Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations

Sedillo, Joni C.; Badduke, Chansonette; Schrodi, Steven J.; Scaria, Vinod; Onat, Onur Emre; Alfadhel, Majid; Ober, Carole; Wentworth-Sheilds, William; Steiner, Robert D.; Saba, Julie D.

doi:10.1016/j.gimo.2023.100840

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…One pair of siblings each harboring 3 SGPL1 variants (Y15C, K353E and M409R) are alive at age 4 and 7 at time of last report. Based on our in vitro analysis, the high prevalence variant Y15C [15] does not reduce SPL enzyme activity and is likely benign. Based on the the predicted loss of function K353E, and the likely benignity of Y15C, the M409R variant might provide some residual SPL function.…”

Section: Splis-associated Spl Variantsmentioning

confidence: 85%

“…SPLIS was rst recognized as a monogenic cause of steroid resistant nephrotic syndrome and primary adrenal insu ciency in 2017 [5 6]. We recently reported that the estimated worldwide prevalence of SPLIS to be approximately 11,000 [15]. However, the number of recognized cases is only a fraction of that, likely due to lack of awareness about this new condition (Fig.…”

Section: Demographics Of Splismentioning

confidence: 99%

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Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome: A Retrospective Cross-Sectional Study of 76 Patients

Keller,

Midgley,

Khalid

et al. 2024

Preprint

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Background Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized metabolic disorder associated with kidney, endocrine, immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Targeted therapies for SPLIS are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 SPLIS patients about whom sufficient data were available for comparison of factors influencing survival. Results Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 42 SPLIS patients with SPLIS nephropathy who had not received a transplant, two clinical subgroups were distinguished. Children diagnosed with SPLIS nephropathy before age one exhibited 78% mortality by age of last report. All remaining SPLIS nephropathy patients exhibited 27% mortality. Kidney transplantation afforded a significant benefit over dialysis or palliative care in SPLIS patients with nephropathy. SPLIS patients homozygous for the SPLR222Q variant survived longer compared to patients with other genotypes. Conclusion Our results demonstrate that SPLIS is a phenotypically heterogeneous condition, and that patients diagnosed with SPLIS nephropathy in the first year of life represent a high-risk subgroup.

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Section: Splis-associated Spl Variantsmentioning

confidence: 85%

Section: Demographics Of Splismentioning

confidence: 99%

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome: A Retrospective Cross-Sectional Study of 76 Patients

Keller,

Midgley,

Khalid

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients

Keller,

Midgley,

Khalid

et al. 2024

Orphanet J Rare Dis

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Background Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5’phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects. Results Overall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes. Conclusion Our results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

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Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations

Cited by 2 publications

References 42 publications

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome: A Retrospective Cross-Sectional Study of 76 Patients

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome: A Retrospective Cross-Sectional Study of 76 Patients

Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients

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