An observational study in Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS), sponsored by University of California, San Francisco. Recruiting at 1 site in United States. Per ClinicalTrials.gov, last updated 2026-08-04.
Sponsored by University of California, San Francisco · Observational
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.
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:
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.
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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.
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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:
Living or deceased patients diagnosed with SPLIS based on
Exclusion Criteria:
Subjects with SPLIS (or their parents) who are currently using or have a history of using an agent in the last 30 days with the exception of off-label use of medications will be excluded from the study
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
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.
Survival
The primary outcome of this study is survival (age at death).
Time frame: 3 years
Height
Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.
Time frame: 3 years
Weight
Weight in kilograms will be measured by weight scale over time.
Time frame: 3 years
Head circumference
Head circumference in centimeters will be measured by insertion tape over time.
Time frame: 3 years
Triceps skin fold measurement
Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.
Time frame: 3 years
Subscapular skin fold measurement
Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.
Time frame: 3 years
Upper arm muscle circumference
Upper arm muscle circumference in centimeters will be measured using a tape measure over time.
Time frame: 3 years
Sitting height
Sitting height in centimeters will be measured using a stadiometer over time.
Time frame: 3 years
Knee height
Knee height in centimeters will be measured using a knee height caliper over time.
Time frame: 3 years
Tibial length
Tibial length in centimeters will be measured using a tape measure over time.
Time frame: 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.
Time frame: 3 years
Retinal condition
Retinal condition will be assessed using a non-dilated eye exam.
Time frame: 3 years
Skin condition
Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.
Time frame: 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.
Time frame: 3 years
Abdominal ultrasound
An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.
Time frame: At baseline
Audiology testing
Hearing will be tested over time using standard audiology testing methods.
Time frame: 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.
Time frame: 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.
Time frame: 3 years
Proteinuria
Proteinuria will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.
Time frame: 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.
Time frame: 3 years
Thyroid function
Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.
Time frame: 3 years
Cortisol
Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.
Time frame: 3 years
Adrenocorticotropin hormone (ACTH)
ACTH in picograms per milliliter will be measured by blood sample over time.
Time frame: 3 years
Renin
Blood renin measured in nanograms/milliliter/hour will be measured over time.
Time frame: 3 years
Testosterone
Testosterone will be measured in nanograms/deciliter by blood sample over time.
Time frame: 3 years
Estradiol
Estradiol will be measured in picograms per milliliter by blood sample over time.
Time frame: 3 years
Anti-mullerian hormone (AMH)
Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.
Time frame: 3 years
Inhibin B
Inhibin B will be measured in picograms per milliliter by blood sample over time.
Time frame: 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.
Time frame: 3 years
Luteinizing hormone (LH)
Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.
Time frame: 3 years
Insulin-like growth factor 1 (IGF-1)
IGF-1 will be measured in nanograms/mL by blood over time.
Time frame: 3 years
Blood glucose
Blood glucose will be measured in milligrams per deciliter by blood sample over time.
Time frame: 3 years
Serum sodium
Serum sodium will be measured in milliequivalents per liter by blood sample over time.
Time frame: 3 years
Serum potassium
Serum potassium will be measured in milliequivalents per liter by blood sample over time.
Time frame: 3 years
Serum chloride
Serum chloride will be measured in milliequivalents per liter by blood sample over time.
Time frame: 3 years
Serum carbon dioxide (CO2)
Serum CO2 will be measured in milliequivalents per liter by blood sample over time.
Time frame: 3 years
Complete blood count
A complete automated blood count will be performed by blood sample over time.
Time frame: 3 years
Serum immunoglobulins
Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.
Time frame: 3 years
Antibodies to vaccine
Antibodies to childhood vaccinations by blood sample will be measured.
Time frame: At baseline
Blood urea nitrogen (BUN)
BUN will be measured in mg/dL by blood sample over time.
Time frame: 3 years
Patient journey questionnaire
A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 3 years
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 1-6 weeks
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.
Time frame: 3 years
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.
Time frame: 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.
Time frame: 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.
Time frame: 3 years
Stool fat by stool sample
Stool fat will be tested by stool sample only if gastrointestinal symptoms are present.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: At baseline
Plan to share: No
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