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

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

This protocol aims to gather information about 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.

Study Overview

• Status: Recruiting
• Conditions: Sphingolipidoses; Enzyme Deficiency
• Intervention / Treatment: Other: no intervention

Detailed Description

This protocol aims to gather information about 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.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Julie D Saba, MD, PhD; Phone Number: 510-414-6317; Email: Julie.Saba@ucsf.edu
• Study Contact Backup: Name: Joanna Y Lee, PhD; Phone Number: 510-590-8292; Email: Joanna.Lee@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California San Francisco
      • Contact: Julie D Saba, MD, PhD; Phone Number: 510-414-6317; Email: Julie.Saba@ucsf.edu
      • Contact: Joanna Y Lee, PhD; Phone Number: 510-590-8292; Email: Joanna.Lee@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

SPLIS is a genetic disorder caused by recessive mutations in SGPL1. The study population includes individuals with confirmed bi-allelic mutations in SGPL1, regardless of age, gender, disease manifestations, or treatments received. Some patients with SPLIS will have kidney failure, adrenal insufficiency and/or neurological problems. Parents, family members and unrelated healthy individuals enrolled during routine health appointments, elective surgical procedures and other medical interactions will be included as healthy controls.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Individuals with SPLIS; Individuals diagnosed with SPLIS based on genetic testing that confirms bi-allelic pathogenic variants in SGPL1	Other: no intervention; No interventions are involved in this observational study.
Parents of individuals with SPLIS; Parents of individuals diagnosed with SPLIS based on genetic testing that confirms bi-allelic pathogenic variants in SGPL1	Other: no intervention; No interventions are involved in this observational study.
age and gender-matched controls; The investigators will attempt to collect biological specimens from individuals closely matched to SPLIS patient cohort by age and gender. This group may include siblings, cousins, and unrelated healthy children and adults.	Other: no intervention; No interventions are involved in this observational study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	The primary outcome of this study is survival (age at death).	0-99 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Onset of nephrotic syndrome	Age at onset of proteinuria greater than 3.5 grams per 24h	0-99 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Onset of primary adrenal insufficiency	Age at onset of glucocorticoid insufficiency with or without other endocrine defects	0-99 years
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
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
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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Julie D Saba, MD, PhD, University of California, San Francisco

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK562988/

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: April 29, 2021
• First Submitted That Met QC Criteria: May 7, 2021
• First Posted (Actual): May 13, 2021

Study Record Updates

• Last Update Posted (Estimated): October 24, 2025
• Last Update Submitted That Met QC Criteria: October 22, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: SPLIS; sphingosine phosphate lyase; SGPL1; sphingolipidosis; steroid-resistant nephrotic syndrome; primary adrenal insufficiency; neurological defect
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Lipid Metabolism Disorders; Adrenal Gland Diseases; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Lipidoses; Nephrosis; Adrenal Insufficiency; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Nephrotic Syndrome; Sphingolipidoses; Addison Disease
• Other Study ID Numbers: 20-32291

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No