Last updated:
5/1/2024
Years published: 2024
NORD gratefully acknowledges Julie Saba MD, PhD, Professor of Pediatrics, Hematology/Oncology, John and Edna Beck Chair in Pediatric Cancer Research, University of California, for the preparation of this report.
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a very rare genetic condition that affects the kidneys, adrenal glands and nervous system. Symptoms vary from individual to individual, but most people with SPLIS have signs of abnormal kidney and adrenal gland function, which can include a buildup of extra fluid, vomiting and diarrhea. Some people with SPLIS have dry, scaly, cracked or darkened skin and problems with their immune system. SPLIS is caused by changes (disease-causing variants) of the sphingosine-1-phosphate lyase 1 gene (SGPL1) and is inherited in an autosomal recessive pattern. SPLIS is diagnosed based on the symptoms, clinical examination and through genetic testing. There is no specific treatment for SPLIS. Medication and supportive care can help with some of the symptoms. The long-term outlook for people with this disorder is unknown.
The age of onset is not the same for everyone, but signs and symptoms of SPLIS usually appear in infancy or early childhood. Some people with SPLIS may be more severely affected than others, with the most severe cases of this condition resulting in early fetal death due to excess fluid accumulation. Some of the more common signs and symptoms of SPLIS include:
Other organs that may be affected include the eyes, heart and gonads (sex organs).
SPLIS is caused by variants in the spingosine-1-phosphate lyase 1 (SGPL1) gene. The protein made by this gene, sphingosine-1-phosphate lyase (SPL) is found in many different organs, including the kidneys, adrenal and other endocrine glands. It is involved in many important processes of cellular function. SPL is a vitamin B6-dependent enzyme, i.e, it needs vitamin B6 to function.
SPLIS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Less than 100 people have been reported in the medical literature with SPLIS.
SPLIS may be suspected based on symptoms and clinical examination. The diagnosis is confirmed by genetic testing that identifies disease-causing variants in both copies of the SGPL1 gene.
Treatment
The treatment for people with SPLIS is focused on treating specific symptoms.
The long-term outlook for people with SPLIS is unclear, and may depend on the age of onset, severity of the symptoms and the presence of any underlying medical conditions. Some people with SPLIS have kidney failure and require dialysis and a kidney transplant. Other signs and symptoms are treated as needed. A recent study suggest that some symptoms of people with SPLIS may improve with pyridoxine (vitamin B6) supplementation, but this should be done only under the supervision of a healthcare provider.
Gene therapy for SPLIS is in development.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Zhao P, Tassew GB, Lee JY et al. Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome. JCI Insight. 2021 Apr 22;6(8):e145936.
Lovric S, Goncalves S, Gee HY, et al. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017 Mar 1;127(3):912-928. PMID 28165339 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330730/
Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017 Mar 1;127(3):942-953.
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