Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI).
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) was recently localized on chromosome 22q (tel) and 26 different mutations of the gene MLC1 have been found.
Autosomal-recessive mutations in MLC1 cause MLC type 1, and autosomal-recessive or dominant mutations in HEPACAM (also called GLIALCAM) cause MLC type 2A and type 2B, respectively.
We included 204 patients with classic MLC, 187 of whom had recessive mutations in <i>MLC1</i> (MLC1 variant) and 17 in <i>GLIALCAM</i> (MLC2A variant) and 38 patients with remitting MLC caused by dominant <i>GLIALCAM</i> mutations (MLC2B variant).
These data demonstrate, for the first time, that MLC1 plays a role in astrocyte osmo-homeostasis and that defects in intracellular calcium dynamics may contribute to MLC pathogenesis.
Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895-226T>G) abrogated in vitro using an antisense morpholino oligonucleotide.
GLIALCAM mutations also affect the trafficking of its associated molecule MLC1, explaining why GLIALCAM and MLC1 mutations lead to the same disease: MLC.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes.
The mutation in the MLC1 gene of the patient is considered to be a common mutation responsible for MLC in Japanese patients because the same mutation had been detected in two other Japanese patients with MLC.
Our results suggest that blood-derived macrophages may give relevant information on MLC1 function and may be considered as valid biomarkers for MLC diagnosis and for investigating therapeutic strategies aimed to restore MLC1 trafficking in patient cells.
These results indicate a previously unrecognized role of GlialCAM in facilitating the biosynthetic maturation and cell surface expression of MLC1, and suggest that pharmacological strategies aimed to increase surface expression of MLC1 and/or VRAC activity may be beneficial for MLC patients.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a heterogeneous neurodegenerative leukodystrophy caused by recessive mutations in MLC1 or GLIALCAM (types MLC1 and MLC2A) of by dominant mutations in GLIALCAM (MLC2B).