A novel locus for dementia with Lewy bodies: a clinically and genetically heterogeneous disorder

Brain. 2007 Sep;130(Pt 9):2277-91. doi: 10.1093/brain/awm167. Epub 2007 Aug 6.

Abstract

Dementia with Lewy bodies (DLB) represents the second most frequent type of neurodegenerative dementia in the elderly. Although most patients have sporadic DLB, a limited number of DLB families have been described, suggesting that genetic factors may contribute to DLB pathogenesis. Here, we describe a three-generation Belgian family with prominent dementia and parkinsonism, consistent with a diagnosis of DLB, that was autopsy confirmed for the index patient. In a genome-wide scan and subsequent finemapping of candidate loci we obtained significant linkage to 2q35-q36 (Z = 3.01 at D2S1242). Segregation analysis defined a candidate region of 9.2 Mb between D2S433 and chr2q36.3-8, adjacent to the previously reported PARK11 locus. In addition, haplotype sharing studies in another DLB family of close geographical origin with similar clinical and neuropathological features highlighted the specificity of a 2q35-q36 haplotype harbouring a pathogenic mutation that causes DLB in the Belgian family. So far, extensive sequence analysis of five candidate genes within the 2q35-q36 region has not revealed a disease-causing mutation. Together, our data re-emphasize the genetic heterogeneity of DLB, and strongly support the existence of a gene for familial DLB on 2q35-q36. Once identified this will be the first novel causal gene for DLB and can be expected to open new avenues for biological studies of the disease process.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Brain / pathology
  • Chromosomes, Human, Pair 2 / genetics
  • DNA Mutational Analysis / methods
  • Female
  • Genetic Heterogeneity*
  • Genetic Linkage
  • Genotype
  • Humans
  • Lewy Body Disease / genetics*
  • Lewy Body Disease / pathology
  • Lod Score
  • Male
  • Middle Aged
  • Mutation
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / pathology
  • Pedigree