Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

NCT06669949 | Recruiting

• 2 other identifiers: 22-37968R01HD113778
• Study Type: observational
• Target: 28
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (50)

• Survival

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

  3 years

• Height

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

  3 years

• Weight

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

  3 years

• Head circumference

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

  3 years

• Triceps skin fold measurement

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

  3 years

• Subscapular skin fold measurement

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

  3 years

• Upper arm muscle circumference

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

  3 years

• Sitting height

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

  3 years

• Knee height

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

  3 years

• Tibial length

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

  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.

  3 years

• Retinal condition

  Retinal condition will be assessed using a non-dilated eye exam.

  3 years

• Skin condition

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

  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.

  3 years

• Abdominal ultrasound

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

  At baseline

• Audiology testing

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

  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.

  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.

  3 years

• Proteinuria

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

  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.

  3 years

• Thyroid function

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

  3 years

• Cortisol

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

  3 years

• Adrenocorticotropin hormone (ACTH)

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

  3 years

• Renin

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

  3 years

• Testosterone

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

  3 years

• Estradiol

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

  3 years

• Anti-mullerian hormone (AMH)

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

  3 years

• Inhibin B

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

  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.

  3 years

• Luteinizing hormone (LH)

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

  3 years

• Insulin-like growth factor 1 (IGF-1)

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

  3 years

• Blood glucose

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

  3 years

• Serum sodium

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

  3 years

• Serum potassium

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

  3 years

• Serum chloride

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

  3 years

• Serum carbon dioxide (CO2)

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

  3 years

• Complete blood count

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

  3 years

• Serum immunoglobulins

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

  3 years

• Antibodies to vaccine

  Antibodies to childhood vaccinations by blood sample will be measured.

  At baseline

• Blood urea nitrogen (BUN)

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

  3 years

• Patient journey questionnaire

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

  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.

  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.

  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).

  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.

  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.

  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.

  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.

  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.

  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).

  3 years

Secondary Outcomes (4)

• Blood sphingolipid levels

  3 years

• Urine sphingolipid levels

  3 years

• Sphingolipid levels from skin biopsy

  1-6 weeks

• Sphingosine phosphate lyase (SPL) enzyme activity from skin biopsy

  1-6 weeks

Other Outcomes (10)

• Lymphocyte subsets

  3 years

• Multi-Domain Responder Index

  3 years

• Pyridoxal 5'-phosphate (PLP)

  3 years

Study Arms (3)

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

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

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.

Other: no intervention

Interventions

no intervention OTHER

No interventions are involved in this observational study.

Individuals with sphingosine phosphate lyase insufficiency syndrome; Parents of individuals with sphingosine phosphate lyase insufficiency syndrome; age and gender-matched controls

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of California San Francisco

San Francisco, California, 94143, United States

RECRUITING

Related Publications (7)

• 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.

  PMID: 39334450 BACKGROUND

• Lovric 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.

  PMID: 28165339 BACKGROUND

• Prasad 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.

  PMID: 28165343 BACKGROUND

• Weaver KN, Sullivan B, Hildebrandt F, Strober J, Cooper M, Prasad R, Saba J. Sphingosine Phosphate Lyase Insufficiency Syndrome. 2020 Oct 15. 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/

  PMID: 33074640 BACKGROUND

• Zhao 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.

  PMID: 32233035 BACKGROUND

• Martin 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.

  PMID: 32855188 BACKGROUND

• Zhao 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.

  PMID: 33755599 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood will be collected for plasma and peripheral blood mononuclear cells. Urine and stool samples will be collected. Leftover material not used in clinical testing will be retained for future research use. Leftover skin biopsy material or fibroblasts derived from skin biopsies obtained as part of medical care may be used to create a cell line that will be analyzed and stored in a specimen bank at University of California San Francisco.

MeSH Terms

Conditions

Sphingolipidoses; Nephrotic Syndrome; Addison Disease; Primary Immunodeficiency Diseases; Charcot-Marie-Tooth Disease; Hypothyroidism; Ichthyosis

Condition Hierarchy (Ancestors)

Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; Nephrosis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Immunologic Deficiency Syndromes; Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Thyroid Diseases; Skin Abnormalities; Infant, Newborn, Diseases; Keratosis; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Julie D Saba, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Julie D Saba, MD, PhD

CONTACT

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

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Target Duration: 3 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2024
• First Posted: November 1, 2024
• Study Start: April 22, 2025
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: May 13, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)