Encephalopathy due to prosaposin deficiency

Encephalopathy due to prosaposin deficiency, also known as combined saposin deficiency or prosaposin deficiency, is an extremely rare and severe autosomal recessive lysosomal storage disorder caused by mutations in the PSAP gene. Prosaposin is the precursor protein that is processed into four saposin activator proteins (saposins A, B, C, and D), which are essential cofactors for the lysosomal degradation of various sphingolipids. When prosaposin itself is deficient, all four saposins are absent, leading to the simultaneous accumulation of multiple sphingolipids including glucosylceramide, galactosylceramide, sulfatides, and ceramide in the brain and other tissues. This results in a combined phenotype resembling features of Gaucher disease, metachromatic leukodystrophy, Krabbe disease, and Farber disease. The disease primarily affects the central nervous system and presents in the neonatal or early infantile period with severe and rapidly progressive neurological deterioration. Key clinical features include massive hepatosplenomegaly, profound hypotonia, seizures, failure to thrive, and progressive encephalopathy. Affected infants typically show absent or rapidly lost developmental milestones, myoclonus, and progressive loss of neurological function. Skin abnormalities and adrenal calcification may also be observed. Neuropathological examination reveals widespread neuronal storage and white matter involvement. The prognosis is extremely poor, with most affected infants dying within the first few months of life. There is currently no curative treatment available for this condition. Management is entirely supportive and palliative, focusing on seizure control, nutritional support, and comfort care. The condition has been reported in only a handful of families worldwide.

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