Linkage of AD HSP and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates variable expression and low or delayed penetrance

Eur J Hum Genet. 1998 May-Jun;6(3):275-82. doi: 10.1038/sj.ejhg.5200185.

Abstract

We report linkage of a family affected with autosomal dominant hereditary spastic paraparesis (HSP) and/or cognitive impairment to the HSP locus on chromosome 2p. To date all families linked to this locus have been affected with 'pure' HSP. The specific pattern of cognitive impairment in this family is characterised primarily by deficits in visuo-spatial functions. We also present genetic studies that indicate variable expression and low or delayed penetrance. We have constructed a haplotype flanked by polymorphic markers D2S400 and D2S2331 that was present in 12 individuals affected with spastic paraparesis. The severity of spasticity varied markedly among these individuals. In addition four of these individuals (aged 62-70) also had a specific form of cognitive impairment. The disease haplotype was also present in an individual (age 57) who had an identical pattern of cognitive impairment as the only sign of the disease supporting the hypothesis that spastic paraparesis and cognitive impairment are the result of variable expression of a single gene (rather than a co-incidental occurrence). Haplotype reconstruction for all participating family members revealed the presence of this disease haplotype in six individuals who had normal neurological and neuropsychological examinations. All six are below the maximal age of onset in the family--60 years. This is evidence for low or late penetrance of the AD HSP gene in this family. The identification of normal individuals carrying the disease haplotype demonstrates the importance of genetic studies in combination with clinical examination when counselling at risk family members.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Chromosomes, Human, Pair 2*
  • Cognition Disorders / genetics*
  • Female
  • Genetic Linkage*
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics*