Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS) (SPLIS-HIS)

Natural History and Phenotypic Spectrum of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

This is a prospective longitudinal natural history study with a retrospective cross-sectional arm aimed at determining the natural history of sphingosine phosphate lyase insufficiency syndrome (SPLIS), a recently recognized inborn error of metabolism. The central hypothesis is that age of onset, other disease features, and disease biomarkers will be predictive of quality of life (QOL) and survival in SPLIS patients.

Study Overview

• Status: Recruiting
• Conditions: Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
• Intervention / Treatment: Other: no intervention

Detailed Description

The main purpose of the study is to characterize the natural history of sphingosine phosphate lyase insufficiency syndrome (SPLIS) including the full spectrum of presentations (clinical, biochemical, radiological and pathological) and their change (progression or improvement) over time by collecting and analyzing data from prospective assessments on patients with SPLIS over a three-year time period and retrospective chart review of treatment history. By necessity, the investigators will also endeavor to explore the range of medical treatments and interventions currently being used in the care of SPLIS patients and their impact on the natural history of SPLIS. A retrospective arm will collect data on patients who are deceased and/or who are willing to share medical data but unwilling to participate in the prospective arm of the study.

The secondary objective of the study is to establish a set of biomarkers including plasma sphingosine-1-phosphate (S1P) and absolute lymphocyte count (ALC) that may aid in:

• Characterizing distinct phenotypic subgroups of SPLIS patients within the larger SPLIS population
• Predicting the change (progression or improvement) in symptoms of SPLIS patients over time

The exploratory objectives of the study are to explore the potential of plasma sphingolipids other than S1P, urinary sphingolipids including S1P, and immunological markers including cytokines and T cell subsets to serve as disease biomarkers. A SPLIS multi-domain responder index (MDRI) will be developed. Induced pluripotent stem cells derived from peripheral blood mononuclear cells and/or skin fibroblasts will be generated as a research tool.

• Study Type: Observational
• Enrollment (Estimated): 28

Contacts and Locations

• Study Contact: Name: Julie D Saba, MD, PhD; Phone Number: 510-414-6317; Email: Julie.Saba@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
      • Principal Investigator: Julie D Saba, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• 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

All identified patients with SPLIS diagnosed by genetic criteria are eligible for enrollment in this study, regardless of baseline demographic, biochemical or metabolic features and regardless of interventions such as vitamin B6 supplementation, dialysis or kidney transplantation at time of enrollment. This study may include siblings of index SPLIS cases if the sibling has been genetically confirmed to have SPLIS, regardless of whether they have active disease at the time of enrollment. Data from deceased SPLIS patients will also be collected.

Inclusion Criteria:

Potential subjects fulfilling the following criteria will be eligible to participate in this study:

1. Living or deceased patients diagnosed with SPLIS based on

   1. harbor biallelic pathogenic variant (PV) or likely PV (LPV) in the SGPL1 gene, regardless of phenotype OR
   2. harbor nucleotide changes in both SGPL1 alleles, regardless of variant classification, if they also have one of the following: b1) exhibit at least 1 phenotypic feature of SPLIS (nephrosis, endocrine defect, ichthyosis, neuropathy, male gonadal dysgenesis, lymphopenia) b2) have evidence from biochemical or molecular data (such as enzyme expression or activity in skin fibroblasts) that indicate a possible loss of function in the S1P lyase (SPL) protein b3) are a sibling of a subject with nucleotide changes in both alleles of SGPL1 and at least 1 phenotypic feature of SPLIS
2. Informed consent and (if appropriate) assent for living subjects. For deceased subjects, the Principal Investigator (PI) will be responsible for ensuring that all requirements have been met in regard to the relevant local laws and regulations. Parents of participating SPLIS patients may be included as controls.

Exclusion Criteria:

Subjects with SPLIS (or their parents) who are currently using or have a history of using an investigational agent in the last 30 days with the exception of off-label use of medications will be excluded from the study

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.
Individuals with sphingosine phosphate lyase insufficiency syndrome; Individuals diagnosed with sphingosine phosphate lyase insufficiency syndrome based on genetic testing that confirms bi-allelic pathogenic variants in the SGPL1 gene	Other: no intervention; No interventions are involved in this observational study.
Parents of individuals with sphingosine phosphate lyase insufficiency syndrome; Parents of individuals diagnosed with sphingosine phosphate lyase insufficiency syndrome based on genetic testing that confirms bi-allelic pathogenic variants in the SGPL1 gene	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).	3 years
Renin	Blood renin measured in nanograms/milliliter/hour will be measured over time.	3 years
Height	Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.	3 years
Weight	Weight in kilograms will be measured by weight scale over time.	3 years
Head circumference	Head circumference in centimeters will be measured by insertion tape over time.	3 years
Triceps skin fold measurement	Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.	3 years
Subscapular skin fold measurement	Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.	3 years
Upper arm muscle circumference	Upper arm muscle circumference in centimeters will be measured using a tape measure over time.	3 years
Sitting height	Sitting height in centimeters will be measured using a stadiometer over time.	3 years
Knee height	Knee height in centimeters will be measured using a knee height caliper over time.	3 years
Tibial length	Tibial length in centimeters will be measured using a tape measure over time.	3 years
Retinal condition	Retinal condition will be assessed using a non-dilated eye exam.	3 years
Skin condition	Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.	3 years
Charcot Marie Tooth Neuropathy Score (CMTNS)	Charcot Marie Tooth neuropathy scores are made up of nine assessments, including three symptoms, four signs, and two neurophysiology items tested by nerve conduction study. Each assessment is scored on a scale of 0-4, with higher scores indicating greater impairment.	3 years
Abdominal ultrasound	An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.	At baseline
Audiology testing	Hearing will be tested over time using standard audiology testing methods.	3 years
Tanner stage	Sexual maturity will be determined by Tanner stage during physical exam. As Tanner stages move 1 through 5 to characterize the development of secondary sexual characteristics for males and females.	3 years
Proteinuria	Proteinuria will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.	3 years
Serum creatinine	Serum creatinine will be measured in mg/dL and used to determine estimated glomerular filtration rate (eGFR) in units of (mL/min/1.73m2) over time.	3 years
Thyroid function	Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.	3 years
Cortisol	Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.	3 years
Adrenocorticotropin hormone (ACTH)	ACTH in picograms per milliliter will be measured by blood sample over time.	3 years
Testosterone	Testosterone will be measured in nanograms/deciliter by blood sample over time.	3 years
Estradiol	Estradiol will be measured in picograms per milliliter by blood sample over time.	3 years
Anti-mullerian hormone (AMH)	Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.	3 years
Inhibin B	Inhibin B will be measured in picograms per milliliter by blood sample over time.	3 years
Follicle stimulating hormone (FSH)	Follicle stimulating hormone will be measured in milli international units per milliliter (mIU/ml) by blood sample over time.	3 years
Luteinizing hormone (LH)	Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.	3 years
Insulin-like growth factor 1 (IGF-1)	IGF-1 will be measured in nanograms/mL by blood over time.	3 years
Blood glucose	Blood glucose will be measured in milligrams per deciliter by blood sample over time.	3 years
Serum sodium	Serum sodium will be measured in milliequivalents per liter by blood sample over time.	3 years
Serum potassium	Serum potassium will be measured in milliequivalents per liter by blood sample over time.	3 years
Serum chloride	Serum chloride will be measured in milliequivalents per liter by blood sample over time.	3 years
Serum carbon dioxide (CO2)	Serum CO2 will be measured in milliequivalents per liter by blood sample over time.	3 years
Complete blood count	A complete automated blood count will be performed by blood sample over time.	3 years
Serum immunoglobulins	Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.	3 years
Antibodies to vaccine	Antibodies to childhood vaccinations by blood sample will be measured.	At baseline
Blood urea nitrogen (BUN)	BUN will be measured in mg/dL by blood sample over time.	3 years
Patient journey questionnaire	A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.	At baseline
Cholesterol panel	A cholesterol profile including high, low, and very low density lipoprotein (HDL, LDL, VLDL) and total cholesterol by blood sample will be measured.	3 years
Pre- and Post-Kidney Transplant Questionnaire	A questionnaire capturing pre- and post-kidney transplant clinical information will be completed by the patient's physician (if applicable).	3 years
Nutritional intake assessment	A questionnaire assessing 24-hour recall of nutritional intake will be performed using using a 3-day food log. The information will be assessed using the online Automated Self-Administered 24-Hour Dietary Recall (ASA24) tool. The nutritional intake assessment will additionally include information on emesis and stool consistently using the Bristol Stool Chart.	3 years
Cognitive function	Cognitive function will be tested using the Vineland Adaptive Behavior Scales developmental test. The Vineland scales consist of questions about communication, daily living, socialization, and motor skills, and questions are targeted to age and developmental stage, rated on a scale of 0 (not able to perform behavior) to 2 (completely able to perform behavior). Cognitive testing will additionally include the Leiter-3.0, a nonverbal intelligence test designed to assess the cognitive abilities of individuals, primarily those who may have language or communication barriers. The exact interpretation of these scores is typically done by a trained psychologist or clinician, who will consider the test results in context with other information to provide a comprehensive assessment.	3 years
Pediatric Quality of Life (PedsQL) Questionnaires	PedsQL is a validated and standardized questionnaire capturing information on pediatric quality of life. The study will use 4 modules to capture various patients: End Stage Renal Disease Module, Family Impact Module, Generic Core Scales, and the Infant Scales. A higher score indicates a higher quality of life.	At baseline
Echocardiography	A standard cardiac ultrasound will be performed by a pediatric cardiologist to track SPLIS-related cardiovascular changes or abnormalities including left and chamber sizes and masses, Doppler measurements, and aortic diameter.	3 years
Edema-Related Quality of Life	As SPLIS patients often experience edema as a result of kidney failure, PREPARE-NS is a questionnaire that will be used to gage how kidney failure symptoms like edema alter a patient's quality of living.	3 years
Patient-Reported Outcomes Measurement Information System (PROMIS)	PROMIS assesses quality of life in several domains including physical functioning, mental health, social functioning, pain, sleep, fatigue, cognitive functioning, emotional distress, and ability to participate in social roles and activities. A higher score indicates a high quality of life.	3 years
Cystatin C	Cystatin C will be measured in milligrams per liter (mg/L) or micrograms per milliliter (µg/mL) using a blood sample to assess kidney function.	3 years
Urine specific gravity	Urine specific gravity will be measured using a urine sample, a unitless measure comparing the ratio of the density of urine to water, providing information about the kidney's ability to concentrate or dilute urine.	3 years
Skin Barrier Function uingTewameter, Sebumeter, and Corneometer	Skin barrier function will be measured using a device called a Multi-Probe Adapter-5 (MPA5) manufactured by Courage + Khazaka, which uses a tewameter probe (measuring transepidermal water loss), a sebumeter (measuring skin sebum), and a corneometer (measuring skin hydration).	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood sphingolipid levels	Blood levels of sphingosine-1-phosphate, dihydrosphingosine-1-phosphate, sphingosine, dihydrosphingosine and ceramides will be measured by blood sample using tandem mass spectrometry over time and reported in micromolarity units.	3 years
Urine sphingolipid levels	Urine levels of sphingosine-1-phosphate, dihydrosphingosine-1-phosphate, sphingosine, dihydrosphingosine and ceramides will be measured in a 24 hour urine collection using tandem mass spectrometry over time and reported in micromolarity units.	3 years
Sphingolipid levels from skin biopsy	Skin fibroblast sphingolipid levels will be collected using skin biopsy, and compared by liquid chromatography/mass spectrometry in medium containing various therapeutic agents. This test will be performed to characterize the response to interventions in fibroblasts.	1-6 weeks
Sphingosine phosphate lyase (SPL) enzyme activity from skin biopsy	Skin fibroblast SPL activity levels will be measured by skin biopsy using liquid chromatography/mass spectrometry in response to interventions in fibroblasts.	1-6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lymphocyte subsets	CD3, CD4, CD8, CD20, CD56/16 positive cells and recent thymic emigrants representing lymphocyte subsets in the peripheral blood will be measured over time by blood sample and reported as absolute numbers of cells/mm^3.	3 years
Pyridoxal 5'-phosphate (PLP)	PLP, the active form of vitamin B6, will be measured by blood sample over time if patients are planning to or have initiated cofactor supplementation with pyridoxine.	3 years
Occult blood presence by stool sample	Occult blood will be tested by stool sample only if gastrointestinal symptoms are present. This test is done through a chemical detection of heme.	3 years
Stool fat by stool sample	Stool fat will be tested by stool sample only if gastrointestinal symptoms are present.	3 years
Stool reducing substances by stool sample	Stool reducing substances will be tested by stool sample only if gastrointestinal symptoms are present using qualitative chromaticity - the process of identifying the hue or color of stool (brown, green, yellow, black, or red) to detect an underlying gut health abnormality. Brown is normal, while a change to any other color suggests a deviation from normal.	3 years
Calprotectin by stool sample	Calprotectin will be tested by stool sample only if gastrointestinal symptoms are present, using quantitative chemiluminescent immunoassay - a technique that replies on the use of light to detect the concentration of calprotectin in stool. Moderate (50-120 ug/g) to high (>120 ug/g) levels of calprotectin indicate moderate to high levels of gut inflammation.	3 years
Gut microbiome by stool sample	Gut microbiome analysis will be performed using DNA extraction and 16s gene sequencing from a stool sample over time to assess the microorganism composition of the intestines, affecting gut health.	3 years
Skin fibroblasts for neural reprogramming	Skin fibroblasts will be obtained through a skin biopsy and subsequently reprogrammed to differentiate into neurons. This process will be used for basic science research.	At baseline
Skin fibroblasts for induced pluripotent stem cells (iPSCs)	Skin fibroblasts or peripheral blood mononuclear cells will be obtained through a skin biopsy and subsequently reprogrammed to become iPSCs. This process will be used for basic science research purposes.	At baseline
Multi-Domain Responder Index	Patients will be asked to review their symptoms every 6 months, while their parents (when applicable) will be asked to review their own, and recall their family history of relevant symptoms. The multidomain responder index is a scoring system that tailors a score to the patient's worst symptoms, which will be created as a result of symptom tracking. Scoring arbitrarily starts at 0 on the first measurement and may stay at 0 on subsequent exams (no change over time), increase to +1 (improvement over time), or decrease to -1 (worsening over time). This will be tested for ability to measure overall patient status over time.	3 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• 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.
• 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.
• Keller N, Midgley J, Khalid E, Lesmana H, Mathew G, Mincham C, Teig N, Khan Z, Khosla I, Mehr S, Guran T, Buder K, Xu H, Alhasan K, Buyukyilmaz G, Weaver N, Saba JD. Factors influencing survival in sphingosine phosphate lyase insufficiency syndrome: a retrospective cross-sectional natural history study of 76 patients. Orphanet J Rare Dis. 2024 Sep 27;19(1):355. doi: 10.1186/s13023-024-03311-w.
• 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 31, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: October 26, 2024
• First Submitted That Met QC Criteria: October 31, 2024
• First Posted (Actual): November 1, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2025
• Last Update Submitted That Met QC Criteria: May 7, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: primary immunodeficiency; sphingosine phosphate lyase; SGPL1; sphingolipidosis; steroid-resistant nephrotic syndrome; primary adrenal insufficiency; neurological defect; hypothyroidism; nephrotic syndrome; sphingolipid; ichthyosis; Charcot-Marie-Tooth Disease; sphingosine phosphate lyase insufficiency syndrome; RENI syndrome; NPHS14
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome
• Other Study ID Numbers: 22-37968; R01HD113778 (U.S. NIH Grant/Contract)

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