Table 1.

Hereditary Ataxias Caused by Nucleotide Repeat Expansions

Gene 1Disorder 2MOIDistinguishing Non-Ataxic Clinical FeaturesComment
Most commonly involved genes 3
ATN1 DRPLA ADChorea, dementia, myoclonus, seizures; mimics Huntington disease.
  • Anticipation is prominent.
  • More common in Japan
ATXN1 SCA1 ADPeripheral neuropathy, pyramidal signs; early bulbar features; occasional cognitive declineAnticipation is more likely w/paternal transmission.
ATXN2 SCA2 AD↓ DTRs, dementia, peripheral neuropathy, slow saccadic eye movements
  • Anticipation is more likely w/paternal transmission.
  • Large Cuban founder population
ATXN3 SCA3 ADAmyotrophy, fasciculations, sensory loss; lid retraction, nystagmus, & ↓ saccade velocity; pyramidal & extrapyramidal signs; shortened life span
  • Anticipation may be more likely w/paternal transmission.
  • Large Portuguese founder population
  • Also known as Machado-Joseph disease
ATXN7 SCA7 ADVisual loss w/retinopathy; often rapidly progressive; shortened life spanAnticipation is prominent w/more marked repeat expansions w/paternal transmission.
ATXN8 SCA8 ADSlowly progressive, sometimes brisk DTRs, ↓ vibration sense; rarely, cognitive impairment in persons w/earlier onsetAnticipation is more likely w/maternal transmission.
ATXN8OS
ATXN10 SCA10 ADSeizures in certain families
  • Anticipation can occur w/paternal transmission.
  • Large Mexican founder population
CACNA1A SCA6 ADMay begin w/episodic ataxia, very slow progression; onset often after age 50 yrs; normal life span
  • Anticipation is not seen.
  • See Table 2 for ataxia caused by missense variants.
FGF14 3 SCA27B ADAdult-onset ataxia; episodic features; downbeat nystagmus; vertigo; peripheral neuropathy
  • Differential diagnosis: RFC1 CANVAS / spectrum disorder
  • Manifestations responsive to 4-aminopyridine
FXN Friedreich ataxia ARGenerally childhood onset w/slowly progressive ataxia, absent tendon reflexes, Babinski responses, posterior column sensory loss, cardiomyopathy, scoliosis, pes cavus, & diabetes; in some: onset ≥25 yrs, slower progression, & retained reflexesAnticipation is not seen.
RFC1 RFC1 CANVAS / spectrum disorder ARSpectrum ranges from typical cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), to cerebellar, sensory, & vestibular impairment, to more limited phenotypes involving predominantly or exclusively 1 of the systems involved in balance control.Anticipation is not seen.
TBP SCA17 ADMental deterioration; occasional chorea, dystonia, myoclonus, epilepsyAnticipation is infrequently observed.
Less commonly involved genes
BEAN1 4, 5SCA31 (OMIM 117210)ADNormal sensationCommon in Japan
FMR1 Fragile X-associated tremor/ataxia syndrome (FXTAS) (See FMR1 Disorders.)XL
  • Anticipation occurs almost exclusively w/maternal transmission.
  • Most common X-linked ataxia; occurs in male & female premutation carriers
NOP56 4, 5 SCA36 ADHyperreflexia, muscle fasciculations, tongue atrophyInsufficient evidence for anticipation
PPP2R2B 4, 5SCA12 (OMIM 604326)ADAction tremor in the 4th decade, cognitive/psychiatric disorders incl dementia, hyperreflexia, slowly progressive ataxia, subtle parkinsonism possibleInsufficient evidence for anticipation

DRPLA = dentatorubral-pallidoluysian atrophy; DTR = deep tendon reflex; SCA = spinocerebellar ataxia

1.

Genes are listed in alphabetic order within prevalence categories.

2.

For more information see hyperlinked GeneReview. An OMIM phenotype entry is provided if a GeneReview is not available.

3.
4.
5.

Nucleotide repeat expansions in BEAN1, NOP56, and PPP2R2B represent relatively rare causes of hereditary ataxia.

From: Hereditary Ataxia Overview

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