Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

The primary outcome of this study is survival (age at death).

Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.

Weight in kilograms will be measured by weight scale over time.

Head circumference in centimeters will be measured by insertion tape over time.

Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.

Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.

Upper arm muscle circumference in centimeters will be measured using a tape measure over time.

Sitting height in centimeters will be measured using a stadiometer over time.

Knee height in centimeters will be measured using a knee height caliper over time.

Tibial length in centimeters will be measured using a tape measure over time.

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 will be assessed using a non-dilated eye exam.

Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.

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.

An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.

Hearing will be tested over time using standard audiology testing methods.

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.

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 will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.

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.

Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.

Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.

ACTH in picograms per milliliter will be measured by blood sample over time.

Blood renin measured in nanograms/milliliter/hour will be measured over time.

Testosterone will be measured in nanograms/deciliter by blood sample over time.

Estradiol will be measured in picograms per milliliter by blood sample over time.

Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.

Inhibin B will be measured in picograms per milliliter by blood sample over time.

Follicle stimulating hormone will be measured in milli international units per milliliter (mIU/ml) by blood sample over time.

Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.

IGF-1 will be measured in nanograms/mL by blood over time.

Blood glucose will be measured in milligrams per deciliter by blood sample over time.

Serum sodium will be measured in milliequivalents per liter by blood sample over time.

Serum potassium will be measured in milliequivalents per liter by blood sample over time.

Serum chloride will be measured in milliequivalents per liter by blood sample over time.

Serum CO2 will be measured in milliequivalents per liter by blood sample over time.

A complete automated blood count will be performed by blood sample over time.

Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.

Antibodies to childhood vaccinations by blood sample will be measured.

BUN will be measured in mg/dL by blood sample over time.

A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.

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.

A cholesterol profile including high, low, and very low density lipoprotein (HDL, LDL, VLDL) and total cholesterol by blood sample will be measured.

A questionnaire capturing pre- and post-kidney transplant clinical information will be completed by the patient's physician (if applicable).

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.

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.

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 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 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 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).

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.

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.

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.

Skin fibroblast SPL activity levels will be measured by skin biopsy using liquid chromatography/mass spectrometry in response to interventions in fibroblasts.

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.

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.

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.

Occult blood will be tested by stool sample only if gastrointestinal symptoms are present. This test is done through a chemical detection of heme.

Stool fat will be tested by stool sample only if gastrointestinal symptoms are present.

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.

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.

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.

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.

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.