Megalencephalic leukoencephalopathy with subcortical cysts; a founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.

Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis ofMLC1

“…The mutations are distributed evenly in number and throughout the whole gene. In five unrelated Libyan Jewish families and in several patients from a single Jewish Turkish family, descending from the same ancestors, the same common mutation (c.176G4A), which leads to p.Gly59Glu, was found [Ben-Zeev et al, 2002].…”

“…All patients within this community share the same insertion (c.135_136insC) causing a frameshift and the appearance of a premature stop at position 46 [Gorospe et al, 2004;Leegwater et al, 2002b]. In addition, Ben-Zeev et al [2002] has described a common mutation, c.176G4A, which leads to the p.Gly59Glu substitution at the protein level, in five unrelated Libyan Jewish families and in several patients from a single Jewish Turkish family, descending from the same ancestors. This mutation has recently been reported in two other related Lebanese patients [Koussa et al, 2005].…”

“…In several works mutations in the MLC1 gene have been reported [Ben-Zeev et al, 2002;Gorospe et al, 2004;Koussa et al, 2005;Leegwater et al, 2002bLeegwater et al, , 2001Patrono et al, 2003;Rubie et al, 2003;Saijo et al, 2003;Tsujino et al, 2003]. It is worth noting that in some patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found.…”

Functional Studies of MLC1 Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts

“…In addition, many MLC1 mutations have been identified in the past years [3], [13]–[19]. Until now, there are around 70 MLC-related mutations of MLC1 have been reported in patients of various ethnic backgrounds (human gene mutation database, HGMD).…”

Maladies démyélinisantes d’origine génétique

“…Il a été identifié par Leegwater et al [8] en 2001 (MIM # 604004). L'analyse des haplotypes a permis de mettre en évidence un effet fondateur dans certaines populations avec une mutation ancestrale [9]. 20 % des patients atteints de MLC ne sont pas liés à MLC1, confirmant l'hétérogénéité génétique de cette leucodystrophie [10,11].…”