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Encephalopathy due to prosaposin deficiency
A lysosomal storage disease belonging to the group of sphingolipidoses.
ORPHA:139406Classification level: Disorder
It is very rare with less than 10 cases reported in the literature so far.
Clinically, it is a severe neurovisceral disease manifesting immediately after birth and following a rapidly progressive fatal course (death between 1 and 4 months in the cases documented so far). The neurological signs and symptoms include hypotonia, massive myoclonic bursts, abnormal ocular movements and dystonia. Grand mal seizures and seizures triggered by tactile stimuli have been described. Patients also develop hepatosplenomegaly. Death usually occurs from respiratory failure following repeated pulmonary infections.
The disease is caused by mutations in the PSAP gene (10q21) leading to absence or non-functionality of the prosaposin protein. Prosaposin is the common precursor for proteins required for the in vivo lysosomal degradation of several sphingolipids, and has other important but still poorly understood functions. Under normal conditions, proteolytic processing of prosaposin produces four smaller "sphingolipid activator proteins'' called saposins (or Sap) A, B C and D. An isolated deficiency of each of these factors leads to rare variant genetic forms of Krabbe disease (Sap A), metachromatic leukodystrophy (Sap B), Gaucher disease (Sap C) and, putatively, Farber disease (Sap D; see these terms). In prosaposin deficiency, there is a combined deficiency of all four factors.
The final diagnosis is established by identification of the PSAP mutation(s), but the study of sphingolipids in urine sediment (showing a massive combined excretion of globotriaosylceramide (Gb3), sulfatides and other sphingolipids) is a good orientation test. Low galactosylceramidase in leukocytes has also been reported. Bone marrow/liver biopsies usually show the presence of Gaucher-like macrophages.
Prenatal diagnosis is feasible by mutation analysis on uncultured (or cultured) chorionic villi, or amniotic fluid cells.
The mode of inheritance is autosomal recessive.
Management and treatment
No specific treatment is available.
Encephalopathy due to prosaposin deficiency is a very severe metabolic disorder with a poor prognosis.