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).
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).
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of leukodystrophy caused by mutations in either MLC1 or GLIALCAM genes.
Recent studies in Mlc1-, GlialCAM- and Clcn2-knockout mice or Mlc1-knockout zebrafish have provided fresh insight into the pathophysiology of MLC and further details about the molecular interactions between these three proteins.
A case of megalencephalic leukoencephalopathy with subcortical cysts type 1 was identified with a novel compound heterozygous alteration (c.135delC; c.423+2dupT) in China.
Megalencephalic leukoencephalopathy with subcortical cysts 1 (Mlc1) is a transmembrane protein that is expressed in perivascular astrocyte end feet where it controls BBB development and homeostasis.
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.
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).
In order to investigate whether the relationship between Mlc1 and GlialCAM is species-specific, we first identified MLC-related genes in zebrafish and generated an mlc1(-/-) zebrafish.
Our data unmask an unforeseen functional relationship between MLC1 and ClC-2 in vivo, which is probably mediated by GlialCAM, and suggest that ClC-2 participates in the pathogenesis of megalencephalic leukoencephalopathy with subcortical cysts.