West Syndrome Caused By a Chloride/Proton Exchange-Uncoupling CLCN6 Mutation Related to Autophagic-Lysosomal Dysfunction

The molecular and phenotypic spectrum of CLCN4‐related epilepsy

“…The CLC gene family contains nine members in mammals, four of which encode plasma membrane chloride channels (ClC-1, ClC-2, ClC-Ka, ClC-Kb) and five intracellular 2Cl − /H + exchangers (ClC-3-7). 1,2 Dysfunction of some of these leads to severe neurological disorders, including leukodystrophy, neurodegeneration, intellectual disability (ID), epilepsy, and lysosomal storage disease for ClC-2, ClC-3, ClC-4, ClC-6, and ClC-7, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] highlighting the pivotal role of CLC proteins in the central nervous system. ClC-4, which is encoded by the CLCN4 (Online Mendelian Inheritance in Man database # 302910) gene located on human chromosome Xp22.2, is a voltage-dependent 2Cl − / H + exchanger.…”

Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

“…11 A recurrent gain-of-function CLCN6 variant (MIM: 602726) leads to severe global developmental delay, hypotonia, respiratory insufficiency, neurodegeneration, and associated MRI abnormalities in humans, 12 and an individual heterozygous for a different CLCN6 variant presents with West syndrome. 13,14 Loss of lysosomal ClC-7 results in pronounced, mainly neuronal, lysosomal storage disease and severe osteopetrosis in mice and humans (CLCN7 [MIM: 602727]). 15,16 Disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration.…”

Correlation of age of onset and clinical severity in Niemann–Pick disease type C1 with lysosomal abnormalities and gene expression

“…Heterozygous mutation of CLCN6 is associated with a rare neurological disorder that exhibits childhood-onset neurodegeneration with hypotonia, respiratory insufficiency, and brain imaging abnormalities 65 . A missense mutation of CLCN6 has been seen in a single patient with the early infantile epileptic encephalopathy West syndrome, and this sequence change causes autophagosome accumulation and blockage of autophagosome-lysosome fusion 66 . Additionally, a Clcn6 mouse mutant exhibits defects in lysosomal storage and mild, slowly progressing neurological abnormalities 67 , 68 .…”