Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations

Neurology. 2002 Aug 27;59(4):590-5. doi: 10.1212/wnl.59.4.590.

Abstract

Background: Early-onset ataxia with hypoalbuminemia is regarded as a variant form of Friedreich ataxia in Japan. Early-onset ataxia with hypoalbuminemia and ataxia with ocular motor apraxia have been considered as the same clinical entity because of the recent identification of a common mutation in the aprataxin gene. A new clinical entity named early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) has been proposed to explain these two diseases.

Objective: To disclose the clinical features of EAOH and to identify the mutations in the aprataxin gene in six patients in four Japanese families with EAOH.

Methods: The clinical features, laboratory findings, sural nerve biopsy results, and brain MRI or CT findings for these patients were evaluated, and molecular analysis was performed, which involved sequencing of the aprataxin gene directly or use of the subcloning method.

Results: Cerebellar ataxia and peripheral neuropathy were noted in all six patients. Ocular motor apraxia was observed in five patients; two of these patients had obvious head thrust. Choreiform movements of the limbs and mental deterioration were observed in five patients. Although foot deformity was noted in five patients, kyphoscoliosis was noted only in one patient. In all patients, hypoalbuminemia and hypercholesterolemia were evident, and brain MRI or CT showed marked cerebellar atrophy. Nerve biopsy revealed depletion of large myelinated fibers in three of the five patients examined. Molecular analysis of the aprataxin gene revealed an insertion mutation (insT at nt167) and two missense mutations (A-to-G transition at nt80 and C-to-T transition at nt95, the former being novel).

Conclusion: We found clinical heterogeneity in the patients with EAOH in this study. With the disease course, the choreiform movements tended to reduce in degree, and hypoalbuminemia became evident. Molecular analysis identified one insertion and two missense mutations including a novel missense one, which was located at a highly conserved amino acid residue in the aprataxin gene product.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Apraxias / diagnosis
  • Apraxias / epidemiology
  • Apraxias / genetics*
  • Apraxias / physiopathology
  • Brain / diagnostic imaging
  • Brain / pathology
  • Cerebellum / pathology
  • Chromosomes, Human, Pair 9 / genetics*
  • Comorbidity
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics*
  • Disease Progression
  • Female
  • Hematologic Diseases / diagnosis
  • Hematologic Diseases / epidemiology
  • Hematologic Diseases / genetics*
  • Humans
  • Japan / epidemiology
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / genetics*
  • Oculomotor Muscles / physiopathology
  • Pedigree
  • Serum Albumin / deficiency*
  • Spinocerebellar Degenerations / diagnosis
  • Spinocerebellar Degenerations / epidemiology
  • Spinocerebellar Degenerations / genetics*
  • Spinocerebellar Degenerations / pathology
  • Sural Nerve / pathology
  • Tomography, X-Ray Computed

Substances

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