Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome.

ABSTRACT

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by a deficiency in sphingosine-1-phosphate lyase (SPL), the final enzyme in the sphingolipid degradative pathway. Inactivating mutations of SGPL1-the gene encoding SPL-lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease. Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown. In this report, we describe the correlation between SGPL1 genotypes, age at diagnosis, and patient outcome. Vitamin B6 serves as a cofactor for SPL. B6 supplementation may aid some SPLIS patients by overcoming poor binding kinetics and promoting proper folding and stability of mutant SPL proteins. However, this approach remains limited to patients with a susceptible allele. Gene therapy represents a potential targeted therapy for SPLIS patients harboring B6-unresponsive missense mutations, truncations, deletions, and splice-site mutations. When Sgpl1 knockout (SPLKO) mice that model SPLIS were treated with adeno-associated virus (AAV)-mediated SGPL1 gene therapy, they showed profound improvement in survival and kidney and neurological function compared to untreated SPLKO mice. Thus, gene therapy appears promising as a universal, potentially curative treatment for SPLIS.