Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7)

Hum Mol Genet. 1998 Feb;7(2):165-70. doi: 10.1093/hmg/7.2.165.

Abstract

Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Africa, Northern / epidemiology
  • Age of Onset
  • Aged
  • Alleles
  • Belgium / epidemiology
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 3 / genetics*
  • Deglutition Disorders / epidemiology
  • Deglutition Disorders / genetics
  • Exons / genetics
  • Fecal Incontinence / epidemiology
  • Fecal Incontinence / genetics
  • Female
  • France / epidemiology
  • Genes, Dominant*
  • Humans
  • Infant
  • Israel / epidemiology
  • Macular Degeneration / epidemiology
  • Macular Degeneration / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mosaicism
  • Olivopontocerebellar Atrophies / epidemiology
  • Olivopontocerebellar Atrophies / genetics
  • Olivopontocerebellar Atrophies / pathology
  • Ophthalmoplegia / epidemiology
  • Ophthalmoplegia / genetics
  • Scoliosis / epidemiology
  • Scoliosis / genetics
  • Severity of Illness Index
  • Spermatozoa / chemistry
  • Spinocerebellar Degenerations / classification
  • Spinocerebellar Degenerations / epidemiology
  • Spinocerebellar Degenerations / genetics*
  • Syndrome
  • Trinucleotide Repeats*
  • Urinary Incontinence / epidemiology
  • Urinary Incontinence / genetics