frequently misinterpreted as liver disease, leading to unnecessary hepatology referrals and even liver biopsies. Always check CK before attributing elevated ALT to liver disease in a young boy
AST (aspartate aminotransferase)	Same principle as ALT — elevated due to muscle source
LDH (lactate dehydrogenase)	Non-specific marker of tissue damage; elevated in DMD
Aldolase	Another muscle enzyme; elevated in active myopathy

Elevated muscle enzymes (CK + LDH + AST + ALT + Aldolase) indicate muscle damage ^[6]

Classic Exam Trap

A 4-year-old boy is referred to hepatology for persistently elevated ALT and AST. He has no jaundice, normal bilirubin, and normal GGT. Think DMD before liver disease! GGT is liver-specific (not found in muscle) — if GGT is normal but ALT/AST are elevated, the transaminase elevation is likely from muscle, not liver. Check CK immediately.

Test	Purpose	Expected in DMD
TFT	Rule out thyroid myopathy ^[2]^[9]	Normal
ACTH/DST	Rule out Cushing's myopathy ^[2]^[9]	Normal
ANA, anti-ENA, anti-Jo-1	Rule out inflammatory myopathy (myositis-specific autoantibodies) ^[2]^[9]	Negative
Electrolytes (K⁺, Ca²⁺, PO₄³⁻, Na⁺)	Rule out electrolyte-related myopathy	Normal
Lactate	Ischaemic lactate for glycolytic enzyme deficiency; exercise lactate for mitochondrial myopathy ^[2]^[9]	Normal
CBC, inflammatory markers	Rule out infection, inflammation	Usually normal

3.2 Genetic Testing (The Definitive Investigation)

High Yield — Genetic Testing is the Gold Standard

Genetic testing (dystrophin – Xp21.2) is listed as the key investigation for muscular dystrophy ^[3]. Diagnosis is usually based on genetics ^[9]. In 2026, genetic testing has replaced muscle biopsy as the first-line confirmatory test for suspected DMD.

Test	Detail
MLPA (Multiplex Ligation-dependent Probe Amplification)	The standard first-line genetic test. Detects deletions and duplications of individual exons across all 79 exons of the DMD gene. Quick, cost-effective, widely available
CGH array (Comparative Genomic Hybridisation)	Alternative to MLPA with similar sensitivity for copy number variants
Detection rate	Identifies the causative mutation in ~70–80% of DMD cases (because deletions account for 60–70% and duplications for 10–15%)
Key output	Identifies which exons are deleted/duplicated → reading frame analysis determines whether the mutation is out-of-frame (DMD) or in-frame (BMD)

DMD gene mutations: ~30–60% deletions ^[9]. Two deletion hotspots: exons 2–20 and exons 44–55.

Test	Detail
Next-generation sequencing (NGS) / Sanger sequencing	If MLPA is negative, full sequencing of the DMD gene is performed to detect point mutations, small insertions/deletions, and splice-site mutations
Detection rate	Identifies mutations in an additional ~20–25% of cases
Why second-line?	More expensive and time-consuming; not needed if MLPA already identifies the mutation

Test	Indication
RNA analysis (mRNA studies from muscle)	For deep intronic mutations or unusual splice-site variants not detected by genomic DNA sequencing
Long-read sequencing (e.g., PacBio, Oxford Nanopore)	Emerging technology for detecting complex structural variants, deep intronic mutations

The single most important output of genetic testing is determining the reading frame:

Mutation Effect	Reading Frame	Dystrophin	Phenotype
Frameshift (deletion of exons that shift the reading frame)	Out-of-frame	Absent (premature stop codon → truncated, non-functional, degraded)	DMD
In-frame (deletion of exons preserving the reading frame)	In-frame	Reduced but partially functional (internally deleted but stable)	BMD
Nonsense (premature stop codon)	Out-of-frame equivalent	Absent	DMD

The reading frame rule applies ~90–95% of the time. Exceptions exist (e.g., some in-frame deletions disrupting critical domains can cause DMD-like severity).

3.3 Neurophysiology (NCS and EMG)

NCS/EMG: to differentiate between myogenic and neurogenic diseases ^[2]^[9]

Parameter	Finding in DMD	Interpretation
Motor NCS	Normal conduction velocities, normal or mildly reduced compound muscle action potential (CMAP) amplitude	The peripheral nerve is intact in DMD. Slight reduction in CMAP amplitude may occur late due to severe muscle loss (fewer muscle fibres generating the response)
Sensory NCS	Normal	No sensory loss in myopathy — sensory nerves are unaffected
Purpose	To rule out neuropathy ^[3] — if NCS shows slowed conduction velocity or absent sensory potentials, think neuropathy (e.g., CMT, GBS), not myopathy

Parameter	Finding in DMD	Interpretation
Motor unit potential (MUP) morphology	Polyphasic, low-amplitude, short-duration motor unit potentials ^[3]	This is the classic myopathic pattern. Why? In myopathy, individual muscle fibres within a motor unit are destroyed, so fewer fibres contribute to each MUP → smaller amplitude, shorter duration. The polyphasic pattern reflects desynchronised firing of the remaining fibres
Recruitment	Early recruitment (full interference pattern at low force)	Because individual motor units are weak (fewer fibres per unit), the CNS compensates by recruiting many motor units simultaneously even at low force levels
Spontaneous activity	Fibrillation potentials and positive sharp waves may be present	Reflects actively degenerating muscle fibres — these become denervated-like as they lose their connection to the sarcolemma-DGC complex and become electrically unstable

Myopathic vs. Neurogenic EMG Pattern

Feature	Myopathic (DMD)	Neurogenic (SMA, MND)
MUP amplitude	Low	High (large, "giant" MUPs due to reinnervation)
MUP duration	Short	Long
Recruitment	Early (full pattern at low force)	Reduced (incomplete pattern)
Fasciculations	Absent	Present

This distinction is critical for separating DMD (myopathy) from SMA (anterior horn cell disease).

In practice: EMG is uncomfortable and invasive, especially in children. EMG is NOT commonly performed in children and should only be used when diagnosis is uncertain ^[6]. If CK is massively elevated and genetic testing confirms a DMD gene mutation, EMG is unnecessary.

3.4 Muscle Biopsy

Muscle biopsy: at muscle that is most affected ^[2]^[9]

Muscle biopsy was historically the gold standard for DMD diagnosis but has been largely supplanted by genetic testing. It is now reserved for specific indications:

Finding	Description	Pathophysiological Basis
Variation in fibre size	Mix of hypertrophied and atrophic fibres	Cycles of degeneration (atrophic) and compensatory hypertrophy of surviving fibres
Rounded fibres	Loss of normal polygonal fibre shape	Regenerating fibres are round; fibrotic tissue distorts architecture
Central nuclei	Nuclei move from their normal peripheral position to the centre of the fibre	A hallmark of regeneration — newly formed/regenerating myofibres have central nuclei (mimicking embryonic muscle)
Necrotic fibres	Hypercontracted, opaque, invaded by macrophages	Active sarcolemmal damage → calcium influx → hypercontraction → necrosis
Endomysial fibrosis	Increased connective tissue between individual muscle fibres	Chronic damage → fibroblast activation → collagen deposition
Fatty infiltration	Adipocyte replacement of muscle tissue	End-stage replacement — explains pseudohypertrophy
Inflammation	Mild — scattered macrophages and T cells around necrotic fibres	Secondary to necrosis (not a primary inflammatory myopathy) — this is a key distinguishing feature from polymyositis/dermatomyositis, where inflammation is primary

Test	DMD Finding	BMD Finding	Normal
Dystrophin IHC (on frozen section)	Absent staining on sarcolemma (< 3% fibres positive)	Patchy, reduced staining (some fibres positive, some negative, some faintly positive)	Uniform, bright sarcolemmal staining
Western blot	Absent or < 3% of normal dystrophin band	Reduced quantity and/or abnormal molecular weight (truncated band)	427 kDa band at normal intensity

Immunohistochemical classification: Dystrophinopathy (DMD, BMD) ^[9]. The dystrophin stain on biopsy was historically the primary way to classify dystrophinopathies before the genetic era.

3.5 Cardiac Investigations

Cardiac involvement is universal in DMD and a major cause of morbidity and mortality. Cardiac screening should begin at diagnosis and be repeated regularly.

Finding	Prevalence	Explanation
Resting sinus tachycardia	Very common	Autonomic dysfunction + early compensation for declining cardiac output
Tall R waves in V1–V2	~70%	Posterolateral LV fibrosis → loss of electrical forces posteriorly → relative increase in anterior forces (R wave in V1)
Deep Q waves in lateral leads (I, aVL, V5–V6)	~50%	Lateral and posterolateral wall fibrosis mimics a prior lateral MI pattern
Short PR interval	Variable	Possibly due to enhanced AV nodal conduction or atrial involvement
Conduction abnormalities	Late disease	Bundle branch block, atrial/ventricular arrhythmias

ECG / echo: detect cardiac muscle involvement ^[2]^[3]^[9]

Finding	Significance
Reduced LVEF (< 50%)	Systolic dysfunction from progressive cardiomyocyte loss and fibrosis
LV dilation	Dilated cardiomyopathy ^[5] — LV end-diastolic diameter increases as the ventricle remodels
Regional wall motion abnormalities	Posterolateral wall hypokinesis is often the earliest echo abnormality (correlates with the predilection of fibrosis for this region)
Functional mitral regurgitation	LV dilation → annular dilation → incomplete mitral leaflet coaptation
Screening protocol	Baseline echo at diagnosis, then annually from age 6–10, then every 6 months if abnormalities detected

Finding	Significance
Late gadolinium enhancement (LGE) in posterolateral LV wall	LGE pattern → indicating fibrosis ^[5]. This is the most sensitive early marker of cardiac involvement — detectable before echo abnormalities or symptoms
Pattern	Subepicardial or mid-wall (distinguishes from ischaemic cardiomyopathy which is subendocardial)
Reduced LVEF	Quantified more accurately than echo
When to use	When echo is suboptimal (poor windows due to scoliosis/body habitus) or for early detection of subclinical disease

Investigation	Findings in DMD	Interpretation
Spirometry (FVC)	Progressively declining FVC — typically peaks around age 10–12, then declines ~6–10% per year	Restrictive pattern: reduced FVC and TLC with preserved FEV₁/FVC ratio. Caused by respiratory muscle weakness + chest wall deformity (scoliosis)
Peak cough flow (PCF)	Reduced (< 270 L/min = ineffective cough)	Expiratory muscle weakness → inability to generate sufficient intrathoracic pressure. Critical threshold for aspiration risk
Oximetry / capnography	Nocturnal desaturation, elevated end-tidal CO₂	Nocturnal hypoventilation due to diaphragmatic weakness (worse supine) → CO₂ retention
Polysomnography	Sleep-disordered breathing, obstructive and central apnoeas	Pharyngeal muscle weakness + diaphragmatic weakness
Sitting vs. supine FVC	> 20% drop in supine FVC compared to sitting	Indicates significant diaphragmatic weakness (abdominal contents push against weak diaphragm in supine position)

Investigation	Purpose	Expected Findings
DEXA scan	Assess bone mineral density	Osteopenia/osteoporosis due to immobility, reduced muscle-bone crosstalk, and corticosteroid use
Spinal X-ray	Monitor for scoliosis	Progressive thoracolumbar scoliosis (develops after loss of ambulation — paraspinal muscle weakness + gravity + asymmetric muscle loss)
Vitamin D and calcium levels	Assess bone health and guide supplementation	Frequently low — contribute to osteoporosis and fracture risk

Investigation	Purpose	Expected Findings
Psychometric testing (IQ)	Assess cognitive function	Mean IQ ~85 (1 SD below mean); verbal IQ more affected than performance IQ
Developmental screening	Early identification of learning difficulties, ASD, ADHD	~30% have learning difficulties; increased prevalence of ASD and ADHD
Behavioural screening	Identify comorbid psychiatric conditions	Anxiety, depression, OCD

Assessment	Purpose
Timed function tests	10-metre walk/run time, time to rise from floor, time to climb 4 stairs — objective, reproducible measures of motor function used to track progression and treatment response
6-minute walk test (6MWT)	Total distance walked in 6 minutes — primary endpoint in many DMD clinical trials
North Star Ambulatory Assessment (NSAA)	17-item functional scale designed specifically for ambulatory DMD boys — scored 0–34
Brooke Upper Extremity Scale	Functional grading of upper limb function (used in non-ambulatory phase)
Vignos Lower Extremity Scale	Functional grading of lower limb function

Category	Investigation	Key Finding in DMD	When to Order
Blood	CK	50–100× ULN (> 10,000 IU/L)	First-line at clinical suspicion
	ALT, AST	Elevated (muscle source)	Routine — beware liver disease misdiagnosis
	LDH, aldolase	Elevated	Supportive
Genetic	MLPA	Exon deletion/duplication	First-line confirmatory test
	Full DMD gene sequencing	Point mutation / small indel	If MLPA negative
	RNA analysis	Deep intronic / splice-site variants	If all genomic testing negative
Neurophysiology	NCS	Normal (rules out neuropathy)	If diagnosis uncertain
	EMG	Myopathic: polyphasic, low-amplitude, short-duration MUPs	If diagnosis uncertain
Biopsy	Muscle biopsy + dystrophin IHC	Absent dystrophin, dystrophic changes	If genetic testing inconclusive
Cardiac	ECG	Tall R in V1, deep Q lateral, sinus tachycardia	At diagnosis, then annually
	Echocardiography	Reduced LVEF, LV dilation → DCM	At diagnosis, then annually from age 6
	Cardiac MRI	LGE posterolateral LV wall	If echo suboptimal or for early detection
Respiratory	Spirometry (FVC)	Restrictive pattern, progressive FVC decline	Annually from age 5–6
	Peak cough flow	Reduced (< 270 L/min = ineffective)	Annually
	Nocturnal oximetry/capnography	Desaturation, ↑CO₂	When FVC < 50% predicted
MSK/Bone	DEXA, vitamin D	Osteopenia/osteoporosis	Baseline, then regularly
	Spinal X-ray	Scoliosis	After loss of ambulation
Cognitive	IQ testing, developmental screen	Mean IQ ~85, learning difficulties	At diagnosis

This is an important component of the workup, especially if the presentation is atypical ^[2]^[7]^[9]:

Investigations for lower limb weakness — as per clinical suspicion ^[7]:

Purpose	Tests
Basic blood tests	CBC, inflammatory markers, basic biochemistry, vitamin B12, TFT, lipid profile, glucose, creatine kinase ^[7]
Autoimmune markers	ANA, anti-dsDNA, anti-ENA, C3, C4, ANCA, anti-AChR Ab, anti-AQP4 Ab, anti-HMG CoA reductase Ab ^[7]
Genetic studies	^[7] — DMD gene analysis, SMA gene (SMN1 deletion), other myopathy gene panels
Imaging	Joints – XR, CT; Brain – CT/MRI; Spine – XR, MRI ^[7]
Neurophysiological tests	Nerve conduction studies, Electromyography ^[7]
Further blood tests	Tumour markers and paraneoplastic antibodies ^[7]
Lumbar puncture	Total cell count, protein/glucose, microbiological workup, cytology, oligoclonal bands ^[7] — rarely needed for DMD but indicated if inflammatory/infectious CNS cause suspected

High Yield Summary — Diagnosis and Investigations of DMD

Diagnostic pathway: Clinical suspicion (young boy + proximal weakness + pseudohypertrophy) → CK (markedly elevated) → Genetic testing (MLPA first → sequencing if needed) → ± muscle biopsy (if genetic testing inconclusive) ^[9]
CK is elevated from birth, peaks 50–100× ULN in early childhood, then gradually declines as muscle is replaced by fat/fibrosis
CK ranges: 200–1000 = most myopathies; 1000–10,000+ = inflammatory myopathy, rhabdomyolysis, DMD/BMD ^[2]^[9]
Genetic testing is the gold standard: MLPA detects ~70–80% of mutations (deletions/duplications); full sequencing catches the remaining ~20–25% (point mutations)
Reading frame rule: out-of-frame = DMD (absent dystrophin); in-frame = BMD (reduced dystrophin) — ~90–95% predictive
EMG shows myopathic pattern: polyphasic, low-amplitude, short-duration motor unit potentials ^[3]. NCS is normal (rules out neuropathy)
Muscle biopsy (when needed): dystrophic changes + absent dystrophin on IHC confirms DMD; biopsy is done on weak but not atrophied muscle ^[11]
Cardiac screening is mandatory: ECG + echo at diagnosis, then annually. Cardiac MRI with LGE detects subepicardial posterolateral LV fibrosis ^[5]
Respiratory monitoring: annual spirometry (FVC), peak cough flow, nocturnal oximetry when FVC < 50%
Watch for the ALT/AST trap: elevated "liver enzymes" in a young boy may be from muscle → always check CK and GGT
Severe skeletal muscle disease (DMD/rhabdomyolysis) can cause true false positive troponin elevation ^[12]

Active Recall - Diagnosis and Investigations of DMD

References

^[2] Senior notes: Ryan Ho Neurology.pdf (p191–192 — Myopathy investigations, CK levels, NCS/EMG, muscle biopsy) ^[3] Senior notes: Maksim Medicine Notes.pdf (p276 — Myopathy investigations, EMG findings, key investigations table) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (p5, p7 — Familial DCM, cardiac investigations including echo and CMR) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p708–709 — Muscle enzymes, muscle biopsy, EMG in myopathy) ^[7] Lecture slides: Neurology- Two cases of lower limb weakness.pdf (p22–25 — Investigations for lower limb weakness) ^[9] Senior notes: Adrian Lui Pediatrics Notes.pdf (p134, p143–144 — Approach to generalised weakness investigations, CK levels, DMD diagnosis) ^[11] Senior notes: Ryan Ho Rheumatology.pdf (p92 — Muscle biopsy technique, EMG triad, MRI in myositis) ^[12] Lecture slides: General Clerkship_Introduction to CVS Investigations_2026 Yiu (2 Feb 2026).pdf (p11 — Alternative causes of elevated troponin, DMD as true false positive)

Management of Duchenne Muscular Dystrophy

3. Disease-Modifying Therapies

3.1 Corticosteroids — The Cornerstone

This is the single most important pharmacological intervention in DMD. Every student must understand why steroids work and what they do.

Corticosteroids work through multiple mechanisms in DMD — the exact mechanism is debated, but likely includes:

Mechanism	Explanation
Anti-inflammatory	Suppress the chronic inflammatory response to ongoing muscle necrosis (reduce macrophage and T-cell infiltration) → slow fibrosis
Membrane stabilisation	May directly stabilise the sarcolemma, reducing contraction-induced damage
Upregulation of utrophin	Utrophin is a dystrophin homologue normally expressed at the NMJ. Steroids may upregulate utrophin expression, partially compensating for absent dystrophin
Anti-fibrotic	Reduce TGF-β–driven fibroblast activation → slow fibrotic replacement of muscle
Calcium homeostasis	May reduce intracellular calcium overload

Steroid therapy: ↑motor function, strength, pulmonary function, ↓risk of scoliosis ^[2]^[9]

Benefit	Detail
Prolonged ambulation	Delays loss of independent walking by 2–5 years (from ~9–10 years to ~12–14 years)
Improved motor function	Increased muscle strength, improved timed function tests, improved 6MWT distance
Improved pulmonary function	Higher peak FVC and slower rate of FVC decline → delays need for ventilatory support
Reduced scoliosis	Lower incidence and severity of progressive scoliosis (possibly by maintaining trunk strength for longer)
Improved cardiac outcomes	Some evidence suggests delayed onset of cardiomyopathy
Improved survival	Corticosteroid-treated patients live longer than untreated historical controls (median survival now into late 20s–30s+)

Drug	Dose	Notes
Prednisolone	0.75 mg/kg/day (daily)	Standard regimen. Can also be given as intermittent regimens (e.g., 10 days on / 10 days off, or weekend-only high dose) to mitigate side effects
Deflazacort	0.9 mg/kg/day (daily)	An oxazoline derivative of prednisolone. May have a slightly better side-effect profile (less weight gain) but is more expensive. FDA-approved for DMD

This is critical because corticosteroid side effects significantly impact quality of life and create additional management challenges:

Side Effect	Mechanism	Management
Weight gain / obesity	Increased appetite + metabolic effects (insulin resistance, lipogenesis) + reduced activity	Dietary counselling from initiation; caloric restriction; involve dietitian early
Growth retardation	Suppression of GH axis + direct effects on growth plates	Monitor height velocity; deflazacort may cause less growth suppression than prednisolone
Osteoporosis and fractures	Decreased osteoblast activity + increased osteoclast activity + reduced calcium absorption + reduced muscle-bone loading	Vitamin D and calcium supplementation; DEXA monitoring; bisphosphonates if vertebral fractures occur
Cushingoid features	Redistribution of fat (moon face, buffalo hump, truncal obesity)	Cosmetically distressing but not dangerous; counselling and support
Behavioural changes	CNS effects of corticosteroids (irritability, mood swings, hyperactivity, insomnia)	Dose adjustment; behavioural support; consider deflazacort
Immunosuppression	Suppression of cell-mediated and humoral immunity	Ensure vaccinations are up to date BEFORE starting steroids (especially live vaccines — varicella); annual influenza and pneumococcal vaccination; low threshold for investigating infections
Adrenal suppression	Chronic exogenous corticosteroid suppresses HPA axis → adrenal atrophy	Never abruptly stop steroids — risk of adrenal crisis. Stress-dose steroids during illness/surgery. Wear medical alert bracelet
Cataracts	Direct effect on lens crystallin proteins → posterior subcapsular cataracts	Annual ophthalmological screening
Glucose intolerance / diabetes	Insulin resistance, hepatic gluconeogenesis	Monitor fasting glucose/HbA1c regularly
Delayed puberty	Suppression of gonadotropins	Monitor pubertal development; endocrine referral if needed
GI effects	Increased gastric acid, reduced mucosal protection	Consider gastroprotection (PPI/H2 blocker) if symptomatic

Exam-Relevant Clinical Pearl

Steroid myopathy vs. DMD progression: A boy on long-term corticosteroids who worsens — is it disease progression or drug-induced myopathy? Steroid myopathy typically causes proximal weakness without CK elevation (because steroid myopathy is a Type II fibre atrophy, not a necrotising process). In DMD progression, CK may still be elevated (though it trends down over time). The distinction is difficult and may require dose adjustment and clinical observation.

3.2 Mutation-Specific (Genetic/Molecular) Therapies

These represent the new frontier of DMD treatment and are mutation-specific — meaning they only work for patients with particular types of mutations. This is the essence of precision medicine in DMD.

Aspect	Detail
Concept	Use antisense oligonucleotides (ASOs) to "skip" a specific exon during pre-mRNA splicing → restore the reading frame → convert an out-of-frame mutation (DMD) into an in-frame mutation (BMD-like) → produce a truncated but partially functional dystrophin
Analogy	Imagine a sentence: "THE FAT CAT SAT." If you delete "FAT" (in-frame), the sentence still makes sense: "THE CAT SAT." But if you delete "FA" (out-of-frame), the sentence becomes: "THE TCA TSA T" — nonsense. Exon skipping removes a whole "word" (exon) to restore the reading frame.
Why BMD-like?	The resulting protein is internally deleted (missing the skipped exon's domain) but retains the N-terminal and C-terminal domains → can still partially function as a molecular link between cytoskeleton and ECG

Approved ASO drugs (as of 2026):

Drug	Target	Mutation Amenable	Estimated % of DMD Patients
Eteplirsen (Exondys 51)	Exon 51 skipping	Deletions amenable to exon 51 skip (e.g., exons 45–50, 48–50, 49–50, 50, 52)	~13%
Golodirsen (Vyondys 53)	Exon 53 skipping	Deletions amenable to exon 53 skip	~8%
Viltolarsen (Viltepso)	Exon 53 skipping	Same as golodirsen	~8%
Casimersen (Amondys 45)	Exon 45 skipping	Deletions amenable to exon 45 skip	~8%

Consideration	Detail
Route	IV infusion (weekly) — lifelong
Efficacy	Modest increase in dystrophin production (typically 1–5% of normal on biopsy). Clinical benefit debated — the FDA approved these under accelerated pathways based on surrogate endpoints (dystrophin expression on biopsy) rather than definitive functional improvement
Limitations	Mutation-specific (each drug helps only a subset); modest dystrophin restoration; very expensive (> US$300,000/year); long-term outcomes still being studied
Side effects	Generally well-tolerated; infusion reactions, proteinuria (renal monitoring required)

Drug	Mechanism	Target Mutation	Eligible Patients
Ataluren (Translarna)	Promotes ribosomal readthrough of premature stop codons → allows full-length dystrophin production. The ribosome "ignores" the premature stop codon and continues translating	Nonsense (stop) mutations only	~10–15% of DMD patients

Consideration	Detail
Route	Oral (three times daily)
Regulatory status	Conditionally approved in EU (not FDA-approved in the US as of 2026). Available in some Asian countries
Contraindication	Must NOT be used with aminoglycoside antibiotics — aminoglycosides also promote stop-codon readthrough but through a different mechanism; combined use can cause excessive readthrough at normal stop codons → toxic aberrant proteins. Also, aminoglycosides are nephrotoxic/ototoxic
Efficacy	Slows 6MWT decline by ~30 metres/year compared to placebo. Benefit is most apparent when initiated early (while still ambulant)

Aspect	Detail
Concept	Deliver a functional, miniaturised version of the dystrophin gene ("micro-dystrophin") using an adeno-associated virus (AAV) vector directly into muscle cells
Why "micro"?	The full DMD gene cDNA is ~14 kb — far too large for AAV vectors (packaging limit ~4.7 kb). Micro-dystrophin constructs retain the essential N-terminal, C-terminal, and key spectrin-like repeats but delete much of the central rod domain
Drug	Delandistrogene moxeparvovec (Elevidys / SRP-9001) — uses AAVrh74 vector to deliver micro-dystrophin. FDA-approved under accelerated approval (2023) for ambulatory boys aged 4–5
Route	Single IV infusion (one-time treatment — the AAV transduces muscle cells and the micro-dystrophin gene is expressed episomally)
Efficacy	Significant increase in micro-dystrophin expression on biopsy; functional benefits demonstrated in clinical trials (NSAA improvement) though confirmatory trials are ongoing
Limitations	Pre-existing AAV antibodies may preclude treatment (~30–40% of population); immune response to the vector or transgene; durability of expression uncertain (may wane over years as transduced cells turn over); cannot re-dose with the same serotype due to neutralising antibodies; very expensive (> US$3 million per dose)
Side effects	Immune-mediated reactions (hepatotoxicity, myocarditis, thrombotic microangiopathy); requires immunosuppression peri-infusion (typically prednisolone for several weeks); liver function monitoring essential

Therapy	Mechanism	Status
CRISPR/Cas9 gene editing	Direct correction or exon excision at the genomic level — permanent fix, potentially curative	Preclinical / early Phase I trials
Utrophin upregulation	Pharmacological upregulation of utrophin (dystrophin's autosomal homologue) to compensate for absent dystrophin	Clinical trials ongoing
Anti-myostatin therapies	Myostatin inhibition → promote muscle growth and counteract wasting	Mixed results in trials; not yet approved
Givinostat (HDAC inhibitor)	Histone deacetylase inhibitor → reduces fibrosis and inflammation, promotes muscle regeneration	EU-approved 2024 for DMD aged ≥ 6 (first non-steroidal anti-fibrotic approved); not yet widely available globally
Idebenone	Synthetic analogue of CoQ10; improves mitochondrial electron transport → reduces oxidative stress	Some evidence for respiratory benefit; not widely adopted
CAP-1002 (cardiosphere-derived cells)**	Allogeneic cardiac-derived cell therapy → anti-fibrotic and anti-inflammatory paracrine effects on both heart and skeletal muscle	Phase III trials ongoing

4. Supportive and Complication-Directed Management

Management of complications: heart failure, arrhythmia, respiratory failure ^[3]

Intervention	Indication	Mechanism / Rationale
ACE inhibitors (e.g., perindopril, enalapril) or ARBs (e.g., losartan)	Start by age 10 (or at first sign of cardiac dysfunction) — many centres now start prophylactically by age 6–8 even with normal echo	Reduce afterload → decrease LV wall stress → slow remodelling and fibrosis progression. ACE-i also have direct anti-fibrotic effects via bradykinin pathway
Beta-blockers (e.g., carvedilol, bisoprolol)	When LVEF begins to decline (< 50%) or with symptomatic heart failure	Reduce heart rate → improve diastolic filling time → reduce myocardial oxygen demand. Also have anti-remodelling effects
Mineralocorticoid receptor antagonists (e.g., eplerenone, spironolactone)	Added when LVEF < 40% or with progressive LV dysfunction	Anti-fibrotic effects (aldosterone promotes cardiac fibrosis); reduce preload. Eplerenone has specific evidence in DMD showing slowed decline in LV strain
Diuretics	Symptomatic heart failure with fluid overload	Reduce preload → relieve congestion
Arrhythmia management	Atrial or ventricular arrhythmias	Antiarrhythmics; consider ICD if high risk of sudden cardiac death (though prognosis considerations are complex in DMD)
Cardiac transplantation	End-stage heart failure in selected patients with preserved respiratory and skeletal muscle function	Rare but increasingly considered as respiratory management improves survival

Why start cardiac medications prophylactically? Because cardiac fibrosis in DMD begins silently — by the time echo shows reduced LVEF, significant irreversible fibrosis has already occurred. Early treatment aims to slow fibrosis before it becomes clinically apparent. Cardiac MRI with LGE can detect fibrosis years before echo changes.

Intervention	Indication	Mechanism / Rationale
Lung volume recruitment (air-stacking)	From early non-ambulatory phase	Patient takes successive breaths without exhaling (using a manual resuscitator bag) → stretches the chest wall → maintains compliance → slows FVC decline
Assisted cough techniques	When peak cough flow < 270 L/min	Manual abdominal thrust timed with cough, or mechanical insufflation-exsufflation (cough assist device, e.g., CoughAssist) → generates sufficient airflow to clear secretions and prevent atelectasis/pneumonia
Non-invasive ventilation (NIV) — initially nocturnal	Nocturnal hypoventilation (symptoms: morning headaches, daytime somnolence, fatigue) or FVC < 30–50% predicted or abnormal sleep study	Bilevel positive airway pressure (BiPAP) supports the weak diaphragm → improves gas exchange → reduces CO₂ retention. Nocturnal NIV improves sleep quality, daytime function, and survival
NIV — daytime use	Progressive daytime respiratory failure	Mouthpiece ventilation during the day, mask ventilation at night
Tracheostomy and invasive ventilation	If NIV fails or secretion management becomes impossible	Provides definitive airway control; improves survival but at cost of significant morbidity and quality-of-life considerations
Influenza and pneumococcal vaccination	All DMD patients	Respiratory infections are a major cause of morbidity and mortality; weak cough → mucus retention → pneumonia. Prevention is key
Antibiotic therapy	Prompt treatment of respiratory infections	Low threshold for treatment given impaired airway clearance

Why does respiratory failure occur? Diaphragm and intercostal muscle weakness → reduced vital capacity → ineffective cough → mucus retention → atelectasis → pneumonia. Scoliosis further restricts chest wall compliance. FVC declines ~6–10% per year after loss of ambulation.

Intervention	Indication	Mechanism / Rationale
Physiotherapy (PT)	From diagnosis — lifelong	Stretching exercises to prevent/delay contractures; range-of-motion maintenance; low-impact exercise to maintain function without overloading fragile muscle. Eccentric exercise should be avoided — it causes more contraction-induced damage in dystrophin-deficient muscle
Ankle-foot orthoses (AFOs)	Night-time use to prevent equinovarus contracture	Maintains ankle dorsiflexion range → delays toe-walking progression
Standing frames / standing programmes	After loss of ambulation	Maintains hip and knee extension range; weight-bearing preserves bone density; psychological benefit
Wheelchair provision	Loss of independent ambulation (~12–14 years on steroids)	Power wheelchair with appropriate seating and postural support. Early provision prevents falls and conserves energy
Tendon release surgery	Severe, functionally limiting contractures (Achilles, iliotibial band, hip flexors)	Surgical lengthening of shortened tendons can prolong ambulation. Most effective when done at the right time (before muscle strength falls below antigravity function)
Spinal fusion surgery	Progressive scoliosis (Cobb angle > 20–25° and still progressing)	Posterior spinal instrumentation and fusion stabilises the spine → prevents further curve progression → preserves respiratory function (severe scoliosis compromises lung expansion). Best done early while respiratory function is still adequate for anaesthesia

Critical Anaesthetic Consideration

DMD patients are at risk of malignant hyperthermia-like reactions and rhabdomyolysis under general anaesthesia.

Avoid succinylcholine (depolarising neuromuscular blocker) — can trigger fatal hyperkalaemia from rhabdomyolysis of already-fragile muscle
Avoid volatile (halogenated) anaesthetic agents (e.g., sevoflurane, isoflurane) — risk of rhabdomyolysis and cardiac arrest
Use total intravenous anaesthesia (TIVA) with propofol and non-depolarising muscle relaxants (e.g., rocuronium)
All anaesthesia teams must be alerted to the DMD diagnosis pre-operatively

Intervention	Indication	Rationale
Vitamin D supplementation	All DMD patients (universal)	Maintain 25-OH vitamin D > 75 nmol/L; deficiency is common due to reduced sun exposure (immobility, wheelchair) and steroid-mediated reduced absorption
Calcium supplementation	If dietary intake is inadequate	Steroids reduce intestinal calcium absorption and increase renal calcium excretion
DEXA monitoring	Annually from steroid initiation	Track bone mineral density; identify osteoporosis early
Bisphosphonates (e.g., IV zoledronic acid)	Vertebral compression fractures or Z-score < −2	Inhibit osteoclast-mediated bone resorption → increase bone mineral density → reduce fracture risk

Phase	Nutritional Issue	Approach
Ambulatory phase (on steroids)	Excessive weight gain from increased appetite + reduced activity	Proactive dietary counselling from steroid initiation; caloric restriction; avoid high-sugar/high-fat foods; regular weight monitoring
Non-ambulatory phase (late)	Undernutrition and dysphagia from pharyngeal/oesophageal muscle weakness + reduced lean mass + increased metabolic demands from respiratory work	Swallowing assessment (speech therapist); modified diet texture; gastrostomy tube (PEG) if oral intake is insufficient or aspiration risk is high

Intervention	Rationale
Psychological support	Adjusting to progressive disability; anticipatory grief; depression and anxiety are common in patients and families
Educational support	Learning difficulties in ~30% (mean IQ ~85); IEP (individualised education plan); extra support in school
Social worker involvement	Financial support, disability benefits, respite care, transition planning
Peer support groups	DMD patient and family networks provide emotional and practical support
Transition to adult services	Planned transition from paediatric to adult neurology, cardiology, and respiratory services at age 16–18

Genetic counselling ^[3] is a critical component of DMD management, addressing:

Aspect	Detail
Carrier testing	Mother and sisters of affected boy should be offered carrier testing (CK + genetic testing)
Recurrence risk counselling	If mother is a carrier: 50% of sons affected, 50% of daughters are carriers. If de novo: recurrence risk ~7–10% (germline mosaicism)
Prenatal diagnosis	CVS (11–14 weeks) or amniocentesis (15–18 weeks) with mutation-specific testing
Preimplantation genetic testing (PGT)	For known familial mutations — IVF with embryo selection
Female carrier cardiac screening	All confirmed carriers should have baseline echocardiography and periodic cardiac follow-up (risk of DCM in ~7–10% by age 40)

Stage	Key Management Priorities
Pre-symptomatic / early ambulatory (2–6y)	Diagnosis confirmation; initiate corticosteroids (~age 4–6); physiotherapy and stretching; baseline cardiac + respiratory assessment; psychometric testing; genetic counselling; vaccination review
Late ambulatory (6–12y)	Continue steroids; monitor and manage contractures (AFOs, stretching, ± Achilles tendon release); initiate cardiac prophylaxis (ACE-i by age 10); annual respiratory monitoring; consider mutation-specific therapy eligibility; manage steroid side effects
Early non-ambulatory (12–16y)	Wheelchair provision; standing programme; scoliosis monitoring (± spinal fusion); intensify respiratory management (lung volume recruitment, cough assist); continue cardiac medications; nutritional monitoring (weight gain → undernutrition transition); psychosocial support for major functional milestone loss
Late non-ambulatory ( > 16y)	Nocturnal NIV → daytime ventilatory support; aggressive cardiac failure management; dysphagia management (± PEG); palliative care discussions; advance care planning; transition to adult services

Therapy	Contraindication / Caution
Prednisolone/deflazacort	Active untreated infection; uncontrolled diabetes; severe osteoporosis with fractures (relative); ensure vaccinations (especially varicella) completed before starting
Ataluren	Must NOT be co-administered with aminoglycosides; only for nonsense mutations
Exon-skipping ASOs	Only applicable to specific mutations amenable to the targeted exon skip; renal monitoring required
Gene therapy (micro-dystrophin)	Pre-existing anti-AAV antibodies (contraindication); hepatotoxicity risk; myocarditis risk; requires immunosuppression; single-dose limitation
Succinylcholine	Absolutely contraindicated in DMD — risk of fatal hyperkalaemia from rhabdomyolysis
Volatile anaesthetic agents	Avoid — risk of rhabdomyolysis and cardiac arrest
Vigorous eccentric exercise	Avoid — accelerates contraction-induced muscle damage in dystrophin-deficient fibres
Live vaccines	Contraindicated while on immunosuppressive-dose corticosteroids

High Yield Summary — Management of DMD

No cure exists — management is supportive + steroid therapy + management of complications ^[2]^[3]^[9]
Corticosteroids are the cornerstone: ↑motor function, strength, pulmonary function, ↓risk of scoliosis ^[2]^[9]. Prednisolone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day. Start at age 4–6, continue even after loss of ambulation
Steroid side effects must be proactively managed: weight gain, osteoporosis, growth retardation, immunosuppression, adrenal suppression, cataracts, behavioural changes
Mutation-specific therapies: exon-skipping ASOs (eteplirsen, golodirsen, viltolarsen, casimersen); stop-codon readthrough (ataluren — contraindicated with aminoglycosides); gene therapy (delandistrogene moxeparvovec — single IV dose of micro-dystrophin via AAV)
Cardiac management: ACE-i/ARB from age 6–10 (prophylactic); add beta-blocker when LVEF declines; eplerenone for anti-fibrotic effect
Respiratory management: lung volume recruitment → cough assist → nocturnal NIV → daytime NIV → ± tracheostomy. Annual FVC monitoring
Orthopaedic management: physiotherapy and stretching (avoid eccentric exercise); AFOs; wheelchair; tendon release; spinal fusion for scoliosis
Anaesthesia: AVOID succinylcholine and volatile anaesthetic agents — risk of fatal rhabdomyolysis/hyperkalaemia. Use TIVA
Genetic counselling: carrier testing, prenatal diagnosis, PGT, female carrier cardiac screening
Multidisciplinary team: neurology, cardiology, respiratory, orthopaedics, physiotherapy, occupational therapy, dietetics, speech therapy, psychology, social work, genetics

Active Recall - Management of DMD

References

^[2] Senior notes: Ryan Ho Neurology.pdf (p192 — DMD management: supportive + steroid therapy) ^[3] Senior notes: Maksim Medicine Notes.pdf (p276 — Myopathy management: no specific treatment, supportive care, complication management) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (p5, p8 — Familial DCM, cardiac investigations and management) ^[9] Senior notes: Adrian Lui Pediatrics Notes.pdf (p144 — DMD management: supportive + steroid therapy benefits)

Complications of Duchenne Muscular Dystrophy

The complications of DMD arise from two sources: (1) the disease process itself — progressive dystrophin deficiency across multiple organ systems, and (2) the treatment — primarily long-term corticosteroid side effects. Understanding each complication requires tracing it back to first principles.

Organ System	Disease-Related Complications	Treatment-Related Complications
Cardiac	Dilated cardiomyopathy, heart failure, arrhythmias, sudden cardiac death	—
Respiratory	Restrictive lung disease, nocturnal hypoventilation, respiratory failure, pneumonia	—
Musculoskeletal	Contractures, scoliosis, loss of ambulation	Steroid myopathy
Bone	Osteoporosis, pathological fractures, vertebral compression fractures	Steroid-induced osteoporosis
Gastrointestinal	Constipation, gastroparesis, dysphagia, aspiration, pseudo-obstruction	Steroid-induced weight gain, GI ulceration
Endocrine/Metabolic	—	Adrenal suppression, growth retardation, delayed puberty, glucose intolerance, Cushingoid features
Neuropsychiatric	Intellectual disability, learning difficulties, ASD, ADHD, depression, anxiety	Behavioural changes from steroids
Ophthalmic	—	Posterior subcapsular cataracts
Immune	—	Immunosuppression, infection risk
Anaesthetic	Malignant hyperthermia-like reactions, fatal rhabdomyolysis/hyperkalaemia	—

2. Cardiac Complications

GC Lecture Slide — High Yield

Cardiomyopathy is listed as a key feature/complication of DMD ^[1]^[2]^[9].

Neuromuscular disorders — Duchenne muscular dystrophy, Becker muscular dystrophy, Myotonic dystrophy are listed as diseases where familial dilated cardiomyopathy forms a part of a greater syndrome ^[5].

Two severe consequences of dilated cardiomyopathy: heart failure and sudden cardiac death due to ventricular arrhythmias ^[5].

Aspect	Detail
Prevalence	Virtually 100% of DMD patients develop cardiac involvement; clinically evident dilated cardiomyopathy emerges in the mid-to-late teens ^[5]^[13]
Pathophysiology	Cardiac muscle expresses the same Dp427m dystrophin isoform → sarcolemma fragility → contraction-induced cardiomyocyte necrosis → progressive fibrosis (begins in the posterolateral LV wall subepicardially) → LV dilation → systolic dysfunction → heart failure
Why posterolateral wall first?	This region experiences the greatest wall stress during contraction (thin wall relative to curvature, high mechanical load). Without dystrophin, these cardiomyocytes are the first to succumb
Cardiac MRI pattern	Late gadolinium enhancement (LGE) in the posterolateral LV wall — subepicardial (distinguishing it from ischaemic cardiomyopathy which is subendocardial)
Why is it often clinically silent initially?	DMD boys become progressively sedentary due to skeletal muscle weakness → they never exert themselves enough to unmask exertional cardiac symptoms like dyspnoea or exercise intolerance. The heart failure is "hidden" behind the skeletal muscle disease
Why it eventually becomes the dominant problem	As respiratory management improves survival, cardiac failure has emerged as the leading cause of death in DMD (previously respiratory failure dominated)

Aspect	Detail
Type	Systolic heart failure (HFrEF) — ↓contractility → ↓CO, LV dilatation, HF ^[13]
Signs	↓CO: cool extremities, ↓BP, tachycardia. Signs of HF: pulmonary and systemic congestion. Auscultation: displaced, thrusting apex, functional MR/TR, S3 ^[13]
Clinical presentation	SOBOE (masked by immobility), orthopnoea, PND, peripheral oedema, hepatomegaly. In non-ambulatory patients, first signs may be resting tachycardia, weight loss, or new-onset nausea
Management	ACE-i/ARB, beta-blockers, MRA (eplerenone), diuretics. See Management section for details

Aspect	Detail
Mechanism	Myocardial fibrosis creates electrically heterogeneous substrate → re-entrant circuits → ventricular tachycardia (VT) and ventricular fibrillation (VF). Sinus tachycardia is very common (autonomic dysfunction + compensation). Atrial flutter/fibrillation can occur from atrial dilation
Risk	Sudden cardiac death due to ventricular arrhythmias is a recognised consequence of DCM ^[5]. Sudden death accounts for a proportion of DMD deaths
ECG abnormalities	Tall R in V1–V2, deep Q waves laterally, short PR interval, conduction delays. These are NOT ischaemic — they reflect the distinctive pattern of fibrosis
Monitoring	Annual ECG, Holter monitoring if arrhythmia suspected, echocardiography

3. Respiratory Complications

Respiratory failure is mentioned as a cause of death in DMD by the late teens (untreated) ^[2]^[9]^[14].

Aspect	Detail
Mechanism	Progressive weakness of the diaphragm and intercostal muscles → reduced ability to expand the chest wall → decreased vital capacity (VC), total lung capacity (TLC), and functional residual capacity (FRC). The airways and lung parenchyma are intrinsically normal — this is a purely "pump failure" problem
Progressive scoliosis worsens restriction	Once the boy loses ambulation, paraspinal muscle weakness allows the spine to curve (scoliosis) → further reduces chest wall compliance → accelerates respiratory decline. This is one reason steroid therapy ↓risk of scoliosis is so important ^[2]^[9]
FVC trajectory	Peaks around age 10–12 years, then declines ~6–10% per year. When FVC falls below 1 litre (or ~30% predicted), the risk of respiratory failure is imminent

Aspect	Detail
Mechanism	Cough requires rapid generation of high intrathoracic pressure (expiratory muscles — abdominals and internal intercostals) followed by explosive airflow. In DMD, these muscles are weak → peak cough flow falls below the effective threshold (270 L/min) → inability to clear secretions → mucus retention → atelectasis → bacterial colonisation → recurrent lower respiratory tract infections
Why pneumonia is the acute killer	A viral URTI in a normal person is a nuisance. In DMD, the inability to cough effectively means mucus accumulates → secondary bacterial pneumonia → further atelectasis → hypoxaemia → respiratory failure → death if not aggressively managed
Prevention	Cough assist devices, chest physiotherapy, influenza and pneumococcal vaccination, early antibiotic treatment of infections

Aspect	Detail
Why nocturnal first?	During sleep, respiratory drive decreases (loss of wakeful ventilatory drive) and the diaphragm bears the entire burden of ventilation (intercostals become hypotonic in REM sleep). In DMD, the already-weak diaphragm cannot maintain adequate ventilation during sleep → CO₂ retention (hypercapnia) → morning headaches, daytime somnolence, poor sleep quality
Progression	Nocturnal hypoventilation → progressive daytime hypercapnia → chronic respiratory failure. Without NIV intervention, this culminates in death from respiratory failure
Management	Nocturnal BiPAP → daytime mouthpiece ventilation → ± tracheostomy and invasive ventilation

Aspect	Detail
Mechanism	Progressive pharyngeal and oesophageal muscle weakness → dysphagia → aspiration of food/saliva into the lungs. Compounded by weak cough (cannot clear aspirated material) and GORD (weak lower oesophageal sphincter)
Consequence	Aspiration pneumonia — a major cause of acute deterioration and death
Management	Swallowing assessment by speech therapist; modified diet textures; upright positioning during and after meals; gastrostomy (PEG) when oral feeding becomes unsafe

4. Musculoskeletal Complications

Aspect	Detail
Affected joints	Ankle (equinovarus — tight Achilles), hip flexors, iliotibial band, knee flexors, elbow flexors (later stage)
Mechanism	Progressive fibrosis of muscle shortens the muscle-tendon unit → loss of range of motion. Exacerbated by immobility (wheelchair use) and postural compensations
Consequence	Contractures directly impair function: ankle contractures force toe-walking; hip flexion contractures make standing impossible; upper limb contractures limit hand function
Prevention	Daily stretching (physiotherapy), night-time ankle-foot orthoses (AFOs), standing programmes

Aspect	Detail
Prevalence	Develops in ~90% of non-ambulatory DMD boys who are not on corticosteroids; much lower (~25–30%) in steroid-treated patients
Mechanism	Loss of paraspinal muscle support + gravity + asymmetric muscle weakness → progressive thoracolumbar curvature. Begins after loss of ambulation (loss of dynamic postural support)
Why it matters	Severe scoliosis (Cobb angle > 40°) significantly worsens respiratory function by restricting chest wall expansion. It also causes pain and impairs sitting balance
Management	Steroid therapy ↓risk of scoliosis ^[2]^[9]; spinal bracing (limited benefit — delays but does not prevent curve progression); posterior spinal fusion surgery when Cobb angle > 20–25° and progressing, ideally while FVC > 30–40% (to tolerate anaesthesia)

Aspect	Detail
Timing	Wheelchair-bound by 9–12 ^[14] years (untreated); delayed to 12–14 years with corticosteroids
Mechanism	Cumulative loss of lower limb muscle strength (especially quadriceps, hip extensors) below the threshold needed for antigravity function + worsening contractures
Psychosocial impact	This is one of the most devastating milestones for patients and families — loss of independence, altered self-image, social isolation. Requires proactive psychological support

5.1 Osteoporosis and Fractures

Aspect	Detail
Multifactorial aetiology	(1) Reduced mechanical loading — immobility and wheelchair use remove the normal muscle-bone mechanical interaction (Wolff's law: bone adapts to the loads placed upon it; no load → bone loss). (2) Corticosteroid use — glucocorticoids directly suppress osteoblast activity, increase osteoclast-mediated resorption, and reduce intestinal calcium absorption. (3) Vitamin D deficiency — reduced sun exposure. (4) Loss of muscle-bone crosstalk — muscle releases osteogenic factors (myokines like IGF-1, irisin) that stimulate bone formation; in DMD, muscle loss removes this signal
Types of fractures	Long bone fractures (especially femur) from falls during the ambulatory phase; vertebral compression fractures in the non-ambulatory phase (often asymptomatic — discovered incidentally on spinal imaging)
Clinical significance	A long bone fracture in a still-ambulatory DMD boy can be the event that permanently ends ambulation — the period of immobilisation during healing leads to further muscle deconditioning and contractures from which recovery is impossible
Monitoring	DEXA scan annually from steroid initiation; lateral spine X-ray for vertebral fractures
Management	Vitamin D + calcium supplementation; bisphosphonates (IV zoledronic acid) for vertebral fractures or Z-score < −2

Complication	Mechanism	Management
Constipation	Smooth muscle dystrophin deficiency → impaired gut motility + weak abdominal wall muscles → poor Valsalva → inability to generate adequate intra-abdominal pressure for defecation + immobility + dehydration + opioid use (if given for pain)	Dietary fibre, adequate hydration, stool softeners, osmotic laxatives (lactulose, PEG 3350); prokinetics if needed
Gastroparesis	Smooth muscle involvement → delayed gastric emptying → early satiety, nausea, vomiting, bloating	Prokinetics (domperidone, metoclopramide — caution with extrapyramidal side effects); small frequent meals
Acute gastric dilatation / pseudo-obstruction	Rare but life-threatening. Smooth muscle failure → massive gastric or intestinal distension → vascular compromise → necrosis. Can present as acute abdomen	Emergency — nasogastric decompression; IV fluids; surgical consultation. High mortality if not recognised early
Dysphagia	Pharyngeal and oesophageal striated muscle weakness (late disease) → ineffective swallowing	Swallowing assessment; texture-modified diet; PEG tube
GORD	Weak lower oesophageal sphincter + supine positioning + weak abdominal muscles	PPI; postural measures
Steroid-induced GI effects	Increased gastric acid production; reduced mucosal protection	PPI or H₂ receptor blocker

Acute Gastric Dilatation — Rare but Fatal

Acute gastric dilatation is an under-recognised life-threatening complication of DMD. The massively distended stomach compresses the splenic and mesenteric vasculature, leading to ischaemia and necrosis. It can present with sudden abdominal distension, vomiting (may be absent if gastric outlet is obstructed), tachycardia, and shock. Immediate nasogastric decompression is essential. DMD patients with acute abdominal symptoms must be taken seriously — this is not just constipation.

These are primarily treatment-related (corticosteroid side effects):

Complication	Mechanism	Clinical Significance
Adrenal suppression	Chronic exogenous corticosteroids suppress the hypothalamic-pituitary-adrenal (HPA) axis → adrenal atrophy → inability to mount an endogenous cortisol response to stress	Adrenal crisis can be precipitated by acute illness, surgery, or abrupt steroid withdrawal → hypotension, hypoglycaemia, shock, death. All DMD patients on steroids should carry a medical alert and receive stress-dose hydrocortisone during illness/procedures
Growth retardation	Corticosteroids suppress GH secretion and directly inhibit growth plate chondrocyte proliferation	Short stature is common; monitor height velocity; consider endocrine referral if growth arrest is severe
Delayed puberty	Corticosteroids suppress gonadotropins (FSH, LH) → delayed testosterone production	Monitor pubertal staging (Tanner stages); endocrine referral for testosterone supplementation if indicated (also has potential benefit for bone health and mood)
Glucose intolerance / diabetes	Corticosteroids increase hepatic gluconeogenesis, impair insulin signalling, cause insulin resistance	Monitor fasting glucose and HbA1c; manage with dietary modification and/or hypoglycaemic agents if needed
Cushingoid features	Fat redistribution (moon face, buffalo hump, truncal obesity) due to cortisol-mediated lipogenesis in central depots	Cosmetically distressing; no specific treatment other than dose minimisation
Obesity	Increased appetite (steroid effect) + reduced physical activity → energy imbalance → excessive weight gain, especially in the ambulatory phase	Proactive dietary counselling from steroid initiation; caloric restriction

Complication	Mechanism	Details
Mild mental impairment	Absence of brain dystrophin isoforms (Dp427c, Dp140, Dp71) disrupts synaptic structure, GABAergic neurotransmission, and blood-brain barrier function ^[2]^[9]^[14]	Mean IQ ~85; verbal IQ more affected than performance IQ; non-progressive (present from birth, does not worsen). ~30% have clinically significant learning difficulties
ADHD	Dystrophin's role in dopaminergic and GABAergic circuits in the prefrontal cortex	Prevalence ~30% in DMD (higher than general population ~5–7%). Manage with behavioural strategies ± medication (methylphenidate, atomoxetine)
Autism spectrum disorder (ASD)	Dystrophin in cerebellar and cortical synaptic development	Prevalence ~15–20% in DMD vs ~1–2% in general population
Depression and anxiety	Both neurobiological (brain dystrophin deficiency) and reactive/psychosocial (progressive disability, loss of function, dependency, social isolation, anticipatory grief)	Screen regularly; psychological support; CBT; antidepressants if indicated
Behavioural problems from steroids	CNS effects of corticosteroids — irritability, mood lability, aggression, insomnia, hyperactivity	Distinguish from underlying neurodevelopmental issues; dose adjustment; consider deflazacort (may have fewer behavioural side effects)

Complication	Mechanism	Prevention
Fatal rhabdomyolysis with succinylcholine	Succinylcholine (depolarising neuromuscular blocker) causes sustained depolarisation → massive potassium efflux from already-fragile, sarcolemma-leaky myofibres → fatal hyperkalaemia → cardiac arrest	Absolute contraindication: never use succinylcholine in DMD or any suspected myopathy
Rhabdomyolysis with volatile anaesthetics	Sevoflurane, isoflurane, desflurane can trigger malignant hyperthermia-like syndrome in DMD — massive rhabdomyolysis, hypermetabolism, acidosis, hyperkalaemia, cardiac arrest	Avoid all volatile agents. Use total intravenous anaesthesia (TIVA) with propofol + non-depolarising agents (e.g., rocuronium)
Respiratory complications peri-operatively	Weak cough, reduced respiratory reserve → prolonged intubation, difficulty weaning from ventilator, atelectasis, post-operative pneumonia	Pre-operative respiratory assessment; plan for NIV post-extubation; aggressive cough assist; avoid excessive opioids (respiratory depression)
Cardiac complications peri-operatively	Cardiomyopathy → reduced cardiac reserve → haemodynamic instability under anaesthesia	Pre-operative cardiac assessment (ECG, echo); careful fluid management; invasive monitoring in high-risk cases

Therapy	Potential Complications
Exon-skipping ASOs	Proteinuria (renal toxicity — monitor creatinine and urine protein); infusion reactions
Ataluren	GI side effects (nausea, vomiting, diarrhoea); must avoid aminoglycoside co-administration (toxic aberrant protein production)
Gene therapy (micro-dystrophin / AAV)	Hepatotoxicity (elevated transaminases — from immune response to AAV capsid, not muscle damage this time); myocarditis; thrombotic microangiopathy (TMA); complement activation; immune-mediated rejection of transduced cells. Requires peri-infusion immunosuppression
Givinostat (HDAC inhibitor)	Thrombocytopenia; elevated triglycerides; GI disturbances; hepatotoxicity

Understanding the final common pathways:

Era	Primary Cause of Death	Explanation
Pre-ventilatory support era	Respiratory failure ^[2]	Respiratory failure by late teens ^[14]. Progressive restrictive lung disease → respiratory failure. Pneumonia as the acute terminal event
Modern era (with NIV and corticosteroids)	Cardiac failure	As respiratory management improves survival into the late 20s–30s, heart failure and sudden cardiac death due to ventricular arrhythmias ^[5] have become the leading cause of death. Median survival now ~27–30 years with modern multidisciplinary care
Other causes	Aspiration pneumonia, acute gastric dilatation, complications of surgery/anaesthesia, renal failure (rare)	Less common but important to recognise

Age Range	Key Complications
Birth–5 years	Elevated CK (asymptomatic); mild motor delay; cognitive/behavioural issues may emerge
5–12 years	Progressive weakness; contractures begin; falls and fractures; steroid side effects (weight gain, behaviour, growth); learning difficulties become apparent
12–16 years	Loss of ambulation; scoliosis develops; respiratory function begins to decline; cardiac function starts declining; osteoporosis worsens; psychological impact of wheelchair dependency
16–25 years	Nocturnal hypoventilation → daytime respiratory failure; clinically evident cardiomyopathy → heart failure; upper limb function declines; dysphagia emerges; complete dependency for ADLs
25+ years	Advanced heart failure; ventilator-dependent; severe dysphagia (PEG-dependent); end-of-life care considerations

High Yield Summary — Complications of DMD

Cardiac: Dilated cardiomyopathy is universal; leads to heart failure and sudden cardiac death due to ventricular arrhythmias ^[5]. Now the leading cause of death in the modern era
Respiratory: Respiratory failure by late teens ^[14] (untreated). Caused by diaphragm/intercostal weakness + scoliosis → restrictive lung disease → ineffective cough → pneumonia → respiratory failure
Musculoskeletal: Contractures (ankle, hip, knee), scoliosis (in ~90% of non-ambulatory untreated patients, reduced by steroids ^[2]^[9]), loss of ambulation by 9–12 years ^[14]
Bone: Osteoporosis from immobility + steroids → pathological fractures; a long bone fracture can permanently end ambulation
GI: Constipation, dysphagia, acute gastric dilatation (rare but fatal)
Endocrine (steroid-related): Adrenal suppression (risk of adrenal crisis), growth retardation, delayed puberty, glucose intolerance, Cushingoid features
Neuropsychiatric: Mild mental impairment ^[14] (mean IQ ~85); ADHD, ASD, depression — both neurobiological and psychosocial
Anaesthetic: Fatal rhabdomyolysis/hyperkalaemia with succinylcholine and volatile agents — use TIVA only
Survival: Untreated = death late teens–early 20s; with modern care (steroids + NIV + cardiac therapy) = late 20s–30s+

Active Recall - Complications of DMD

References

^[2] Senior notes: Ryan Ho Neurology.pdf (p192 — DMD complications: cardiomyopathy, respiratory failure, mental impairment; management with steroids) ^[3] Senior notes: Maksim Medicine Notes.pdf (p276 — Management of complications: heart failure, arrhythmia, respiratory failure) ^[5] Senior notes: Block A - Inherited Cardiac conditions.pdf (p4–5 — DCM causes including DMD; severe consequences: heart failure and sudden cardiac death) ^[9] Senior notes: Adrian Lui Pediatrics Notes.pdf (p144 — DMD features and steroid therapy benefits) ^[13] Senior notes: Ryan Ho Cardiology.pdf (p169 — DCMP pathogenesis, presentation, signs of HF) ^[14] Lecture slides: GC 056. Generalized muscle weakness.pdf (p25 — DMD: wheelchair-bound by 9–12, respiratory failure by late teens, cardiomyopathy, mild mental impairment)

High Yield Summary

Definition: DMD is an X-linked recessive progressive muscular dystrophy caused by out-of-frame mutations in the DMD gene (Xp21.2) → absent dystrophin → sarcolemma fragility → muscle fibre necrosis → fibrosis and fatty replacement
Epidemiology: ~1 in 3,500 live male births; most common lethal genetic disorder in childhood; 1/3 are de novo mutations
Key Gene: DMD gene — largest known human gene (2.4 Mb, 79 exons); ~60–70% deletions, ~10–15% duplications, ~20–25% point mutations
Pathophysiology: Absent dystrophin → DGC disassembly → sarcolemma tears with contraction → Ca²⁺ influx → calpain activation → necrosis → inflammation → satellite cell exhaustion → fibrosis + fat → progressive weakness
Reading Frame Rule: Out-of-frame = DMD (absent dystrophin); In-frame = BMD (reduced dystrophin) — ~90–95% predictive accuracy
Clinical triad: Calf pseudohypertrophy + Gower's sign + Tip-toe gait in a young boy
Motor progression: Onset ~2–5y → loss of ambulation ~9–12y → respiratory failure late teens → death late 20s–30s (with current care)
Key non-motor features: Dilated cardiomyopathy (universal), mild intellectual impairment (mean IQ ~85), scoliosis, osteoporosis
Investigations: Markedly elevated CK (50–100× ULN); genetic testing (dystrophin gene at Xp21.2); ECG/echo for dilated cardiomyopathy ^[3]^[5]
DMD vs. BMD: Same gene, different reading frame → DMD is severe (loss of ambulation < 13y, death 20s–30s); BMD is milder (ambulation beyond 15y, death 40–60y)

High Yield Summary — Differential Diagnosis of DMD

First step: Localise the lesion — DMD is a muscle-level problem (proximal weakness, no sensory loss, no fasciculations, markedly elevated CK, no fatigability)
Closest differential: BMD — same gene, same protein, but in-frame mutation → partial dystrophin → milder course (ambulate > 15y, death 40–60y). Distinguished by genetic testing
Most important non-muscle DDx in a floppy child: SMA — anterior horn cell disease, AR inheritance, absent reflexes, fasciculations, normal CK
Most important NMJ DDx: Myasthenia gravis — distinguished by fatigability, normal CK, response to anticholinesterase, AChR antibodies
Most important acquired myopathy DDx: Inflammatory myopathy (JDM/PM) — subacute onset, pain/tenderness, rash (DM), autoantibodies, responds to steroids
Always exclude: Endocrine myopathy (thyroid, Cushing's), drug-induced myopathy (especially steroids in treated DMD patients), metabolic myopathy, electrolyte disturbance
Clinical features of myopathy: motor involvement only, no sensory and rarely affects sphincters ^[2]^[9]
CK levels guide DDx: 200–1000 IU/L for most myopathies; > 1000 for inflammatory myopathies, rhabdomyolysis, DMD/BMD ^[9]

High Yield Summary — Diagnosis and Investigations of DMD

Diagnostic pathway: Clinical suspicion (young boy + proximal weakness + pseudohypertrophy) → CK (markedly elevated) → Genetic testing (MLPA first → sequencing if needed) → ± muscle biopsy (if genetic testing inconclusive) ^[9]
CK is elevated from birth, peaks 50–100× ULN in early childhood, then gradually declines as muscle is replaced by fat/fibrosis
CK ranges: 200–1000 = most myopathies; 1000–10,000+ = inflammatory myopathy, rhabdomyolysis, DMD/BMD ^[2]^[9]
Genetic testing is the gold standard: MLPA detects ~70–80% of mutations (deletions/duplications); full sequencing catches the remaining ~20–25% (point mutations)
Reading frame rule: out-of-frame = DMD (absent dystrophin); in-frame = BMD (reduced dystrophin) — ~90–95% predictive
EMG shows myopathic pattern: polyphasic, low-amplitude, short-duration motor unit potentials ^[3]. NCS is normal (rules out neuropathy)
Muscle biopsy (when needed): dystrophic changes + absent dystrophin on IHC confirms DMD; biopsy is done on weak but not atrophied muscle ^[11]
Cardiac screening is mandatory: ECG + echo at diagnosis, then annually. Cardiac MRI with LGE detects subepicardial posterolateral LV fibrosis ^[5]
Respiratory monitoring: annual spirometry (FVC), peak cough flow, nocturnal oximetry when FVC < 50%
Watch for the ALT/AST trap: elevated "liver enzymes" in a young boy may be from muscle → always check CK and GGT
Severe skeletal muscle disease (DMD/rhabdomyolysis) can cause true false positive troponin elevation ^[12]

High Yield Summary — Management of DMD

No cure exists — management is supportive + steroid therapy + management of complications ^[2]^[3]^[9]
Corticosteroids are the cornerstone: ↑motor function, strength, pulmonary function, ↓risk of scoliosis ^[2]^[9]. Prednisolone 0.75 mg/kg/day or deflazacort 0.9 mg/kg/day. Start at age 4–6, continue even after loss of ambulation
Steroid side effects must be proactively managed: weight gain, osteoporosis, growth retardation, immunosuppression, adrenal suppression, cataracts, behavioural changes
Mutation-specific therapies: exon-skipping ASOs (eteplirsen, golodirsen, viltolarsen, casimersen); stop-codon readthrough (ataluren — contraindicated with aminoglycosides); gene therapy (delandistrogene moxeparvovec — single IV dose of micro-dystrophin via AAV)
Cardiac management: ACE-i/ARB from age 6–10 (prophylactic); add beta-blocker when LVEF declines; eplerenone for anti-fibrotic effect
Respiratory management: lung volume recruitment → cough assist → nocturnal NIV → daytime NIV → ± tracheostomy. Annual FVC monitoring
Orthopaedic management: physiotherapy and stretching (avoid eccentric exercise); AFOs; wheelchair; tendon release; spinal fusion for scoliosis
Anaesthesia: AVOID succinylcholine and volatile anaesthetic agents — risk of fatal rhabdomyolysis/hyperkalaemia. Use TIVA
Genetic counselling: carrier testing, prenatal diagnosis, PGT, female carrier cardiac screening
Multidisciplinary team: neurology, cardiology, respiratory, orthopaedics, physiotherapy, occupational therapy, dietetics, speech therapy, psychology, social work, genetics

High Yield Summary — Complications of DMD

Cardiac: Dilated cardiomyopathy is universal; leads to heart failure and sudden cardiac death due to ventricular arrhythmias ^[5]. Now the leading cause of death in the modern era
Respiratory: Respiratory failure by late teens ^[14] (untreated). Caused by diaphragm/intercostal weakness + scoliosis → restrictive lung disease → ineffective cough → pneumonia → respiratory failure
Musculoskeletal: Contractures (ankle, hip, knee), scoliosis (in ~90% of non-ambulatory untreated patients, reduced by steroids ^[2]^[9]), loss of ambulation by 9–12 years ^[14]
Bone: Osteoporosis from immobility + steroids → pathological fractures; a long bone fracture can permanently end ambulation
GI: Constipation, dysphagia, acute gastric dilatation (rare but fatal)
Endocrine (steroid-related): Adrenal suppression (risk of adrenal crisis), growth retardation, delayed puberty, glucose intolerance, Cushingoid features
Neuropsychiatric: Mild mental impairment ^[14] (mean IQ ~85); ADHD, ASD, depression — both neurobiological and psychosocial
Anaesthetic: Fatal rhabdomyolysis/hyperkalaemia with succinylcholine and volatile agents — use TIVA only
Survival: Untreated = death late teens–early 20s; with modern care (steroids + NIV + cardiac therapy) = late 20s–30s+

Duchenne Muscular Dystrophy

1. Definition

2. Epidemiology

2.1 Incidence and Prevalence

2.2 Sex Distribution

2.3 Hong Kong Context

2.4 Natural History (Untreated)

3. Anatomy and Function of Dystrophin

3.1 The DMD Gene

3.2 Dystrophin Protein Structure

3.3 The Dystrophin-Associated Glycoprotein Complex (DGC)

3.4 Dystrophin Isoforms

4. Aetiology and Genetics

4.1 Inheritance Pattern

4.2 Types of Mutations

4.3 The Reading Frame Rule (Frame-Shift Hypothesis)

4.4 Genetic Counselling Considerations

5. Pathophysiology

5.1 The Cascade of Muscle Destruction

5.2 Cardiac Pathophysiology

5.3 CNS Pathophysiology

5.4 Why Certain Muscles Are Affected First

5.5 Why CK Is So High

6. Classification

6.1 Within the Muscular Dystrophy Family

6.2 DMD vs BMD Comparison

6.3 Pathological Differential Diagnosis in the Floppy Infant / Weak Child

7. Clinical Features

7.1 Symptoms

A. Motor Symptoms (Progressive Proximal Weakness)

B. Respiratory Symptoms

C. Cardiac Symptoms

D. Cognitive and Behavioural Symptoms

E. Gastrointestinal Symptoms

7.2 Signs

A. Musculoskeletal Signs

B. Neurological Signs

C. Cardiac Signs

D. Respiratory Signs

7.3 Clinical Stages of DMD

7.4 Carrier Manifestations (Females)

8. Associated Conditions and Systems Involved

Active Recall - Duchenne Muscular Dystrophy (Overview, Pathophysiology, Clinical Features)

References

1. Framework: Where Is the Lesion?

2. The Differential Diagnosis — Structured by Category

2.1 Other Muscular Dystrophies (Genetic Myopathies — Most Important DDx)

A. Becker Muscular Dystrophy (BMD)

B. Limb-Girdle Muscular Dystrophy (LGMD)

C. Facioscapulohumeral Muscular Dystrophy (FSHD)

D. Emery-Dreifuss Muscular Dystrophy

E. Myotonic Dystrophy (MyD)

2.2 Anterior Horn Cell Diseases (Neurogenic, Not Myopathic — But Key DDx in Floppy Child)

2.3 Neuromuscular Junction Disorders

2.4 Inflammatory Myopathies

2.5 Metabolic and Endocrine Myopathies

A. Metabolic Myopathies (Glycogen Storage Diseases, Lipid Metabolism Disorders)

B. Endocrine Myopathies

2.6 Drug-Induced Myopathy

2.7 Congenital Myopathies (Non-Progressive)

2.8 Central (Non-Paralytic) Causes of Floppy/Weak Child

2.9 Peripheral Nerve Disorders

2.10 Other Rare but Important DDx

3. Differential Diagnosis Decision Diagram

4. Summary Table: Key Differentiators

Active Recall - Differential Diagnosis of DMD

1. Diagnostic Criteria

1.1 Clinical Diagnostic Criteria (Working Definition)

1.2 When to Suspect DMD — Clinical Red Flags

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Blood Tests

A. Creatine Kinase (CK)

B. Other Muscle Enzymes

C. Additional Blood Tests (to Exclude Differentials)

3.2 Genetic Testing (The Definitive Investigation)

Step 1: Deletion/Duplication Analysis (First-Line)

Step 2: Full Gene Sequencing (Second-Line)

Step 3: Additional Genetic Approaches (Rare Cases)

Reading Frame Analysis — Why It Matters