Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

University of California, San Francisco28 enrolled

Overview

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: * Characterizing distinct phenotypic subgroups of SPLIS patients within the larger SPLIS population * Predicting the change (progression or improvement) in symptoms of SPLIS patients over time The exploratory objectives of the study are to explore the potential of plasma sphingolipids other than S1P, urinary sphingolipids including S1P, and immunological markers including cytokines and T cell subsets to serve as disease biomarkers. A SPLIS multi-domain responder index (MDRI) will be developed. Induced pluripotent stem cells derived from peripheral blood mononuclear cells and/or skin fibroblasts will be generated as a research tool.

Study Type

OBSERVATIONAL

Enrollment

Conditions

Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

Interventions

no interventionOTHER

No interventions are involved in this observational study.

Eligibility

Sex: ALL

Medical Language ↔ Plain English

All identified patients with SPLIS diagnosed by genetic criteria are eligible for enrollment in this study, regardless of baseline demographic, biochemical or metabolic features and regardless of interventions such as vitamin B6 supplementation, dialysis or kidney transplantation at time of enrollment. This study may include siblings of index SPLIS cases if the sibling has been genetically confirmed to have SPLIS, regardless of whether they have active disease at the time of enrollment. Data from deceased SPLIS patients will also be collected. Inclusion Criteria: Potential subjects fulfilling the following criteria will be eligible to participate in this study: 1. Living or deceased patients diagnosed with SPLIS based on 1. harbor biallelic pathogenic variant (PV) or likely PV (LPV) in the SGPL1 gene, regardless of phenotype OR 2. harbor nucleotide changes in both SGPL1 alleles, regardless of variant classification, if they also have one of the following: b1) exhibit at least 1 phenotypic feature of SPLIS (nephrosis, endocrine defect, ichthyosis, neuropathy, male gonadal dysgenesis, lymphopenia) b2) have evidence from biochemical or molecular data (such as enzyme expression or activity in skin fibroblasts) that indicate a possible loss of function in the S1P lyase (SPL) protein b3) are a sibling of a subject with nucleotide changes in both alleles of SGPL1 and at least 1 phenotypic feature of SPLIS 2. Informed consent and (if appropriate) assent for living subjects. For deceased subjects, the Principal Investigator (PI) will be responsible for ensuring that all requirements have been met in regard to the relevant local laws and regulations. Parents of participating SPLIS patients may be included as controls. Exclusion Criteria: Subjects with SPLIS (or their parents) who are currently using or have a history of using an investigational agent in the last 30 days with the exception of off-label use of medications will be excluded from the study

Locations (1)

University of California San Francisco

San Francisco, California, United States

RECRUITING

Outcomes

Primary Outcomes

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.

Central Contacts

Julie D Saba, MD, PhD

CONTACT

510-414-6317 Julie.Saba@ucsf.edu

Data from ClinicalTrials.gov

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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

Secondary Outcomes

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