Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)SPLIS-HISNCT06669949

Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

An observational study of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS), run by University of California, San Francisco at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

Who is it for?: Any age
Conditions the study is for: Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
How many people: 28 participants
Where: 1 siteUnited States
Study dates: 22 Apr 2025to 31 Dec 2030
How long will I take part?: 3 Years
Phase: Observational

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages Any age
All sexes
No healthy volunteers
Child, Adult, Older adult

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.

Who may be able to join

Potential subjects fulfilling the following criteria will be eligible to participate in this study:
Living or deceased patients diagnosed with SPLIS based on
harbor biallelic pathogenic variant (PV) or likely PV (LPV) in the SGPL1 gene, regardless of phenotype OR
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
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.

Who cannot join

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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Julie D Saba, MD, PhD contact

510-414-6317

Julie.Saba@ucsf.edu

United States1 site, 1 recruiting

University of California San Francisco
San Francisco, California, 94143
Julie D Saba, MD, PhD, 510-414-6317, Julie.Saba@ucsf.edu
Julie D Saba, MD, PhD
Recruiting

Other trials in United States

About this study

Official title: 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.

Read the 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.

Conditions: Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
Being tested: no intervention
Keywords: sphingosine phosphate lyase, SGPL1, sphingolipidosis, steroid-resistant nephrotic syndrome, neurological defect, sphingolipid, nephrotic syndrome, primary adrenal insufficiency, primary immunodeficiency, Charcot-Marie-Tooth Disease, hypothyroidism, ichthyosis, sphingosine phosphate lyase insufficiency syndrome, RENI syndrome, NPHS14
Medical subject headings: Sphingolipidoses, Nephrotic Syndrome, Addison Disease, Primary Immunodeficiency Diseases, Charcot-Marie-Tooth Disease, Hypothyroidism, Ichthyosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

no interventionOther
No interventions are involved in this observational study.

Study groups in NCT06669949
Study group	Role	What they receive
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 Receives: Other: no intervention
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 Receives: Other: no intervention
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. Receives: Other: no intervention

What is being measured

The primary outcome is the main question the study is designed to answer.

Survival
The primary outcome of this study is survival (age at death).
Measured: 3 years
Height
Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.
Measured: 3 years
Weight
Weight in kilograms will be measured by weight scale over time.
Measured: 3 years
Head circumference
Head circumference in centimeters will be measured by insertion tape over time.
Measured: 3 years
Triceps skin fold measurement
Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.
Measured: 3 years
Subscapular skin fold measurement
Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.
Measured: 3 years
Upper arm muscle circumference
Upper arm muscle circumference in centimeters will be measured using a tape measure over time.
Measured: 3 years
Sitting height
Sitting height in centimeters will be measured using a stadiometer over time.
Measured: 3 years
Knee height
Knee height in centimeters will be measured using a knee height caliper over time.
Measured: 3 years
Tibial length
Tibial length in centimeters will be measured using a tape measure over time.
Measured: 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.
Measured: 3 years
Retinal condition
Retinal condition will be assessed using a non-dilated eye exam.
Measured: 3 years
Skin condition
Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.
Measured: 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.
Measured: 3 years
Abdominal ultrasound
An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.
Measured: At baseline
Audiology testing
Hearing will be tested over time using standard audiology testing methods.
Measured: 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.
Measured: 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.
Measured: 3 years
Proteinuria
Proteinuria will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.
Measured: 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.
Measured: 3 years
Thyroid function
Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.
Measured: 3 years
Cortisol
Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.
Measured: 3 years
Adrenocorticotropin hormone (ACTH)
ACTH in picograms per milliliter will be measured by blood sample over time.
Measured: 3 years
Renin
Blood renin measured in nanograms/milliliter/hour will be measured over time.
Measured: 3 years
Testosterone
Testosterone will be measured in nanograms/deciliter by blood sample over time.
Measured: 3 years
Estradiol
Estradiol will be measured in picograms per milliliter by blood sample over time.
Measured: 3 years
Anti-mullerian hormone (AMH)
Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.
Measured: 3 years
Inhibin B
Inhibin B will be measured in picograms per milliliter by blood sample over time.
Measured: 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.
Measured: 3 years
Luteinizing hormone (LH)
Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.
Measured: 3 years
Insulin-like growth factor 1 (IGF-1)
IGF-1 will be measured in nanograms/mL by blood over time.
Measured: 3 years
Blood glucose
Blood glucose will be measured in milligrams per deciliter by blood sample over time.
Measured: 3 years
Serum sodium
Serum sodium will be measured in milliequivalents per liter by blood sample over time.
Measured: 3 years
Serum potassium
Serum potassium will be measured in milliequivalents per liter by blood sample over time.
Measured: 3 years
Serum chloride
Serum chloride will be measured in milliequivalents per liter by blood sample over time.
Measured: 3 years
Serum carbon dioxide (CO2)
Serum CO2 will be measured in milliequivalents per liter by blood sample over time.
Measured: 3 years
Complete blood count
A complete automated blood count will be performed by blood sample over time.
Measured: 3 years
Serum immunoglobulins
Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.
Measured: 3 years
Antibodies to vaccine
Antibodies to childhood vaccinations by blood sample will be measured.
Measured: At baseline
Blood urea nitrogen (BUN)
BUN will be measured in mg/dL by blood sample over time.
Measured: 3 years
Patient journey questionnaire
A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.
Measured: At baseline
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.
Measured: 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.
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).
Measured: 3 years
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 3 years

Secondary outcomes (4)

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 1-6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

22 Apr 202531 Dec 2030

First posted1 Nov 2024
Study start22 Apr 2025
Primary completion31 Dec 2030 (estimated)
Study completion31 Dec 2030 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (7)Papers the sponsor has linked to this study.
Other trials for Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)Studies of the same condition, open and under way.
More trials run by University of California, San FranciscoThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Other
Time perspective: Prospective
Enrolment: 28 participants (estimated)
Target duration: 3 Years

IDs, dates and publications

ClinicalTrials.gov ID: NCT06669949
Sponsor's protocol ID: 22-37968
Other IDs: R01HD113778
Acronym: SPLIS-HIS
Status last verified: Jul 2026
First submitted: 26 Oct 2024
Last updated: 4 Aug 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 39334450
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.
PubMed 28165339
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.
PubMed 28165343
Weaver KN, Sullivan B, Hildebrandt F, Strober J, Prasad R, Saba J, Samuel M, Hegele R, McIntyre A. Sphingosine Phosphate Lyase Insufficiency Syndrome. 2020 Oct 15 [updated 2026 Apr 9]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK562988/
PubMed 33074640
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.
PubMed 32233035
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.
PubMed 32855188
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.
PubMed 33755599