Fatal infantile leukodystrophy - A severe variant of CACH/VWM syndrome, allelic to chromosome 3q27

Objective: To describe clinical and neuropathologic studies and linkage ana lysis on two sisters with a severe form of leukodystrophy. Methods: A detai led study was performed on the second sister. Genotyping markers for chromo some 3, including eight additional markers surrounding the vanishing white matter (VWM) locus, were used. Results: During the first year of life, two sisters developed a severe neurologic condition after an intercurrent infec tion. It was accompanied by irritability and stupor with rapid loss of thei r motor abilities. Results of extensive metabolic studies were negative. Br ain MRI showed severe and diffuse abnormalities of the encephalic white mat ter. Neuropathologic examination showed a severe lack of myelin with diffus e vacuolating white matter lesions in the brain, associated with an increas ed density of oligodendrocytes and a reduced number of astrocytes on morpho metric analysis. In sharp contrast, the spinal cord white matter was preser ved. The affected sibpairs shared a common haplotype for a broad region in chromosome 3. They were homozygous between markers D3S1565 and D3S3669, inc luding the VWM locus. Conclusions: This condition is an unusual variant of childhood ataxia with diffuse central hypomyelination (CACH)/VWM, with char acteristic shrinking and perivascular clustering of astrocytes, Haplotype a nalysis suggests that this variant is allelic to the VWM locus located on c hromosome 3q27.