title: Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.
abstract: Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3-10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3-10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.
authors.affiliation: Laboratoire de neurogénétique de la motricité, Neuromics Center for Excellence of Université de Montréal, CRCHUM, 1560 Sherbrooke East, Montreal, Quebec, H2L 4M1, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Bernard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.forename: Martine
authors.initials: M
authors.lastname: Tetreault
authors.forename: Maria Lisa
authors.initials: ML
authors.lastname: Putorti
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bouchard
authors.forename: Michel
authors.initials: M
authors.lastname: Sylvain
authors.forename: Serge
authors.initials: S
authors.lastname: Melançon
authors.forename: Rachel
authors.initials: R
authors.lastname: Laframboise
authors.forename: Pierre
authors.initials: P
authors.lastname: Langevin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bouchard
authors.forename: Michel
authors.initials: M
authors.lastname: Vanasse
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sébire
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D017668:Age of Onset; D001259:Ataxia / Q000208:ethnology / Q000235:genetics*; D001927:Brain Diseases / Q000208:ethnology / Q000235:genetics*; D002170:Canada; D002675:Child, Preschool; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008126:Lod Score; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D014202:Tremor / Q000208:ethnology / Q000235:genetics*
chemical_list: D005819:Genetic Markers