SPL Insufficiency Syndrome (SPLIS)/NPHS14: a SPLIS Observational Study and Patient Registry (International)

Sphingolipidoses Clinical Trial

— SPLIS-OSPRI  

Official title:

Sphingosine Phosphate Lyase Insufficiency Syndrome - Observational Study and Patient Registry (International)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04885179
• Other study ID #: 20-32291
• Status: Recruiting
• Start date: June 30, 2020
• Est. completion date: June 30, 2025

Study information

• Verified date: August 2023
• Source: University of California, San Francisco
• Contact: Julie D Saba, MD, PhD
• Phone: 510-414-6317
• Email: Julie.Saba[@]ucsf.edu
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

This protocol aims to characterize the natural history of sphingosine phosphate lyase insufficiency syndrome (SPLIS), also known as NPHS14, and to create a SPLIS patient registry. Medical records, radiological and pathology results, blood test results, and genetic information will be collected. Samples of blood, cheek cells, urine and stool may be collected for analysis. If a skin biopsy has been performed for medical care, cells from the biopsy may be analyzed. No treatment or other intervention is involved in this study. However, the effect of treatments administered by the patient's physician may be detected and monitored based on changes in the blood or urine.

Description:

This protocol aims to characterize the natural history and create a patient registry of sphingosine phosphate lyase insufficiency syndrome (SPLIS), a condition also known as NPHS14 or familial steroid-resistant nephrotic syndrome with adrenal insufficiency. SPLIS is a recently discovered genetic disease caused by recessive mutations in the SGPL1 gene. SPLIS can have effects on the kidney, adrenal gland, brain, skin, and blood cells. Some patients with SPLIS do not survive beyond infancy, whereas others live to adulthood. By monitoring the natural history of SPLIS over time in affected patients, the investigators will establish a clinical baseline that reflects how the disease progresses over time. This information may be useful in future clinical trials. The results may reveal which types of SGPL1 mutations correlate with best and worst patient outcomes. Some SPLIS patients are current on a regimen of high dose vitamin B6 supplementation on the advice of their treating physician. By including patients treated with B6, our study may provide evidence for the impact of B6 treatment on biochemical and blood markers of the disease. Our overall goals are to characterize the clinical, biochemical and metabolic manifestations of SPLIS and how these manifestations change over time within individuals with this condition.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: June 30, 2025
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria: Individuals of all ages diagnosed with SPLIS based on bi-allelic pathogenic variants of SGPL1, including children and neonates, as well as family members or caregivers, healthy volunteers and individuals with other sphingolipidoses.

Exclusion Criteria: the investigators will not include:

• prisoners

• pregnant women

• healthy volunteers with:

• diabetes,

• infection,

• fever,

• known HIV/AIDS,

• cardiac disease

• or anemia.

Related Conditions & MeSH terms

• Sphingolipidoses

Intervention

Other:
• no intervention
No interventions are involved in this observational study.

Locations

Country	Name	City	State
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of California, San Francisco

Country where clinical trial is conducted

United States, 

References & Publications (7)

Choi YJ, Saba JD. Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. Adv Biol Regul. 2019 Jan;71:128-140. doi: 10.1016/j.jbior.2018.09.004. Epub 2018 Sep 25. — View Citation

Lovric S, Goncalves S, Gee HY, Oskouian B, Srinivas H, Choi WI, Shril S, Ashraf S, Tan W, Rao J, Airik M, Schapiro D, Braun DA, Sadowski CE, Widmeier E, Jobst-Schwan T, Schmidt JM, Girik V, Capitani G, Suh JH, Lachaussee N, Arrondel C, Patat J, Gribouval O, Furlano M, Boyer O, Schmitt A, Vuiblet V, Hashmi S, Wilcken R, Bernier FP, Innes AM, Parboosingh JS, Lamont RE, Midgley JP, Wright N, Majewski J, Zenker M, Schaefer F, Kuss N, Greil J, Giese T, Schwarz K, Catheline V, Schanze D, Franke I, Sznajer Y, Truant AS, Adams B, Desir J, Biemann R, Pei Y, Ars E, Lloberas N, Madrid A, Dharnidharka VR, Connolly AM, Willing MC, Cooper MA, Lifton RP, Simons M, Riezman H, Antignac C, Saba JD, Hildebrandt F. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017 Mar 1;127(3):912-928. doi: 10.1172/JCI89626. Epub 2017 Feb 6. — View Citation

Martin KW, Weaver N, Alhasan K, Gumus E, Sullivan BR, Zenker M, Hildebrandt F, Saba JD. MRI Spectrum of Brain Involvement in Sphingosine-1-Phosphate Lyase Insufficiency Syndrome. AJNR Am J Neuroradiol. 2020 Oct;41(10):1943-1948. doi: 10.3174/ajnr.A6746. Epub 2020 Aug 27. — View Citation

Prasad R, Hadjidemetriou I, Maharaj A, Meimaridou E, Buonocore F, Saleem M, Hurcombe J, Bierzynska A, Barbagelata E, Bergada I, Cassinelli H, Das U, Krone R, Hacihamdioglu B, Sari E, Yesilkaya E, Storr HL, Clemente M, Fernandez-Cancio M, Camats N, Ram N, Achermann JC, Van Veldhoven PP, Guasti L, Braslavsky D, Guran T, Metherell LA. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017 Mar 1;127(3):942-953. doi: 10.1172/JCI90171. Epub 2017 Feb 6. — View Citation

Weaver KN, Sullivan B, Hildebrandt F, Strober J, Cooper M, Prasad R, Saba J. Sphingosine Phosphate Lyase Insufficiency Syndrome. 2020 Oct 15. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK562988/ — View Citation

Zhao P, Liu ID, Hodgin JB, Benke PI, Selva J, Torta F, Wenk MR, Endrizzi JA, West O, Ou W, Tang E, Goh DL, Tay SK, Yap HK, Loh A, Weaver N, Sullivan B, Larson A, Cooper MA, Alhasan K, Alangari AA, Salim S, Gumus E, Chen K, Zenker M, Hildebrandt F, Saba JD. Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation. J Inherit Metab Dis. 2020 Sep;43(5):1131-1142. doi: 10.1002/jimd.12238. Epub 2020 May 4. — View Citation

Zhao P, Tassew GB, Lee JY, Oskouian B, Munoz DP, Hodgin JB, Watson GL, Tang F, Wang JY, Luo J, Yang Y, King S, Krauss RM, Keller N, Saba JD. Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome. JCI Insight. 2021 Apr 22;6(8):e145936. doi: 10.1172/jci.insight.145936. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Onset of primary adrenal insufficiency	Age at onset of glucocorticoid insufficiency with or without other endocrine defects	0-99 years
Other	Responsiveness of blood sphingolipid levels to vitamin B6 supplementation	Changes in blood sphingolipid levels before and after caring physician-initiated vitamin B6 supplementation	0-99 years
Other	Skin fibroblast sphingolipid levels in response to vitamin B6	Skin fibroblast sphingolipid levels compared by liquid chromatography/mass spectrometry in medium containing various forms of vitamin B6 or lacking vitamin B6.	1-6 weeks
Other	Responsiveness of absolute lymphocyte count to vitamin B6 supplementation	Changes in blood absolute lymphocyte count before and after caring physician-initiated vitamin B6	0-99 years
Primary	Survival	The primary outcome of this study is survival (age at death).	0-99 years
Secondary	Onset of nephrotic syndrome	Age at onset of proteinuria greater than 3.5 grams per 24h	0-99 years