• Most common inherited ataxia worldwide
• Prevalence: approximately 1 in 50,000 in Caucasian populations
• Carrier frequency: approximately 1 in 100 in European populations
• Much rarer in East Asian populations, including Hong Kong Chinese — the prevalence is markedly lower compared to European populations. In Hong Kong and other East Asian settings, spinocerebellar ataxias (SCAs, autosomal dominant) are more common causes of hereditary ataxia than FRDA
• No sex predilection (autosomal recessive — affects males and females equally)

• Typical onset: 5–15 years of age (mean ~10–12 years)
  • By definition, onset is almost always before age 25
  • "Late-onset" FRDA (LOFA): onset between 25–50 years (milder phenotype, fewer GAA repeats)
  • "Very late-onset" FRDA (VLOFA): onset > 50 years (uncommon)
• Important: this is predominantly a paediatric-onset disease, making it a key topic for paediatric neurology

• Progressive disability: most patients are wheelchair-bound within 10–15 years of symptom onset
• Mean age of death: ~35–40 years (range 20s–60s)
• Leading cause of death: cardiomyopathy (cardiac failure or arrhythmia) — accounts for ~60% of deaths

• Dorsal root ganglia (DRG): primary sensory neurones — the earliest and most severely affected structure
  • DRG neurones are large cells with high metabolic demand → vulnerable to mitochondrial dysfunction
  • Degeneration of DRG leads to → loss of proprioception and vibration sense (large fibre modalities carried by posterior columns)

• Posterior columns (fasciculus gracilis > cuneatus): carry proprioception, vibration, fine touch from DRG → medulla
  • Degeneration → sensory ataxia (loss of position sense → cannot coordinate limbs without visual input)
• Spinocerebellar tracts (posterior > anterior): carry unconscious proprioception from peripheral receptors → cerebellum
  • Degeneration → cerebellar ataxia component (cerebellum no longer receives afferent data about limb position)
• Corticospinal (pyramidal) tracts: lateral corticospinal tracts — upper motor neurone pathways
  • Degeneration → extensor plantar responses (Babinski sign positive) and eventual spastic paraparesis
  • This is why FRDA has an unusual combination: absent reflexes + upgoing plantars (see below)

• Dentate nucleus of cerebellum: the major output nucleus of the cerebellar hemisphere
  • Degeneration → impaired motor planning, dysarthria, and limb coordination deficits
  • Note: the cerebellar cortex itself is relatively spared (unlike spinocerebellar ataxias) — the damage is predominantly in deep nuclei and afferent tracts

• Myocardium: frataxin deficiency → mitochondrial iron overload in cardiomyocytes → hypertrophic cardiomyopathy (HCM)
  • Later stages: dilated cardiomyopathy (as myocytes die and fibrosis supervenes)
  • Cardiac conduction system involvement → arrhythmias

• Pancreatic β-cells: high metabolic demand, vulnerable to oxidative stress → diabetes mellitus (~10–30% of patients)

• Spinal column: progressive scoliosis due to paraspinal muscle weakness and imbalance
• Feet: pes cavus (high-arched foot) due to intrinsic foot muscle imbalance from denervation

• Optic atrophy may develop in some patients

Key point from lecture slides: Examples of trinucleotide repeat expansion diseases include Fragile X syndrome (CGG), Friedreich ataxia (GAA), Myotonic dystrophy (CTG), Huntington disease (CAG), and Spinocerebellar ataxia (CAG). ^[1][2]

Trinucleotide repeat disorders show anticipation: increasing severity and earlier age of onset in subsequent generations, because triplet repeats tend to expand during transmission. ^[1][2]

• In FRDA, anticipation is less prominent clinically compared to Huntington disease or myotonic dystrophy, because it is AR (requires both alleles to be affected)
• However, the underlying principle — that repeats are unstable and tend to expand during meiosis — still applies
• Larger GAA repeat size correlates with:
  • Earlier age of onset
  • More severe disease
  • Higher risk of cardiomyopathy and diabetes
  • Faster progression to wheelchair dependence

• The GAA expansion in intron 1 causes the DNA to form an abnormal triple-helical structure (R-loop / sticky DNA)
• This structure physically blocks RNA polymerase during transcription → gene silencing
• Also promotes heterochromatin formation (epigenetic silencing via histone deacetylation and DNA methylation)
• Result: markedly reduced (not absent) frataxin protein levels — typically 5–30% of normal
  • Carriers (heterozygous) have ~50% frataxin — clinically unaffected
  • Patients (homozygous) have 5–30% frataxin — clinically affected
  • Complete absence of frataxin is embryonically lethal

• Frataxin is a small mitochondrial protein (210 amino acids) that functions in:

  1. Iron-sulphur (Fe-S) cluster biogenesis — essential cofactors for mitochondrial respiratory chain complexes (Complexes I, II, III) and aconitase
  2. Iron homeostasis within mitochondria — acts as an iron chaperone, preventing free iron accumulation
  3. Heme biosynthesis — last step occurs in mitochondria and requires iron delivery

• When frataxin is deficient:

  • Iron accumulates in mitochondria as free (non-sequestered) iron
  • Fe-S cluster assembly is impaired → dysfunctional respiratory chain complexes
  • Cytoplasmic iron is depleted → upregulation of cellular iron uptake → even more iron floods into mitochondria (vicious cycle)

• Free mitochondrial iron participates in Fenton reactions:
  • Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH• (hydroxyl radical — extremely damaging)
• This generates massive reactive oxygen species (ROS)
• ROS damage:
  • Mitochondrial DNA (which lacks protective histones and has limited repair capacity)
  • Mitochondrial membranes (lipid peroxidation)
  • Respiratory chain enzymes (further ↓ ATP production)
• Combined effect: impaired ATP production + oxidative damage → cell death

Why certain tissues? The key is metabolic demand and dependence on oxidative phosphorylation:

• FRDA with retained reflexes (FARR): a subset of patients with smaller expansions who retain knee/ankle jerks — contradicts the "classic" teaching of universal areflexia
• Acadian FRDA: described in the Acadian population of Louisiana — slower progression despite typical repeat sizes

• Typical presentation: a child aged 5–15 years presenting with progressive gait unsteadiness and frequent falls
• Initially may be mistaken for "clumsiness" or dismissed
• The progressive nature and combination of neurological + cardiac + skeletal findings should raise suspicion
• Family history may reveal consanguinity or affected siblings (AR inheritance)

1. Progressive ataxia beginning in childhood/adolescence (age 5–15)
2. Areflexia with upgoing plantars — this combination is near-pathognomonic
3. Pes cavus — especially bilateral in a child with gait difficulties
4. Scoliosis — especially progressive, in combination with neurological signs
5. Family history of ataxia, cardiomyopathy, or consanguinity (AR pattern)
6. Cardiac murmur or ECG abnormalities in a child with ataxia

• Progressive ataxia significantly impacts motor development milestones — initially the child may have achieved normal milestones, but regression or plateau is noted
• Cognitive function is typically preserved — this is an important distinction from many other neurodegenerative disorders. The child is intellectually intact but physically disabled
• Psychosocial impact is enormous: a previously active child who played sport becomes wheelchair-bound → depression, anxiety, school difficulties, social isolation → family-centred care and psychological support are essential

• The child (especially adolescents) should be involved in discussions about their condition (assent)
• Genetic counselling for the family is critical — AR inheritance means:
  • Each sibling has a 25% chance of being affected
  • Each sibling has a 50% chance of being a carrier
  • Carrier testing and prenatal diagnosis are available

• As FRDA patients survive into adulthood, transition from paediatric to adult services is an important consideration
• Involves coordination between paediatric neurology, cardiology, endocrinology, orthopaedics, physiotherapy, occupational therapy, speech therapy, and psychological services

The core presentation of Friedreich ataxia is:

• Progressive ataxia (combined sensory + cerebellar)
• Areflexia with extensor plantars (mixed LMN + UMN pattern)
• Pes cavus and scoliosis (skeletal deformities)
• Cardiomyopathy (hypertrophic)
• Onset in childhood/adolescence

Therefore, the differential diagnosis must address:

1. Other causes of progressive ataxia in childhood (the primary differential)
2. Conditions that mimic the mixed LMN/UMN pattern (areflexia + upgoing plantars)
3. Other causes of childhood hypertrophic cardiomyopathy with neurological features

From GC lecture slides: The approach to any neurological presentation should systematically ask "Where is the lesion?" (anatomical localisation) then "What is the lesion?" (pathological differentials), using the mnemonic: Vascular, Infection, Neoplasm, Degenerative, Inflammatory, Congenital, Autoimmune, Trauma/Toxins, Endocrine ^[5][6]

Where is the lesion? ^[5][6] In FRDA, multiple sites are involved simultaneously:

• Posterior columns (sensory ataxia)
• Spinocerebellar tracts (cerebellar ataxia)
• Corticospinal tracts (UMN signs)
• Dorsal root ganglia (areflexia, sensory loss)
• Dentate nucleus of cerebellum

The differential must therefore include any condition that can affect multiple levels of the neuraxis — the spinal cord, cerebellum, peripheral nerves, and/or dorsal root ganglia.

Physical examination should assess: distribution and character of weakness (unilateral/bilateral, proximal/distal, UMN/LMN pattern), sensory impairment (proprioception, vibration, dermatomal/sensory level), cranial nerve and cerebellar signs, and sphincter disturbances. ^[7]

The signature finding in FRDA is areflexia + upgoing plantars. Other conditions with this mixed pattern:

From senior notes: Wilson disease can mimic Parkinsonism (extrapyramidal deposition of copper). Penicillamine causes worsened neurological symptoms initially. Fulminant hepatic failure from Wilson disease presents with Coombs-negative haemolytic anaemia. ^[10]

In any child with progressive ataxia, the priority is to identify treatable conditions before settling on an untreatable diagnosis like FRDA:

If any of the following are present, reconsider the diagnosis:

• Cognitive decline or intellectual disability → think metabolic/storage disorders, NCL, mitochondrial
• Seizures → think NCL, mitochondrial, metabolic
• Ophthalmoplegia → think mitochondrial (Kearns-Sayre), SCA
• Skin findings (telangiectasia, ichthyosis) → think A-T, Refsum
• Hepatosplenomegaly or liver disease → think Wilson, metabolic/storage
• Brisk reflexes throughout → think SCA, HSP (not FRDA)
• Non-progressive course → think CP
• Acute onset → think post-infectious, tumour, stroke

Unlike many conditions (e.g., rheumatic fever with Jones criteria, or SLE with SLICC criteria), Friedreich ataxia does not have a universally adopted clinical diagnostic criteria set published by an international body. This is because:

1. Genetic testing is definitive — since 1996, when the FXN gene and GAA expansion were identified, diagnosis has shifted from clinical criteria to molecular confirmation
2. Historical clinical criteria (e.g., Harding 1981, Geoffroy 1976) were used before the genetic era and remain useful for clinical suspicion — telling you when to order the genetic test

These criteria were developed by Professor Anita Harding and remain the most widely cited clinical diagnostic framework. They define who should be suspected of having FRDA based on clinical features alone.

Harding Essential (Mandatory) Criteria:

Harding Additional (Supportive) Criteria — present within 5 years of onset:

In current clinical practice (2024–2026), the diagnosis of FRDA is confirmed by genetic testing:

Key principle: Friedreich ataxia is caused by GAA trinucleotide repeat expansion in the non-coding intron 1 of the FXN gene (chromosome 9q21). Homozygous expansion in ~96% of cases. Compound heterozygotes account for ~4%. ^[1][2][13]

Severity depends on number of expansions: earlier onset and loss of ambulation, more cardiomyopathy with larger expansions. ^[13]

The diagnostic pathway for a paediatric patient with suspected FRDA involves:

1. Clinical suspicion — based on history and examination findings
2. Exclusion of treatable mimics — AVED, Wilson disease (as discussed in DDx section)
3. Molecular genetic testing — the definitive diagnostic step
4. Baseline assessment of multi-system involvement — cardiac, endocrine, skeletal, ophthalmological

Why exclude treatable mimics before genetic testing?

• Genetic testing may take weeks to return results
• If the child has AVED (vitamin E deficiency), every week of delay means ongoing neuronal damage that could have been prevented
• Wilson disease can cause irreversible neurological damage if untreated
• These screening tests (vitamin E, caeruloplasmin, slit-lamp) are cheap, fast, and widely available

Why sequence the coding region if only one expanded allele is found?

• ~4% of FRDA patients are compound heterozygotes — they carry a GAA expansion on one allele and a point mutation, missense mutation, or deletion on the other
• Standard GAA repeat analysis only detects expansions, NOT point mutations
• If you find one expanded allele in a patient with a convincing clinical picture, you must sequence the FXN coding region to look for the second pathogenic variant

Paediatric consideration: In Hong Kong, genetic testing for FRDA is available through referral centres (e.g., Clinical Genetic Service, Department of Health). Genetic counselling should be offered to the family before and after testing, covering implications for siblings (25% recurrence risk in AR), carrier testing, and prenatal diagnosis options.

Interpreting repeat sizes:

• The smaller of the two GAA alleles (GAA1) is the strongest predictor of disease severity and age of onset
• Why? Because the allele with the fewer repeats produces more residual frataxin than the allele with more repeats, so it is the "rate-limiting" allele

There is currently no cure for Friedreich ataxia. Until very recently, management was entirely supportive and symptomatic. However, in 2023 the first disease-modifying therapy — omaveloxolone (Skyclarys®) — was approved by the FDA, representing a paradigm shift.

Management of Friedreich ataxia is supportive. ^[14]

Despite this historic teaching point, the management framework in 2025–2026 has evolved to include:

1. Disease-modifying pharmacotherapy (omaveloxolone — approved FDA 2023, EMA 2024)
2. Symptomatic and supportive multidisciplinary care (the backbone of management)
3. Surveillance and prevention of complications (cardiac, endocrine, skeletal, respiratory)
4. Genetic counselling and family-centred care (central to paediatric practice)
5. Emerging therapies (gene therapy, frataxin replacement — investigational)

FRDA is a multi-system disease affecting the nervous system, heart, endocrine pancreas, skeleton, eyes, and ears. No single specialist can manage all aspects. The paediatric MDT should include:

Why does HCM develop rather than DCM initially?

• In the early phase, cardiomyocytes are stressed but still viable → they hypertrophy as a compensatory response to impaired energy production (trying to maintain contractile force with more muscle mass)
• This is similar to how skeletal muscle hypertrophies under resistance training — except here the stimulus is pathological

• ~60% of FRDA patients die from cardiac causes: either progressive heart failure or sudden arrhythmic death
• Mean age of death: ~35–40 years (range 20s–60s; larger GAA repeats → earlier cardiac death)
• In paediatric patients, cardiac death can occur in the late teens or twenties — emphasising the need for aggressive cardiac monitoring from childhood