sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a rare autosomal recessive disorder caused by mutations in the SGPL1 gene located on human chromosome 10.[2][3] It is also known as Renal, Endocrine, Neurologic and Imune Syndrome (RENI), or Nephrotic Syndrome, type 14 (NPHS14).
| Sphingosine phosphate lyase insufficiency syndrome | |
|---|---|
| Other names | Renal Endocrine Neurologic and Immune syndrome, Nephrotic Syndrome type 14 |
 | |
| Visualization of the SGPL1 protein. | |
| Specialty | Nephrology, endocrinology, neurology |
| Symptoms | nephrotic syndrome, adrenal insufficiency, |
| Complications | kidney failure |
| Usual onset | childhood |
| Duration | lifelong |
| Causes | family history (genetics) |
| Risk factors | family history (genetics) |
| Diagnostic method | genetic testing |
| Treatment | management to maintain function |
| Prognosis | progressive |
| Frequency | prevalence: 1 in 6,666,667[1] |
Signs and symptoms
editThis disease can cause a variety of symptoms, including steroid-resistant nephrotic syndrome, endocrine deficiency (particularly adrenal insufficiency), neurological deficiency, immunodeficiency, skin manifestations, and failure to thrive.
History
editSphingosine phosphate lyase deficiency was first identified in 2017[4] through genetic sequencing of several patients.[5] A scientific study published in 2024 identified 76 cases diagnosed historically, including 31 in the year the disease was identified.[6] With an estimated prevalence of 0.015 per 100,000, 11,000 to 12,000 people worldwide could be affected[7].
Causes and genetics
editSphingosine-1-phosphate lyase is an enzyme required for the catabolism of sphingosine-1-phosphate, a cell signaling molecule. Various pathogenic variants in the gene encoding this enzyme result in a more or less severe deficiency of the enzyme, leading to an accumulation of sphingosine at the cellular level. This accumulation leads to biological dysfunction.
Treatment and management
editIn 2025, treatment is primarily symptomatic, with hormone replacement therapy in cases of adrenal insufficiency, and dialysis or transplant in cases of kidney failure. Gene therapy is a promising avenue of research[8]. For certain variants that produce a poorly functional enzyme, vitamin B6 supplementation may have a positive effect[9].
See also
editReferences
edit- ↑ Sedillo JC, Badduke C, Schrodi SJ, et al. (Oct 2023). "Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations". Genet Med Open. 2 100840. doi:10.1016/j.gimo.2023.100840. PMC 11613930. PMID 39669624.
- ↑ Choi YJ, Saba JD (Jan 2019). "Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism". Adv Biol Regul. 71: 128–140. doi:10.1016/j.jbior.2018.09.004. PMC 6347531. PMID 30274713.
- ↑ Maharaj A, Kwong R, Williams J, et al. (Jun 2022). "A retrospective analysis of endocrine disease in sphingosine-1-phosphate lyase insufficiency: case series and literature review". Endocr Connect. 11 (8). doi:10.1530/EC-22-0250. PMC 9346324. PMID 35904228.
- ↑ Lovric S, Goncalves S, Gee HY, et al. (Feb 2017). "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency". J Clin Invest. 127 (3): 912–928. doi:10.1172/JCI89626. PMC 5330730. PMID 28165339.
- ↑ Saba JD (Mar 2019). "Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease". J Lipid Res. 60 (3): 456–463. doi:10.1194/jlr.S091181. PMC 6399507. PMID 30635364.
- ↑ Keller, Nancy, et al. (Sep 2024). "Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients". Orphanet J Rare Dis. 19 (1) 355. doi:10.1186/s13023-024-03311-w. PMC 11429486. PMID 39334450.
- ↑ Sedillo JC, Badduke C, Schrodi SJ, et al. (Oct 2023). "Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations". Genet Med Open. 2 100840. doi:10.1016/j.gimo.2023.100840. PMC 11613930. PMID 39669624.
- ↑ Khan R, Oskouian B, Lee J, et al. (Oct 2023). "AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome". Int J Mol Sci. 24 (21) 15560. doi:10.3390/ijms242115560. PMC 10648410. PMID 37958544.
- ↑ Zhao P, Liu I, Hodgin J, et al. (Sep 2020). "Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation". J Inherit Metab Dis. 43 (5): 1131–1142. doi:10.1002/jimd.12238. PMC 8072405. PMID 32233035.