Tremor–ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3–10q23.31

• Published in: Neurogenetics 2010-10, Vol.11 (4), p.457-464
• Main Authors: Bernard, Geneviève, Thiffault, Isabelle, Tetreault, Martine, Putorti, Maria Lisa, Bouchard, Isabelle, Sylvain, Michel, Melançon, Serge, Laframboise, Rachel, Langevin, Pierre, Bouchard, Jean-Pierre, Vanasse, Michel, Vanderver, Adeline, Sébire, Guillaume, Brais, Bernard
• Format: Article
• Language: English
• Subjects: Age of Onset; Ataxia - ethnology; Ataxia - genetics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Brain Diseases - ethnology; Brain Diseases - genetics; Canada; Child, Preschool; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 10; Classical genetics, quantitative genetics, hybrids; Cohort Studies; Developmental disabilities; Female; Fundamental and applied biological sciences. Psychology; Genetic Markers; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Genomics; Human; Human Genetics; Humans; Infant; Lod Score; Male; Medical sciences; Models, Genetic; Molecular and cellular biology; Molecular Medicine; Mutation; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurosciences; Original Article; Pedigree; Tremor - ethnology; Tremor - genetics; Vertebrates: nervous system and sense organs
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-010-0251-8

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.