Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies

Brain. 2003 Dec;126(Pt 12):2761-72. doi: 10.1093/brain/awg283. Epub 2003 Sep 23.

Abstract

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 +/- 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with 'slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apraxias / genetics*
  • Apraxias / pathology
  • Apraxias / psychology
  • Cerebellar Ataxia / genetics*
  • Cerebellar Ataxia / pathology
  • Cerebellar Ataxia / psychology
  • Cognition Disorders / etiology
  • DNA-Binding Proteins / genetics
  • Disease Progression
  • Electrooculography
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Neuropsychological Tests
  • Nuclear Proteins / genetics
  • Ocular Motility Disorders / genetics*
  • Ocular Motility Disorders / pathology
  • Ocular Motility Disorders / psychology
  • Phenotype
  • Sural Nerve / ultrastructure

Substances

  • APTX protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins