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11 notes available
1 Last Minute Review 2 Parkinson Disease 3 Atypical Parkinsonism 4 Tremor 5 Dystonia 6 Chorea & Ballism 7 Myoclonus 8 Tics & Tourette Syndrome 9 Wilson Disease & NBIA 10 Hereditary Ataxias 11 Drug-Induced Movement Disorders
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Hereditary Ataxias

Hereditary Ataxias

What You'll Learn

  • Friedreich ataxia — AR, GAA trinucleotide repeat in FXN gene (frataxin), onset <25 years, progressive gait/limb ataxia, absent DTRs + upgoing toes, hypertrophic cardiomyopathy (#1 cause of death), scoliosis, pes cavus, diabetes
  • SCA3 (Machado-Joseph disease) is the most common autosomal dominant SCA worldwide — the classic board-tested dominant SCAs (1, 2, 3, 6, 7, 17) are CAG polyglutamine repeat disorders with anticipation, but the broader SCA universe includes non-CAG and noncoding repeat disorders
  • Ataxia-telangiectasia — AR, ATM gene, cerebellar ataxia onset 1–3 years, oculomotor apraxia, conjunctival telangiectasias, immunodeficiency (low IgA), elevated AFP, cancer risk (lymphoma/leukemia), radiosensitivity
  • SCA6, EA2, and FHM1 are allelic disorders of CACNA1A — high-yield board association
  • Always exclude acquired causes: alcohol, paraneoplastic (anti-Yo, anti-Tr), gluten ataxia, vitamin E/B12 deficiency
HighYield Pearls
  • Friedreich ataxia (FXN, GAA repeat in intron 1, chromosome 9, AR): teenager with gait ataxia + areflexia + extensor plantar response + dysarthria + scoliosis + pes cavus + hypertrophic cardiomyopathy (#1 cause of death) + diabetes; frataxin loss → mitochondrial iron accumulation; sensory axonal neuropathy with absent vibration/proprioception.
  • SCA3 / Machado-Joseph (ATXN3, CAG, chr 14) is the most common SCA worldwide: bulging eyes (lid retraction), faciolingual fasciculations, dystonia, parkinsonism, restless legs.
  • SCA2 (ATXN2, CAG, chr 12) → slow saccades + areflexia; SCA1 (ATXN1, CAG, chr 6) → pyramidal signs prominent.
  • SCA6 (CACNA1A, CAG, chr 19) = pure late-onset cerebellar ataxia — same gene as EA2 and familial hemiplegic migraine type 1 (board favorite triad).
  • SCA7 (ATXN7, CAG, chr 3) = pigmentary macular degeneration + ataxia — only SCA with prominent visual loss; strong genetic anticipation.
  • Episodic ataxias: EA1 (KCNA1) → brief seizure-like attacks + interictal myokymia (AD); EA2 (CACNA1A) → prolonged attacks + interictal nystagmus, acetazolamide-responsive.
  • Ataxia-telangiectasia (ATM, AR): childhood ataxia + oculocutaneous telangiectasias + immunodeficiency + elevated AFP + radiosensitivity.
  • AOA1 (APTX) = ataxia + oculomotor apraxia + hypoalbuminemia/hypercholesterolemia; AOA2 (SETX) = ataxia + oculomotor apraxia + elevated AFP (no telangiectasias).
  • ARSACS (SACS, AR, French-Canadian): spastic ataxia + retinal hypermyelination + sensorimotor neuropathy. AVED (TTPA): Friedreich mimic that is treatable with high-dose vitamin E.
  • Anticipation in CAG SCAs — paternal transmission causes larger expansions and earlier onset.
  • Treatment: supportive; acetazolamide for EA2; vitamin E for AVED; iron chelation has not improved Friedreich outcomes; omaveloxolone (Skyclarys, FDA-approved 2023) for Friedreich ataxia in patients ≥16 years — monitor ALT/AST, bilirubin, BNP, and lipids.
  • Workup of unexplained ataxia: serum vitamin E, copper/ceruloplasmin (Wilson), VLCFA (adult X-ALD), AFP (AT/AOA2), albumin/cholesterol (AOA1), anti-gliadin/tTG (gluten ataxia), ANNA-1 (paraneoplastic), GAD65, B12/copper (vacuolar myelopathy), targeted genetic panel.
  • Pearl: pure cerebellar ataxia after age 50 → SCA6 or sporadic adult-onset cerebellar ataxia (SAOA); add MSA-C to the differential.
🔍 Quick ReferenceClinical · Imaging · Genetics / pathology
Clinical signs
  • Areflexia + extensor plantars + cardiomyopathy + scoliosis + diabetes → Friedreich ataxia
  • Slow saccades + areflexia → SCA2 (intermediate expansions also confer ALS risk)
  • Bulging eyes (lid retraction) + faciolingual fasciculations + parkinsonism + dystonia → SCA3 / Machado-Joseph
  • Pure late-onset cerebellar ataxia (>50 years) → SCA6 (or SAOA / MSA-C)
  • Pigmentary maculopathy + visual loss + ataxia → SCA7
  • Chorea + ataxia + Huntington-like phenotype → SCA17 (HDL4) or DRPLA (myoclonic epilepsy)
  • Brief (seconds–minutes) ataxic attacks + interictal myokymia → EA1
  • Prolonged (hours) ataxic attacks + interictal downbeat nystagmus + acetazolamide-responsive → EA2
  • Episodic ataxia triggered by stress/exertion/caffeine → EA2 (CACNA1A)
  • Oculomotor apraxia + conjunctival telangiectasias + recurrent sinopulmonary infections → ataxia-telangiectasia
  • Oculomotor apraxia without telangiectasias → AOA1 / AOA2
  • Pes cavus + hammer toes + spastic ataxia → Friedreich or ARSACS
Imaging signs
  • Cervical spinal cord atrophy with relatively spared cerebellum → Friedreich ataxia
  • Pancerebellar atrophy in a patient >50 years → SCA6 (or sporadic SAOA)
  • Pontocerebellar atrophy + hot-cross-bun sign → MSA-C (key differential of late-onset SCA)
  • Normal cerebellum early in disease → SCA1/2/3 (atrophy lags behind clinical signs)
  • T2 hyperintensity in pons / transverse pontine fibers → SCA3 (can mimic MSA-C)
  • Thinning of the corpus callosum + linear pontine T2 hypointensities → ARSACS
  • Retinal pigmentary changes on fundoscopy → SCA7 (also NARP, Refsum, abetalipoproteinemia)
  • Thickened/hypermyelinated retinal nerve fibers on OCT → ARSACS
Genetics / pathology
  • GAA repeat in FXN intron 1 (AR, gene silencing — not toxic protein) → Friedreich ataxia
  • CAG polyglutamine repeat (AD, anticipation, paternal expansion) → SCA1 (ATXN1), SCA2 (ATXN2), SCA3 (ATXN3), SCA7 (ATXN7), SCA17 (TBP)
  • CACNA1A — CAG expansion = SCA6; nonsense/loss-of-function = EA2; missense = familial hemiplegic migraine type 1
  • KCNA1 (potassium channel Kv1.1, AD) → EA1
  • ATM (AR, double-strand break repair defect) → ataxia-telangiectasia
  • APTX (aprataxin, AR) → AOA1; SETX (senataxin, AR) → AOA2
  • SACS (sacsin, AR, French-Canadian founder) → ARSACS
  • TTPA (α-tocopherol transfer protein, AR) + very low vitamin E → AVED (treatable Friedreich mimic)
  • CAG repeat in ATN1 (AD, Japanese predominance) → DRPLA (chorea-ataxia-myoclonus)
Friedreich Ataxia

Genetics

  • Autosomal recessive — most common inherited ataxia worldwide and the most common autosomal recessive ataxia
  • FXN gene (chromosome 9q21) encoding frataxin — mitochondrial iron-sulfur cluster assembly protein
  • GAA trinucleotide repeat expansion in intron 1 (only trinucleotide repeat in an intron among board-testable repeats)
    • Normal: 5–33 repeats; borderline/premutation: 34–65; pathogenic: ≥66 repeats (typically 600–1200 on the smaller allele)
    • ~96% homozygous GAA expansions; ~4% compound heterozygous (expansion + point mutation)
  • Mechanism: GAA expansion → DNA triplex structure → gene silencing → frataxin deficiency → mitochondrial iron accumulation → oxidative stress
  • No anticipation (unlike dominant SCAs) — repeat size correlates with earlier onset and cardiomyopathy severity

Clinical Features

Neurologic

  • Onset typically <25 years (mean ~10–15 years); progressive gait and limb ataxia; late-onset FRDA (>25y) with milder phenotype/retained reflexes occurs in ~15%
  • Absent deep tendon reflexes — dorsal root ganglia neuronal loss (large sensory neurons)
  • Upgoing toes (Babinski sign) — corticospinal tract degeneration
  • Dysarthria (cerebellar), loss of vibration and proprioception (posterior columns)

Systemic

  • Hypertrophic cardiomyopathy (HCM) → may progress to dilated cardiomyopathy (DCM); #1 cause of death
  • Scoliosis (>80%), pes cavus (high-arched feet), hammer toes
  • Diabetes mellitus (~25–30%) or glucose intolerance

Diagnosis

  • Genetic testing: GAA repeat expansion analysis (gold standard)
  • MRI: Cervical spinal cord atrophy is dominant; cerebellar atrophy is mild and late
  • NCS/EMG: Sensory axonal neuropathy (absent/reduced SNAPs, normal motor conduction)
  • Echocardiogram: Screen for HCM at diagnosis and regularly thereafter
  • Treatment: Omaveloxolone (Skyclarys) — FDA-approved 2023 for Friedreich ataxia in patients aged ≥16 years; Nrf2 activator. Monitor ALT/AST, bilirubin, BNP, and lipid panel. Supportive: PT/OT, cardiac monitoring, diabetes screening
  • Emerging therapies: HSCT in trials; AAV-based gene therapy in development
💎 Board Pearl
  • Absent DTRs + Babinski sign + cardiomyopathy + scoliosis + pes cavus in a teenager = Friedreich ataxia until proven otherwise.
  • GAA repeat in an intron (not a coding CAG repeat) — causes gene silencing, NOT a toxic protein. Unique among trinucleotide repeat disorders.
  • Cardiomyopathy is the #1 cause of death — always screen with echocardiogram.
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