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A 40-year-old man presents with a 3-year history of progressive unsteadiness, slurred speech, and difficulty with fine motor tasks. His father had similar symptoms starting at age 50 and is now wheelchair-bound. Neurologic exam reveals gait and limb ataxia, dysarthria, and nystagmus. Brain MRI shows cerebellar atrophy.
Hereditary ataxias are a genetically heterogeneous group
- Autosomal dominant: Spinocerebellar ataxias (SCAs); most involve trinucleotide repeat expansions
- Autosomal recessive: Friedreich ataxia (most common), ataxia-telangiectasia, others
- X-linked: Fragile X-associated tremor/ataxia syndrome (FXTAS)
- Mitochondrial: NARP, some MERRF presentations
Autosomal dominant ataxias (SCAs):
- 40+ subtypes identified (SCA1-48+)
- Most common: SCA1, SCA2, SCA3 (Machado-Joseph, most common worldwide), SCA6, SCA7
- CAG (polyglutamine) repeat expansions in SCA1, 2, 3, 6, 7
- Adult onset typically (30s-50s)
- Anticipation: earlier onset and increased severity in successive generations
- Key distinguishing features:
- SCA2: slow saccades
- SCA3: "bulging eyes," dystonia, peripheral neuropathy
- SCA6: pure cerebellar, later onset, more benign
- SCA7: retinal degeneration (pigmentary macular dystrophy)
Autosomal recessive ataxias:
- Friedreich ataxia: most common hereditary ataxia overall. GAA repeat in FXN. Onset <25 years. Cardiomyopathy, scoliosis, diabetes. Absent reflexes + Babinski.
- Ataxia-telangiectasia: ATM gene. Childhood onset. Telangiectasias, immunodeficiency, cancer predisposition, elevated AFP. Radiosensitivity.
- Ataxia with oculomotor apraxia types 1 and 2
- Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
- Clinical evaluation: onset, progression, family history, associated features
- Brain MRI: cerebellar atrophy pattern
- Trinucleotide repeat testing for SCAs (targeted or panel)
- FXN GAA repeat analysis for Friedreich ataxia
- AFP level if ataxia-telangiectasia suspected
- Multi-gene panel or exome sequencing for unexplained ataxia
- EMG/NCS to evaluate peripheral neuropathy
- No disease-modifying therapy for most SCAs
- Omaveloxolone (Skyclarys): FDA approved for Friedreich ataxia (Nrf2 activator)
- Physical therapy, occupational therapy, speech therapy
- Fall prevention and home safety modifications
- Cardiac surveillance for Friedreich ataxia (echocardiogram, ECG)
- Genetic counseling: AD ataxias have 50% recurrence risk; counseling regarding anticipation and predictive testing in at-risk relatives
- Avoidance of radiation exposure in ataxia-telangiectasia
"SCA7 = Seven = Seen": Drop the "V" from "Seven" to get "Seen." SCA7 is the ataxia uniquely associated with vision loss (retinal degeneration / pigmentary macular dystrophy).
SCA3 (Machado-Joseph) is the most common SCA worldwide: It is uniquely associated with "bulging eyes" and dystonia.