IDENTIFICATION OF THE CRITICAL LOCUS IN A NEW FORM OF LEUCODYSTROPHY WITH PROGRESSIVE ATAXIA, DEAFNESS, AND CARDIOMYOPATHY

Objectives: To identify the molecular genetic alteration in a new form of leukodystrophy. We recently reported a large consanguineous family from southern Italy, in which three patients presented a distinctive clinical phenotype characterized by a slowly progressive ataxia and spasticity with an onset between 2 and 3 years of age. After 5–6 years of disease evolution, patients experienced sensorineural deafness, resulting in complete hearing loss in the time-span of two years. Subsequently, they developed a restrictive cardiomyopathy. Brain MRI showed a diffuse abnormal signal of the white matter on T2.

Methods: By pooling the DNA of the three affected patients, we analysed 384 microsatellites of the whole human genome. We selected 7 regions for which the affected patients shared at least 2 alleles. In these regions, we genotyped the 21 unaffected individuals.

Results: Haplotype analysis showed a homozygous region of 9 cM on chromosome 1p34.3-p33. There are at least 176 genes (108 knows and 68 EST) in this region.

Conclusion: Our data indicate that the genetic defect in this family lies in a gene located on short arm of chromosome 1. Work is in progress to identify the disease gene.