Ataxia in the adult

An adult with progressive cerebellar dysfunction: gait unsteadiness, limb dysmetria, dysarthria, oculomotor abnormalities (gaze-evoked nystagmus, slow saccades, square-wave jerks), and sometimes brainstem or extrapyramidal involvement. Onset is typically gradual over years. The key separations are genetic versus acquired, then by inheritance pattern (AD, AR, X-linked, mitochondrial, sporadic), and progressive versus episodic. A meticulous three-generation family history and a careful inventory of treatable mimics save the patient years of diagnostic limbo.

Three questions structure the workup:

1. Acquired or genetic? Alcohol use, paraneoplastic syndromes (anti-Yo, anti-Hu, anti-mGluR1), gluten ataxia, vitamin deficiencies (E, B12, copper), MS, and chronic toxin exposure (lithium, phenytoin, heavy metals) are all acquired adult ataxias that get missed when the workup jumps straight to a gene panel.
2. Family pattern. AD inheritance with anticipation points to the polyglutamine spinocerebellar ataxias. AR with onset in early adulthood is most commonly Friedreich ataxia (late-onset forms exist) or CTX. X-linked older male with intention tremor and parkinsonism is FXTAS. Apparently sporadic adult ataxia covers idiopathic late-onset cerebellar ataxia, multiple system atrophy of the cerebellar type (MSA-C), and de novo or unrecognized inheritance.
3. Progressive or episodic? Discrete attacks lasting minutes to hours with normal interictal exam point to episodic ataxia type 1 or 2 (EA1 KCNA1, EA2 CACNA1A). EA2 responds to acetazolamide.

Autosomal dominant: spinocerebellar ataxias

The spinocerebellar ataxias (SCAs) are the largest AD ataxia group. Most common forms in adults:

Anticipation (worsening severity, earlier onset across generations) is the polyQ-SCA fingerprint, most dramatic in SCA7. A grandfather with adult onset and a grandchild with juvenile onset is the classic vignette.

Autosomal recessive (adult-onset or late-onset forms)

• Friedreich ataxia: the most common AR ataxia; late-onset forms (LOFA, after age 25) exist and are easy to miss. Sensory ataxia, brisk reflexes paradoxically with absent ankle jerks, cardiomyopathy, scoliosis.
• Cerebrotendinous xanthomatosis (CYP27A1): treatable with chenodeoxycholic acid. Adult presentation can be ataxia with cognitive decline, tendon xanthomas, juvenile cataracts, chronic diarrhea history.
• Niemann-Pick disease type C, adult-onset: vertical supranuclear gaze palsy, psychiatric symptoms, splenomegaly, ataxia. Miglustat is partially disease-modifying.
• Ataxia with oculomotor apraxia type 2: AR ataxia with elevated AFP, oculomotor apraxia, peripheral neuropathy.

X-linked

• FXTAS (fragile X-associated tremor/ataxia syndrome): FMR1 premutation (55-200 CGG repeats). Older men (typically > 50) with intention tremor, gait ataxia, parkinsonism, executive dysfunction, neuropathy. Middle cerebellar peduncle T2 hyperintensity (MCP sign) on MRI is highly suggestive. Always ask whether grandchildren have fragile X syndrome; the family link clinches the premutation and reframes the entire pedigree.

Episodic ataxias

• EA1 (KCNA1): seconds-to-minutes attacks of ataxia and dysarthria, often with myokymia between attacks. Triggered by exercise or startle.
• EA2 (CACNA1A): minutes-to-hours attacks, often with vertigo and nausea, sometimes downbeat nystagmus interictally. Responds to acetazolamide. Same gene as SCA6 and familial hemiplegic migraine, so the family history can be revealing.

Mitochondrial

• POLG-related disorders: SANDO / MIRAS / SCAE phenotypes with ataxia, sensory neuropathy, ophthalmoplegia, epilepsy.
• MELAS, MERRF: ataxia as a component of multisystem mitochondrial disease.

Acquired mimics (do not miss)

• Alcohol-related cerebellar degeneration (anterior superior vermis): the most common acquired adult cerebellar atrophy; gait > limb ataxia.
• Paraneoplastic cerebellar degeneration: anti-Yo (ovarian, breast), anti-Hu (small cell lung), anti-Tr (Hodgkin), anti-mGluR1, anti-Ma. Rapidly progressive ataxia in a smoker or woman with a family history of cancer earns a paraneoplastic panel and CT chest/abdomen/pelvis.
• Vitamin deficiencies: B12 (subacute combined degeneration, sensory > cerebellar), copper (myelopathy and sensory ataxia, often after gastric bypass or zinc supplementation), vitamin E.
• Gluten ataxia: anti-gliadin antibodies, may respond to gluten-free diet.
• Multiple system atrophy, cerebellar type (MSA-C): sporadic adult-onset ataxia with autonomic failure and parkinsonism. Hot cross bun sign on MRI pons.

1. MRI brain. Pure cerebellar atrophy (SCA6, idiopathic), olivopontocerebellar atrophy (SCA1/2/3, MSA-C), MCP T2 hyperintensity (FXTAS), hot cross bun (MSA-C), and basal ganglia / brainstem changes all narrow the differential.
2. Acquired-mimic screen: B12, copper, ceruloplasmin, zinc, vitamin E, TSH, HIV, RPR. Anti-gliadin and tissue transglutaminase if gluten ataxia suspected. Paraneoplastic panel if subacute and a malignancy risk exists.
3. Family history and three-generation pedigree. Anticipation, sex pattern, and consanguinity reshape the panel.
4. Genetic testing. AD adult ataxia: SCA panel covering at least SCA1, 2, 3, 6, 7, 8, 10, 17 plus DRPLA (repeat-aware, not just sequencing). FMR1 CGG repeat sizing in any older man with cerebellar + parkinsonism + tremor (sequencing misses premutations). Friedreich repeat sizing if AR or sporadic. CTX: cholestanol level. NPC: oxysterols and filipin staining or NPC1/NPC2 sequencing.
5. Acetazolamide trial for suspected EA2 (also diagnostic).
6. Whole exome if first-tier negative and inheritance unclear.