Hereditary Ataxias
Hereditary Ataxias
What Do You Need to Know?
- 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 — all major SCAs are CAG polyglutamine repeat disorders with anticipation
- 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
Friedreich Ataxia
Genetics
- Autosomal recessive — most common inherited ataxia overall
- 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; disease: ≥66 repeats (typically 600–1200)
- ~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
- 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; cerebellum relatively spared early
- 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); Nrf2 activator. Supportive: PT/OT, cardiac monitoring, diabetes screening
💎 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.
Autosomal Dominant Spinocerebellar Ataxias (SCAs)
Overview
- 40+ subtypes; most are CAG polyglutamine repeat expansions with anticipation (especially paternal)
- Progressive cerebellar ataxia + variable “plus” features; SCA3 (MJD) is the most common worldwide
Major SCAs
| Type | Gene | Repeat | Distinguishing Features |
|---|---|---|---|
| SCA1 | ATXN1 | CAG | Pyramidal signs, early bulbar dysfunction |
| SCA2 | ATXN2 | CAG | Slow saccades (most characteristic), hyporeflexia; intermediate expansions → ALS risk |
| SCA3 (MJD) | ATXN3 | CAG | Most common worldwide; lid retraction (“bulging eyes”), nystagmus, neuropathy, dystonia |
| SCA6 | CACNA1A | CAG | Pure cerebellar, late onset (>50), small repeat (20–33); allelic with EA2 and FHM1 |
| SCA7 | ATXN7 | CAG | Retinal degeneration (pigmentary maculopathy) — only SCA with visual loss |
| SCA17 | TBP | CAG | Huntington-like phenotype (chorea, dementia, psychiatric); also called HDL4 |
💎 Board Pearl
- Ataxia + slow saccades = SCA2. Ataxia + retinal degeneration = SCA7. Ataxia + bulging eyes/lid retraction = SCA3.
- SCA6 = CACNA1A = EA2 = FHM1 — three disorders, one gene. Board favorite.
- SCA6 has uniquely small repeat expansions (20–33 vs. typically >40 for other SCAs).
Ataxia-Telangiectasia (AT)
Genetics & Pathophysiology
- Autosomal recessive — ATM gene (chromosome 11q22); DNA damage response kinase
- Defective double-strand DNA break repair → radiosensitivity + genomic instability + cancer predisposition
Clinical Features
- Cerebellar ataxia onset age 1–3 years (progressive; wheelchair by teens)
- Oculomotor apraxia: Difficulty initiating saccades; head thrusts to shift gaze
- Telangiectasias: Conjunctival and ears/face; appear age 3–6 years (may lag behind ataxia)
- Immunodeficiency: Low IgA (most common), low IgG2, low IgE; recurrent sinopulmonary infections
- Cancer predisposition: Lymphoma and leukemia (especially T-cell); 100-fold increased risk
- Radiosensitivity: Severe reactions to radiation therapy — avoid unnecessary radiation
Diagnosis & Management
- Elevated serum AFP (α-fetoprotein) — present in >95%; key screening marker
- Low immunoglobulins (IgA, IgG2, IgE); elevated chromosomal breakage on karyotype; ATM gene sequencing
- Supportive care; IVIG for immunodeficiency; cancer surveillance; avoid radiation
- Heterozygous ATM carriers (~1% of population) have increased breast cancer risk
💎 Board Pearl
- Ataxia + telangiectasias + elevated AFP + immunodeficiency = ataxia-telangiectasia. Classic board triad.
- Radiosensitivity is a defining feature — if a board question mentions severe radiation reaction in a child with ataxia, think AT.
- ATM carriers (heterozygotes) have increased breast cancer risk — testable fact.
Ataxia with Oculomotor Apraxia (AOA1 & AOA2)
AOA1
- Gene: APTX (aprataxin) — autosomal recessive; onset 2–10 years
- Cerebellar ataxia + oculomotor apraxia + severe sensorimotor axonal neuropathy
- Lab clues: Low serum albumin and elevated cholesterol
AOA2
- Gene: SETX (senataxin) — autosomal recessive; later onset (10–22 years)
- Cerebellar ataxia, milder oculomotor apraxia, sensorimotor neuropathy
- Lab clue: Elevated AFP (like AT, but NO telangiectasias or immunodeficiency)
AOA Comparison
| Feature | AOA1 (APTX) | AOA2 (SETX) | AT (ATM) |
|---|---|---|---|
| Onset | 2–10 years | 10–22 years | 1–3 years |
| Telangiectasias | No | No | Yes |
| Immunodeficiency | No | No | Yes |
| AFP | Normal | Elevated | Elevated |
| Albumin | Low | Normal | Normal |
| Cholesterol | Elevated | Normal | Normal |
| Cancer risk | No | No | Yes |
💎 Board Pearl
- Ataxia + oculomotor apraxia + low albumin + high cholesterol = AOA1 (APTX).
- Ataxia + oculomotor apraxia + elevated AFP but NO telangiectasias = AOA2 (SETX).
- AOA2 and AT both have elevated AFP — but AT has telangiectasias, immunodeficiency, and cancer risk.
Episodic Ataxias
EA1
- Gene: KCNA1 (potassium channel Kv1.1) — autosomal dominant
- Episodes last seconds to minutes; triggered by startle, sudden movement
- Interictal myokymia (continuous rippling muscle movements) — distinguishing feature
- Treatment: Acetazolamide or carbamazepine
EA2
- Gene: CACNA1A (P/Q-type calcium channel) — autosomal dominant
- Episodes last hours; triggered by stress, exercise, caffeine, alcohol
- Interictal downbeat nystagmus; may develop progressive ataxia
- Treatment: Acetazolamide (very effective)
- Allelic with SCA6 and FHM1 — same gene (CACNA1A), different mutations
EA Comparison
| Feature | EA1 (KCNA1) | EA2 (CACNA1A) |
|---|---|---|
| Duration | Seconds to minutes | Hours |
| Interictal finding | Myokymia | Downbeat nystagmus |
| Channel | Potassium (Kv1.1) | Calcium (P/Q-type) |
| Allelic disorders | None major | SCA6, FHM1 |
| Treatment | Acetazolamide, carbamazepine | Acetazolamide |
💎 Board Pearl
- Brief ataxia episodes + myokymia = EA1. Prolonged ataxia episodes + downbeat nystagmus = EA2.
- CACNA1A triad: EA2 / SCA6 / FHM1 — one gene, three phenotypes.
Autosomal Recessive Ataxias — Overview
| Disorder | Gene/Protein | Key Features | Diagnostic Clue |
|---|---|---|---|
| Friedreich | FXN (frataxin) | Absent DTRs + Babinski, cardiomyopathy, scoliosis | GAA repeat; sensory axonal neuropathy |
| AT | ATM | Telangiectasias, oculomotor apraxia, immunodeficiency | Elevated AFP, low IgA |
| AOA1 | APTX | Oculomotor apraxia, severe neuropathy | Low albumin, high cholesterol |
| AOA2 | SETX | Later onset, oculomotor apraxia | Elevated AFP (no telangiectasias) |
| AVED | TTPA (α-TTP) | Friedreich-like WITHOUT cardiomyopathy | Very low vitamin E; treatable |
| Abetalipoproteinemia | MTP | Fat malabsorption, acanthocytes, retinitis pigmentosa | Absent LDL/VLDL; treat with vitamin E |
| Refsum | PHYH | Retinitis pigmentosa, neuropathy, ichthyosis | Elevated phytanic acid; dietary restriction |
| ARSACS | SACS (sacsin) | Spastic ataxia, neuropathy; French-Canadian | Thickened retinal nerve fibers; pontine MRI changes |
AVED (Ataxia with Vitamin E Deficiency)
- TTPA gene encoding α-tocopherol transfer protein — AR
- Mimics Friedreich ataxia (ataxia, absent DTRs, proprioceptive loss) but no cardiomyopathy
- Very low serum vitamin E with normal lipid absorption
- Treatable: High-dose vitamin E supplementation prevents progression
Abetalipoproteinemia (Bassen-Kornzweig)
- MTP gene — AR; inability to form chylomicrons and VLDL
- Fat malabsorption, steatorrhea, acanthocytes on blood smear, retinitis pigmentosa, ataxia, neuropathy
- Labs: Absent LDL/VLDL/apoB; very low cholesterol and triglycerides
- Treatment: High-dose fat-soluble vitamins (especially vitamin E and A)
Refsum Disease
- Defective phytanic acid α-oxidation → phytanic acid accumulation
- Tetrad: Retinitis pigmentosa + peripheral neuropathy + cerebellar ataxia + elevated CSF protein
- Also: ichthyosis, cardiomyopathy; treatment: phytanic acid-restricted diet
Clinical Pearl
- Friedreich-like ataxia without cardiomyopathy → check vitamin E level (AVED is treatable!).
- Acanthocytes + low lipids = abetalipoproteinemia; acanthocytes + normal lipids + lip biting = neuroacanthocytosis.
Acquired Ataxia — Differential Diagnosis
Key Acquired Causes
- Alcohol/nutritional: Anterior superior vermis degeneration; gait > limb ataxia; thiamine deficiency
- Paraneoplastic: Subacute (weeks), severe, often irreversible; anti-Yo (ovarian/breast), anti-Tr/DNER (Hodgkin), anti-Hu (SCLC)
- Gluten ataxia: Anti-gliadin antibodies; may occur without GI symptoms; gluten-free diet can stabilize
- Vitamin deficiencies: Vitamin E, B12 (subacute combined degeneration), thiamine (Wernicke)
- Toxins: Phenytoin (irreversible cerebellar atrophy), lithium, mercury
- Structural: Posterior fossa tumors, Chiari malformation, stroke, MS
💎 Board Pearl
- Subacute cerebellar ataxia in a middle-aged woman → paraneoplastic until proven otherwise (anti-Yo, pelvic imaging).
- Anti-Yo = ovarian/breast; anti-Tr/DNER = Hodgkin lymphoma.
- Chronic phenytoin → irreversible cerebellar atrophy. Purkinje cells are particularly vulnerable.
- New ataxia workup: B12, vitamin E, TSH, anti-gliadin antibodies, paraneoplastic panel.
References
- Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3-8.
- Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe). Lancet Neurol. 2021;20(5):339-351.
- Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019;5(1):24.
- Rothblum-Oviatt C, Wright J, Lefton-Greif MA, et al. Ataxia-telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):159.
- Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636-646.
- Jen JC, Graves TD, Hess EJ, et al. Primary episodic ataxias: diagnosis, pathogenesis, and treatment. Brain. 2007;130(Pt 10):2484-2493.
- Hadjivassiliou M. Gluten ataxia in perspective: epidemiology, genetic susceptibility, and clinical characteristics. Brain. 2003;126(Pt 3):685-691.
- Shams’ili S, Grefkens J, de Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies. Brain. 2003;126(Pt 6):1409-1418.