Clinical trial NCT06669949: Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
Official title: Natural History and Phenotypic Spectrum of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
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
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2024-11-01
Enrollment: 28
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
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.

Brief 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. 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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival
timeFrame: 3 years
measure: Height
timeFrame: 3 years
measure: Weight
timeFrame: 3 years
measure: Head circumference
timeFrame: 3 years
measure: Triceps skin fold measurement
timeFrame: 3 years
measure: Subscapular skin fold measurement
timeFrame: 3 years
measure: Upper arm muscle circumference
timeFrame: 3 years
measure: Sitting height
timeFrame: 3 years
measure: Knee height
timeFrame: 3 years
measure: Tibial length
timeFrame: 3 years
measure: Nutritional intake assessment
timeFrame: 3 years
measure: Retinal condition
timeFrame: 3 years
measure: Skin condition
timeFrame: 3 years
measure: Charcot Marie Tooth Neuropathy Score (CMTNS)
timeFrame: 3 years
measure: Abdominal ultrasound
timeFrame: At baseline
measure: Audiology testing
timeFrame: 3 years
measure: Cognitive function
timeFrame: 3 years
measure: Tanner stage
timeFrame: 3 years
measure: Proteinuria
timeFrame: 3 years
measure: Serum creatinine
timeFrame: 3 years
measure: Thyroid function
timeFrame: 3 years
measure: Cortisol
timeFrame: 3 years
measure: Adrenocorticotropin hormone (ACTH)
timeFrame: 3 years
measure: Renin
timeFrame: 3 years
measure: Testosterone
timeFrame: 3 years
measure: Estradiol
timeFrame: 3 years
measure: Anti-mullerian hormone (AMH)
timeFrame: 3 years
measure: Inhibin B
timeFrame: 3 years
measure: Follicle stimulating hormone (FSH)
timeFrame: 3 years
measure: Luteinizing hormone (LH)
timeFrame: 3 years
measure: Insulin-like growth factor 1 (IGF-1)
timeFrame: 3 years
measure: Blood glucose
timeFrame: 3 years
measure: Serum sodium
timeFrame: 3 years
measure: Serum potassium
timeFrame: 3 years
measure: Serum chloride
timeFrame: 3 years
measure: Serum carbon dioxide (CO2)
timeFrame: 3 years
measure: Complete blood count
timeFrame: 3 years
measure: Serum immunoglobulins
timeFrame: 3 years
measure: Antibodies to vaccine
timeFrame: At baseline
measure: Blood urea nitrogen (BUN)
timeFrame: 3 years
measure: Patient journey questionnaire
timeFrame: At baseline
measure: Pediatric Quality of Life (PedsQL) Questionnaires
timeFrame: At baseline
measure: Cholesterol panel
timeFrame: 3 years
measure: Pre- and Post-Kidney Transplant Questionnaire
timeFrame: 3 years
measure: Echocardiography
timeFrame: 3 years
measure: Edema-Related Quality of Life
timeFrame: 3 years
measure: Patient-Reported Outcomes Measurement Information System (PROMIS)
timeFrame: 3 years
measure: Cystatin C
timeFrame: 3 years
measure: Urine specific gravity
timeFrame: 3 years
measure: Skin Barrier Function uingTewameter, Sebumeter, and Corneometer
timeFrame: 3 years
Secondary outcomes:
measure: Blood sphingolipid levels
timeFrame: 3 years
measure: Urine sphingolipid levels
timeFrame: 3 years
measure: Sphingolipid levels from skin biopsy
timeFrame: 1-6 weeks
measure: Sphingosine phosphate lyase (SPL) enzyme activity from skin biopsy
timeFrame: 1-6 weeks
Other outcomes:
measure: Lymphocyte subsets
timeFrame: 3 years
measure: Multi-Domain Responder Index
timeFrame: 3 years
measure: Pyridoxal 5'-phosphate (PLP)
timeFrame: 3 years
measure: Occult blood presence by stool sample
timeFrame: 3 years
measure: Stool fat by stool sample
timeFrame: 3 years
measure: Stool reducing substances by stool sample
timeFrame: 3 years
measure: Calprotectin by stool sample
timeFrame: 3 years
measure: Gut microbiome by stool sample
timeFrame: 3 years
measure: Skin fibroblasts for neural reprogramming
timeFrame: At baseline
measure: Skin fibroblasts for induced pluripotent stem cells (iPSCs)
timeFrame: At baseline
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Julie D Saba, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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