Liang-Wang Syndrome

Liang-Wang syndrome is a KCNMA1-related multiple-malformation and neurodevelopmental syndrome with developmental delay, intellectual disability, axial hypotonia, cerebellar ataxia and variable seizures or movement abnormalities. Severe cases can include visceral malformations and neonatal diabetes. More info
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Genetics

Typically caused by de novo heterozygous loss-of-function variants in KCNMA1, which encodes the BK calcium- and voltage-activated potassium channel. The recurrent p.Gly375Arg variant causes near-complete loss of BK current.

Molecular Mechanism

Aberrant function of BK-channel function disrupts membrane repolarization and calcium-coupled excitability in neurons, smooth muscle and endocrine cells. This mechanism must be distinguished from other KCNMA1 channelopathies caused by gain-of-function variants.

Therapy

Management is symptomatic, including treatment of epilepsy, movement disorder, feeding, motor impairment and organ-specific complications. No validated variant-directed therapy is available, and channel-modulating drugs require functional stratification because KCNMA1 variants can have opposite effects.

CCP Activity

CCP is developing a KCNMA1 p.Gly375Arg model. Characterization is designed to link channel function alteration to neurobehavioral, EEG, motor, metabolic and visceral phenotypes and to establish endpoints for mechanism-based rescue studies.

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