combined PSAP deficiency

Combined PSAP deficiency is an encephalopathy that belongs to the sphingolipidoses group of lysosomal storage diseases. This condition results from changes in the PSAP gene, which is crucial for producing prosaposin, a protein involved in the breakdown of sphingolipids in lysosomes. It is inherited in an autosomal recessive manner, meaning that affected individuals have inherited altered copies of the gene from both parents. The condition is very rare, affecting fewer than 1 in a million people.

The clinical presentation of combined PSAP deficiency includes consistently observed findings such as hepatomegaly, splenomegaly, myoclonus, and hyperkinetic movements. In a smaller subset of affected individuals, optic atrophy may also occur. Given the involvement of the central nervous system in this encephalopathy, neurological symptoms are prominent. Not all individuals experience every feature, and severity varies considerably.

Combined PSAP deficiency is caused by pathogenic variants in the PSAP gene, which encodes the prosaposin protein. This protein plays an essential role in the lysosomal breakdown of sphingolipids, and its disruption leads to the accumulation of these lipids, contributing to damage in multiple organ systems such as the liver, spleen, and brain. The condition is inherited in an autosomal recessive pattern, meaning that two copies of the altered gene (one from each parent) are required for the condition to manifest. It is more common when parents share a common ancestor, as this increases the likelihood that both carry the same rare genetic variant. Genetic counseling is recommended to help families understand the recurrence risks and implications for future family planning.

Currently, management of combined PSAP deficiency focuses on supportive care and symptom management, as there are no established foundational or targeted therapies available specifically for this condition. Treatment is tailored to the individual and typically involves a multidisciplinary team to address the various organ systems affected. Regular surveillance is an essential part of long-term care, helping to identify potential complications early. Genetic counseling is also recommended to provide guidance on family planning and to discuss available supportive resources with healthcare professionals.

The overall outlook for combined PSAP deficiency varies widely between individuals, with outcomes depending on the severity of symptoms, age at diagnosis, and access to specialized care. While the condition has a lifelong neurological component, modern supportive care and regular monitoring have improved the quality of life for many patients. Outcomes described in medical literature continue to evolve as standards of care improve. Patients and families are encouraged to connect with genetic counselors and specialists who are familiar with the condition to guide them through treatment and management decisions.