Vacuoliting megalencephalic leukoencephalopathy with subcortical cysts, mapped to chromosome 22qtel

Abstract

The leukodystrophies form a complex group of orphan genetic disorders that primarily affect myelin, the main constituent of the brain white matter. Among the leukodystrophies of undetermined etiology, a new clinical entity called "vacuoliting megalencephalic leukoencephalopathy" (VL) was recently recognized. VL is characterized by diffuse swelling of the white matter, large subcortical cysts, and megalencephaly with infantile onset. Family studies in several ethnic groups have suggested an autosomal recessive mode of inheritance. We mapped the VL gene to chromosome 22qtel, within a 3-cM linkage interval between markers D22S1161 and n66c4 (maximum LOD score 10.12 at recombination fraction.0, for marker n66c4; maximum multipoint LOD score 17 for this interval) by genome scan of 13 Turkish families. Linkage analysis under the genetic-heterogeneity hypothesis showed no genetic heterogeneity. No abnormalities were found in three tested candidate genes (fibulin-1 and glutathione S-transferases 1 and 2).

Figure 1

Graphic representation of multipoint LOD-score analysis of the 22q_tel chromosomal region linked to the VL gene. The multipoint LOD score was computed with GENEHUNTER (Kruglyak et al. 1996) by use of a recessive mode of inheritance, complete penetrance, and true marker-allele frequencies. The disease-allele frequency was set to .0001.

Figure 2

Haplotypes of seven 22q_tel DNA markers defining the shortest linkage interval derived from 10 consanguineous families and from 3 families with no known relationship. Haplotypes were inferred by use of GENEHUNTER (Kruglyak et al. 1996). Disease haplotypes are enclosed within ovals. Missing genotypes are indicated by hyphens (-), and recombination events are indicated by “×”. Physical position (in Mb) of the markers along the chromosome is indicated next to the marker names (Dunham et al. 1999).

Figure 2

Haplotypes of seven 22q_tel DNA markers defining the shortest linkage interval derived from 10 consanguineous families and from 3 families with no known relationship. Haplotypes were inferred by use of GENEHUNTER (Kruglyak et al. 1996). Disease haplotypes are enclosed within ovals. Missing genotypes are indicated by hyphens (-), and recombination events are indicated by “×”. Physical position (in Mb) of the markers along the chromosome is indicated next to the marker names (Dunham et al. 1999).