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.

Fig. 1

Pedigrees of the five French-Canadian families with tremor–ataxia with central hypomyelination (TACH), including consanguineous families 4 and 5. Affected cases are shaded black and participants for which a genome scan was performed are marked with an asterisk

Fig. 2

Multipoint LOD scores generated by the analysis of family 4 and family 5 for 20 markers on chromosome 10q21.2–10q23.2 markers

Fig. 3

MRI features in tremor–ataxia with central hypomyelination (TACH). Characteristic MRI images in two subjects: cases 5 (a) and 7 (b) (the least and most affected patients, at ages 11 and 21 years, respectively). The MRI show diffuse hypomyelination with diffusely increased T2 signal, isointense or hyperintense T1 signal, with relative sparing of arcuate fibers and optic radiations. Thinning of the corpus callosum is a constant feature. In the most clinically affected patients, such as in case 7, there is some periventricular deep white matter rarefaction on FLAIR images, as well as atrophy of the cerebellum