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.
Trial summary
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. Read more about this study
- 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
- Are there results?
- Not yet: the study is under way
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.
United States1 site, 1 recruiting
- 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
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.
- 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 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.
- 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
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Julie D Saba, MD, PhD, Principal investigator, University of California, San Francisco
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 39334450Lovric 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 28165339Prasad 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 28165343Weaver 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 33074640Zhao 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 32233035Martin 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 32855188Zhao 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
Study at a glance
From the registry record, last updated by the sponsor on 4 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Natural History and Phenotypic Spectrum of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
- ClinicalTrials.gov ID
- NCT06669949
- Acronym / sponsor ID
- SPLIS-HIS / 22-37968
- Keywords
- sphingosine phosphate lyase, SGPL1, sphingolipidosis, steroid-resistant nephrotic syndrome, neurological defect, sphingolipid, nephrotic syndrome, primary adrenal insufficiency
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 28 participants (estimated)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- 22 Apr 2025 (actual)
- Primary completion
- 31 Dec 2030 (estimated)
- Study completion
- 31 Dec 2030 (estimated)
- First posted
- 1 Nov 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Other
- Time perspective
- Prospective
- Target follow-up
- 3 Years
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Individuals with sphingosine phosphate lyase insufficiency syndrome | – | Other: no interventionIndividuals diagnosed with sphingosine phosphate lyase insufficiency syndrome based on genetic testing that confirms bi-allelic pathogenic variants in the SGPL1 gene |
| Parents of individuals with sphingosine phosphate lyase insufficiency syndrome | – | Other: no interventionParents of individuals diagnosed with sphingosine phosphate lyase insufficiency syndrome based on genetic testing that confirms bi-allelic pathogenic variants in the SGPL1 gene |
| age and gender-matched controls | – | Other: no interventionThe 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. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- 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.
Key inclusion criteria (5 listed)
- Potential subjects fulfilling the following criteria will be eligible to participate in this study:
- Living or deceased patients diagnosed with SPLIS based on
- 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.
Key exclusion criteria (1 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| no interventionNo interventions are involved in this observational study. | Other | Individuals with sphingosine phosphate lyase insufficiency syndrome, Parents of individuals with sphingosine phosphate lyase insufficiency syndrome, age and gender-matched controls |
Primary outcome
Survival
Time frame: 3 years
The primary outcome of this study is survival (age at death).
Height
Time frame: 3 years
Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.
Weight
Time frame: 3 years
Weight in kilograms will be measured by weight scale over time.
Head circumference
Time frame: 3 years
Head circumference in centimeters will be measured by insertion tape over time.
Triceps skin fold measurement
Time frame: 3 years
Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.
Subscapular skin fold measurement
Time frame: 3 years
Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.
Upper arm muscle circumference
Time frame: 3 years
Upper arm muscle circumference in centimeters will be measured using a tape measure over time.
Sitting height
Time frame: 3 years
Sitting height in centimeters will be measured using a stadiometer over time.
Knee height
Time frame: 3 years
Knee height in centimeters will be measured using a knee height caliper over time.
Tibial length
Time frame: 3 years
Tibial length in centimeters will be measured using a tape measure over time.
Nutritional intake assessment
Time frame: 3 years
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.
Retinal condition
Time frame: 3 years
Retinal condition will be assessed using a non-dilated eye exam.
Skin condition
Time frame: 3 years
Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.
Charcot Marie Tooth Neuropathy Score (CMTNS)
Time frame: 3 years
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.
Abdominal ultrasound
Time frame: At baseline
An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.
Audiology testing
Time frame: 3 years
Hearing will be tested over time using standard audiology testing methods.
Cognitive function
Time frame: 3 years
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.
Tanner stage
Time frame: 3 years
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.
Proteinuria
Time frame: 3 years
Proteinuria will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.
Serum creatinine
Time frame: 3 years
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.
Thyroid function
Time frame: 3 years
Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.
Cortisol
Time frame: 3 years
Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.
Adrenocorticotropin hormone (ACTH)
Time frame: 3 years
ACTH in picograms per milliliter will be measured by blood sample over time.
Renin
Time frame: 3 years
Blood renin measured in nanograms/milliliter/hour will be measured over time.
Testosterone
Time frame: 3 years
Testosterone will be measured in nanograms/deciliter by blood sample over time.
Estradiol
Time frame: 3 years
Estradiol will be measured in picograms per milliliter by blood sample over time.
Anti-mullerian hormone (AMH)
Time frame: 3 years
Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.
Inhibin B
Time frame: 3 years
Inhibin B will be measured in picograms per milliliter by blood sample over time.
Follicle stimulating hormone (FSH)
Time frame: 3 years
Follicle stimulating hormone will be measured in milli international units per milliliter (mIU/ml) by blood sample over time.
Luteinizing hormone (LH)
Time frame: 3 years
Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.
Insulin-like growth factor 1 (IGF-1)
Time frame: 3 years
IGF-1 will be measured in nanograms/mL by blood over time.
Blood glucose
Time frame: 3 years
Blood glucose will be measured in milligrams per deciliter by blood sample over time.
Serum sodium
Time frame: 3 years
Serum sodium will be measured in milliequivalents per liter by blood sample over time.
Serum potassium
Time frame: 3 years
Serum potassium will be measured in milliequivalents per liter by blood sample over time.
Serum chloride
Time frame: 3 years
Serum chloride will be measured in milliequivalents per liter by blood sample over time.
Serum carbon dioxide (CO2)
Time frame: 3 years
Serum CO2 will be measured in milliequivalents per liter by blood sample over time.
Complete blood count
Time frame: 3 years
A complete automated blood count will be performed by blood sample over time.
Serum immunoglobulins
Time frame: 3 years
Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.
Antibodies to vaccine
Time frame: At baseline
Antibodies to childhood vaccinations by blood sample will be measured.
Blood urea nitrogen (BUN)
Time frame: 3 years
BUN will be measured in mg/dL by blood sample over time.
Patient journey questionnaire
Time frame: At baseline
A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.
Pediatric Quality of Life (PedsQL) Questionnaires
Time frame: At baseline
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.
Cholesterol panel
Time frame: 3 years
A cholesterol profile including high, low, and very low density lipoprotein (HDL, LDL, VLDL) and total cholesterol by blood sample will be measured.
Pre- and Post-Kidney Transplant Questionnaire
Time frame: 3 years
A questionnaire capturing pre- and post-kidney transplant clinical information will be completed by the patient's physician (if applicable).
Echocardiography
Time frame: 3 years
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.
Edema-Related Quality of Life
Time frame: 3 years
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.
Patient-Reported Outcomes Measurement Information System (PROMIS)
Time frame: 3 years
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.
Cystatin C
Time frame: 3 years
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.
Urine specific gravity
Time frame: 3 years
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.
Skin Barrier Function uingTewameter, Sebumeter, and Corneometer
Time frame: 3 years
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).
4 secondary outcomes
Blood sphingolipid levels
Time frame: 3 years
Urine sphingolipid levels
Time frame: 3 years
Sphingolipid levels from skin biopsy
Time frame: 1-6 weeks
Sphingosine phosphate lyase (SPL) enzyme activity from skin biopsy
Time frame: 1-6 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Aug 2026.
- Background: PubMed 39334450Keller 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.
- Background: PubMed 28165339Lovric 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.
- Background: PubMed 28165343Prasad 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.
- Background: PubMed 33074640Weaver 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/
- Background: PubMed 32233035Zhao 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.
- Background: PubMed 32855188Martin 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.
- Background: PubMed 33755599Zhao 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.
- Individual participant dataSharing planned: No
Related trials for Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Julie D Saba, MD, PhD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS), run by University of California, San Francisco at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 4 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Julie D Saba, MD, PhD (510-414-6317, Julie.Saba@ucsf.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival (time frame: 3 years). The study lists 50 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06669949, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Aug 2026.