Natural History of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

Официальное название

Natural History and Phenotypic Spectrum of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)

Обзор

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.

Подробное описание

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.

Вмешательства

• Другое no intervention
  No interventions are involved in this observational study.

Первичные конечные точки

• Survival [Срок оценки: 3 years]
• Height [Срок оценки: 3 years]
• Weight [Срок оценки: 3 years]
• Head circumference [Срок оценки: 3 years]
• Triceps skin fold measurement [Срок оценки: 3 years]
• Subscapular skin fold measurement [Срок оценки: 3 years]
• Upper arm muscle circumference [Срок оценки: 3 years]
• Sitting height [Срок оценки: 3 years]
• Knee height [Срок оценки: 3 years]
• Tibial length [Срок оценки: 3 years]

Вторичные конечные точки (4)

• Blood sphingolipid levels [Срок оценки: 3 years]
• Urine sphingolipid levels [Срок оценки: 3 years]
• Sphingolipid levels from skin biopsy [Срок оценки: 1-6 weeks]
• Sphingosine phosphate lyase (SPL) enzyme activity from skin biopsy [Срок оценки: 1-6 weeks]

Критерии участия

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.

Критерии включения

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.

Критерии исключения

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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Другое

Центры проведения

США · 1 центр

• University of California San Francisco — San Francisco

Публикации

• 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
• 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 PMID 28165339
• 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 insu PMID 28165343
• Weaver KN, Sullivan B, Hildebrandt F, Strober J, Prasad R, Saba J, Samuel M, Hegele R, McIntyre A. Sphingosine Phosphate Lyase Insufficiency Syndrome. 2020 Oct 15 [updated 2026 Apr 9]. 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/NBK56 PMID 33074640
• 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 PMID 32233035
• 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
• 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

Идентификаторы

NCT: NCT06669949 · 22-37968 · R01HD113778

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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