Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients

Neurogenetics. 2011 Aug;12(3):193-201. doi: 10.1007/s10048-011-0281-x. Epub 2011 Apr 5.

Abstract

Ataxia with oculomotor apraxia type1 (AOA1, MIM 208920) is a rare autosomal recessive disease caused by mutations in the APTX gene. We screened a cohort of 204 patients with cerebellar ataxia and 52 patients with early-onset isolated chorea. APTX gene mutations were found in 13 ataxic patients (6%). Eleven patients were homozygous for the known p.W279X, p.W279R, and p.P206L mutations. Three novel APTX mutations were identified: c.477delC (p.I159fsX171), c.C541T (p.Q181X), and c.C916T (p.R306X). Expression of mutated proteins in lymphocytes from these patients was greatly decreased. No mutations were identified in subjects with isolated chorea. Two heterozygous APTX sequence variants (p.L248M and p.D185E) were found in six families with ataxic phenotype. Analyses of coenzyme Q10 in muscle, fibroblasts, and plasma demonstrated normal levels of coenzyme in five of six mutated subjects. The clinical phenotype was homogeneous, irrespectively of the type and location of the APTX mutation, and it was mainly characterized by early-onset cerebellar signs, sensory neuropathy, cognitive decline, and oculomotor deficits. Three cases had slightly raised alpha-fetoprotein. Our survey describes one of the largest series of AOA1 patients and contributes in defining clinical, molecular, and biochemical characteristics of this rare hereditary neurological condition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / metabolism
  • Adolescent
  • Adult
  • Apraxias / complications
  • Apraxias / genetics*
  • Apraxias / metabolism
  • Ataxia / complications
  • Ataxia / genetics*
  • Ataxia / metabolism
  • Child
  • Cohort Studies
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Frequency
  • Genetic Association Studies
  • Humans
  • Italy
  • Male
  • Middle Aged
  • Mutation* / physiology
  • Nuclear Proteins / genetics*
  • Oculomotor Nerve / metabolism
  • Oculomotor Nerve / pathology
  • Oculomotor Nerve Diseases / complications
  • Oculomotor Nerve Diseases / genetics*
  • Oculomotor Nerve Diseases / metabolism
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / analysis
  • Ubiquinone / metabolism
  • Young Adult

Substances

  • APTX protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Ubiquinone
  • coenzyme Q10