Hereditary Ataxias
5 sections · 25 min
Clinical Approach to Ataxia
Ataxia is the inability to generate a normal voluntary movement trajectory that cannot be attributed to weakness or involuntary movement. It results from dysfunction of the cerebellum, proprioceptive pathways (dorsal columns, peripheral nerves), or vestibular system. The most critical initial step is determining the temporal pattern of ataxia — acute, episodic, subacute, or chronic/progressive — because this guides both the differential diagnosis and the urgency of evaluation.
Key Points
- Cerebellar ataxia: broad-based gait, dysmetria, dysdiadochokinesia, nystagmus, scanning dysarthria — localizes to ipsilateral cerebellar hemisphere or vermis
- Sensory (proprioceptive) ataxia: worsened by eye closure (positive Romberg), absent with cerebellar findings — caused by large-fiber peripheral neuropathy or dorsal column disease
- Acute onset (hours to days): consider toxic/medication exposure, post-infectious cerebellitis, stroke, multiple sclerosis, Wernicke encephalopathy — neuroimaging is urgent
- Episodic ataxia: EA1 (KCNA1, brief seconds-long episodes + myokymia) and EA2 (CACNA1A, prolonged episodes + nystagmus, responds to acetazolamide)
- Chronic/progressive ataxia in a child or young adult with family history: hereditary ataxia until proven otherwise — systematic genetic evaluation is warranted
✦ Check Your Understanding
A 45-year-old woman presents with a 5-year history of progressive gait unsteadiness and bilateral hand tremor. She has no family history of ataxia. Examination shows gait ataxia, limb dysmetria, and downbeat nystagmus. MRI shows cerebellar vermis atrophy. Vitamin B12, vitamin E, thyroid function, and anti-TTG antibodies are all normal. The most appropriate next diagnostic step is:
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Differential Diagnosis of Chronic/Progressive Ataxia
Chronic progressive ataxia has a broad differential spanning genetic, metabolic, structural, and acquired causes. The age of onset, mode of inheritance, associated neurological features (neuropathy, pyramidal signs, ophthalmoplegia), and systemic findings (cardiomyopathy, diabetes) provide critical diagnostic clues. Treatable causes must be excluded before accepting a genetic diagnosis.
Acute Ataxia Differential
| Cause | Key Clue |
|---|---|
| Drug / Toxin | Most common cause in young children |
| Acute cerebellitis | Post-infectious (varicella, EBV) |
| Basilar migraine | Aura + headache; episodic |
| OMA / Neuroblastoma | Opsoclonus-myoclonus; MIBG, urine HVA/VMA |
| Conversion / Functional | Inconsistent exam; positive signs |
| Stroke / MS / Miller-Fisher | Acute onset; MRI, LP |
Recurrent (Episodic) Ataxia Differential
| Disorder | Gene / Distinguishing Feature |
|---|---|
| EA1 | KCNA1 — myokymia pathognomonic; acetazolamide |
| EA2 | CACNA1A — hours-long episodes; same gene as SCA6 |
| GLUT1 deficiency | Fasting-provoked; low CSF glucose |
| PDH deficiency | Ketogenic diet responsive |
| MSUD intermittent | Branched-chain amino acids ↑ |
| Hartnup disease | Aminoaciduria; niacin supplementation |
Chronic / Progressive Ataxia by Inheritance
| Inheritance | Key Disorders |
|---|---|
| Autosomal Recessive | Friedreich (FXN) — GAA repeat; AT (ATM) — elevated AFP; AOA1 (APTX) / AOA2 (SETX); AVED (TTPA) — treatable; Abetalipoproteinemia; VWM (eIF2B); GLUT1 chronic form |
| Autosomal Dominant (SCAs) | SCA1 (ATXN1) — pyramidal; SCA2 (ATXN2) — slow saccades; SCA3 (ATXN3) — most common; SCA6 (CACNA1A) — pure cerebellar; SCA7 (ATXN7) — macular degen; SCA17 (TBP) — cognitive; DRPLA — East Asian |
| X-Linked | X-ALD (ABCD1); PMD (PLP1); FXTAS (FMR1 premutation) |
Key Points
- Autosomal recessive ataxias (typical onset <25 years): Friedreich ataxia (most common AR ataxia, FXN GAA repeat), ataxia-telangiectasia (ATM, elevated AFP, immunodeficiency), ataxia with vitamin E deficiency (TTPA), abetalipoproteinemia
- Autosomal dominant ataxias (SCAs): SCAs 1/2/3/6/7 are most common; SCA3 (Machado-Joseph disease) is most prevalent worldwide; typically adult onset with anticipation
- Metabolic ataxias: Coenzyme Q10 deficiency (CoenzymeQ10 level + lactate/pyruvate), Niemann-Pick type C (filipin staining), mitochondrial disorders (lactate, mtDNA/nuclear gene panel), Wilson disease (serum ceruloplasmin, slit-lamp exam)
- Treatable causes to rule out early: vitamin B12 deficiency, vitamin E deficiency, thiamine deficiency, hypothyroidism, celiac disease (anti-TTG antibodies), paraneoplastic (anti-Yo, anti-Hu in adults >40)
✦ Check Your Understanding
A 55-year-old man presents with progressive gait ataxia, chronic cough, and sensory neuropathy. NCS shows absent sensory nerve action potentials (SNAPs) bilaterally. Vestibular testing reveals bilateral vestibular areflexia. Brain MRI shows mild cerebellar atrophy. This triad of cerebellar ataxia, sensory neuropathy, and bilateral vestibulopathy is most suggestive of:
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Diagnostic Evaluation for Hereditary Ataxia
The evaluation of a patient with chronic progressive ataxia requires a tiered approach beginning with treatable and common diagnoses. Genetic testing strategy depends on the clinical phenotype, mode of inheritance, and age of onset. Neuroimaging, neurophysiology, and targeted metabolic testing should precede broad genetic panels in most cases.
Acute Ataxia Workup
| Test | Indication / Target |
|---|---|
| CT head (stat) | Hemorrhage, posterior fossa mass |
| Urine tox screen | #1 cause of acute ataxia in young children |
| CMP | Electrolytes, glucose |
| MRI/MRA | Stroke, demyelination |
| LP | Cerebellitis, MS, Miller-Fisher (if encephalopathic) |
| MIBG scan + urine HVA/VMA | OMA / neuroblastoma workup |
Recurrent (Episodic) Ataxia Workup
| Test | Target Diagnosis |
|---|---|
| MRI + MRS | Cerebellar atrophy, lactate peak |
| Fasting CSF glucose | GLUT1 deficiency (CSF:serum glucose ratio <0.4) |
| CSF lactate / pyruvate | PDH deficiency, mitochondrial |
| CACNA1A / KCNA1 testing | EA2 / EA1 |
| Plasma amino acids | MSUD intermittent |
| Urine amino acids | Hartnup disease |
Chronic / Progressive Ataxia Workup
| Category | Tests |
|---|---|
| Imaging | MRI + MRS — cerebellar atrophy pattern, lactate peak, white-matter signal |
| Treatable metabolic | Vitamin E level (AVED — treatable!), CoQ10, ceruloplasmin, lipid panel, B12, TSH, anti-TTG |
| CSF | Glucose (GLUT1), OCBs (MS), lactate (mitochondrial) |
| AFP | Elevated in ataxia-telangiectasia (ATM) and AOA2 (SETX) |
| NCS / EMG | Large-fiber sensory neuropathy — cardinal in Friedreich, AVED, CANVAS |
| Genetic testing | Disease-specific repeat testing (FXN, SCAs, RFC1) — standard WES/WGS does NOT detect repeat expansions |
Key Points
- MRI brain: cerebellar atrophy (global vs. vermis-predominant), T2 signal in dentate nuclei or brainstem, spinal cord atrophy — patterns guide differential
- Nerve conduction studies: large-fiber sensory neuropathy is a cardinal feature of Friedreich ataxia and several other ARAs; also present in CMT-associated ataxia
- Metabolic screen: vitamin E, AFP, coenzyme Q10, lactate/pyruvate, amino acids, organic acids, lipid panel; FXN GAA repeat expansion testing (repeat-primed PCR) is the first-line test when FRDA is suspected; frataxin protein level (ELISA) is a supportive/screening test
- Genetic testing algorithm: (1) FXN GAA repeat expansion testing (repeat-primed PCR) if FRDA suspected — this is the definitive first-line test; (2) targeted SCA repeat panel if AD family history; (3) comprehensive ataxia gene panel or exome if above non-diagnostic
- Repeat expansion testing: standard WES does NOT detect trinucleotide or pentanucleotide repeat expansions; modern WGS may screen for some short tandem repeat disorders but with variable sensitivity — dedicated repeat-primed PCR or long-read sequencing remains the gold standard for FXN, ATXN1-3, ATXN7, SCA36. This testing limitation significantly affects diagnostic yields (see the [[diagnostic-yields|Diagnostic Yields]] module)
✦ Check Your Understanding
When ordering genetic testing for a patient with chronic progressive ataxia, why is standard exome sequencing insufficient to detect Friedreich ataxia?
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Friedreich Ataxia: The Most Common Autosomal Recessive Ataxia
Friedreich ataxia (FRDA) is caused by biallelic expanded GAA trinucleotide repeats in intron 1 of the FXN gene, encoding frataxin — a mitochondrial protein critical for iron-sulfur cluster assembly. Repeat expansions silence frataxin expression through heterochromatin formation, leading to mitochondrial iron accumulation, oxidative stress, and progressive neurodegeneration. It is the most common hereditary ataxia worldwide, with a prevalence of approximately 1/50,000.
Key Points
- GAA repeat: normal alleles <33 repeats; pathogenic full-mutation alleles >66 repeats (most patients have 600–1000 repeats); ~96–98% of patients are homozygous for expansion; ~2–4% are compound heterozygous with a point variant
- Clinical features: onset typically by age 25 (mean 10–15 years); gait and limb ataxia, dysarthria, areflexia, large-fiber sensory neuropathy (loss of vibration/proprioception), pyramidal signs
- Systemic involvement: hypertrophic cardiomyopathy (present in ~80% — leading cause of death), diabetes mellitus (10–20%), scoliosis, foot deformity (pes cavus, hammertoes)
- MRI: spinal cord atrophy (especially cervical cord) is characteristic; cerebellar atrophy is a later finding; dentate nucleus T2 hypointensity from iron accumulation
- Omaveloxolone (Skyclarys): FDA-approved (2023) Nrf2 activator — first disease-modifying therapy for FRDA; reduces ataxia progression in patients ≥16 years
✦ Check Your Understanding
A 16-year-old presents with progressive gait ataxia since age 12, absent lower limb reflexes, loss of vibration sense, and cardiomyopathy on echocardiogram. The most appropriate first-line test is:
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Autosomal Dominant Spinocerebellar Ataxias
The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of >40 named disorders caused by variants (most commonly CAG repeat expansions) in different genes. They are characterized by progressive cerebellar ataxia with variable additional features (neuropathy, pyramidal signs, ophthalmoplegia, cognitive impairment). Genetic anticipation — worsening severity and earlier onset in successive generations — is a hallmark of the CAG repeat SCAs.
Key Points
- Most common SCAs worldwide: SCA3 (ATXN3, 14q32.12, most common globally), SCA1 (ATXN1), SCA2 (ATXN2), SCA6 (CACNA1A, mildest, late-onset, pure cerebellar), SCA7 (ATXN7, progressive macular degeneration is pathognomonic)
- Anticipation: expanded CAG repeats are unstable during paternal transmission, tending to increase in length — earlier onset and greater severity in children of affected fathers
- SCA2 distinguishing features: slow saccades + neuropathy; ATXN2 intermediate repeats (27–33) are a genetic risk factor for ALS
- SCA6: allelic disorder with episodic ataxia type 2 (EA2) — both caused by CACNA1A variants; SCA6 caused by small CAG expansions (21–33 repeats) in the same gene
- Genetic counseling: each child of an affected SCA parent has 50% risk of inheriting the expanded allele; penetrance is age-dependent; presymptomatic testing requires careful counseling following ACMG guidelines
✦ Check Your Understanding
A 35-year-old with progressive ataxia and slow saccades is evaluated. Brain MRI shows cerebellar and brainstem atrophy. Family history: his mother had similar symptoms. NCS shows a sensorimotor neuropathy. Which SCA is most consistent with this picture?
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