Background

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder discovered in 2017 and caused by inactivating mutations in SGPL1. SGPL1 encodes sphingosine-1-phosphate lyase (SPL), the final enzyme of sphingolipid metabolism. SPLIS is representative of a new family of atypical, non-lysosomal disorders of sphingolipid metabolism recently recognized through next-generation sequencing diagnostic testing. Researchers from the Department of Pediatrics at the University of California San Francisco (UCSF) estimate the worldwide SPLIS prevalence is 11,000; prevalence is likely to increase as variants of unknown significance are confirmed experimentally to cause loss-of-function.

SPLIS causes steroid-resistant nephrotic syndrome and glomerulosclerosis. Kidney involvement characteristically progresses rapidly to end-stage renal disease, often accompanied by adrenal insufficiency, neurological defects, lymphopenia, ichthyosis, and failure to thrive.