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.
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Acknowledgements
We wish to thank all family members for their participation. We would also like to thank all the clinicians who referred patients to us and who were not included in this article: Drs. Marie-Emmanuelle Dilenge, Chantal Poulin, Michael Shevell, Amelie Nadeau, Bruno Maranda, Renée-Myriam Boucher, and Jean Mathieu. We also wish to thank Alexandre Montpetit and Pierre Lepage from McGill University and Genome Quebec Innovation Center for their technical expertise. Dr. Bernard has received a scholarship grant from the Réseau de medicine génique appliquée (RMGA) and from the Fonds de Recherche en Santé du Québec (FRSQ). I. Thiffault has received a scholarship grant from CIHR and ETP fellowship from the National Bank Financial Group. Dr. Vanderver has received funding from the American Academy of Neurology Foundation Clinical Research Training Fellowship program.
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This research project was supported by the Quebec-base foundation: “Fondation sur les leukodystrophies” (http://www.leucofondation.com/).
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Ethical standards The experiments comply with the current laws of the country in which they were performed.
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The authors declare that they have no conflicts of interest.
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Bernard, G., Thiffault, I., Tetreault, M. et al. Tremor–ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3–10q23.31. Neurogenetics 11, 457–464 (2010). https://doi.org/10.1007/s10048-010-0251-8
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DOI: https://doi.org/10.1007/s10048-010-0251-8