Natural History and Phenotypic Spectrum of Sphingosine Phosphate Lyase Insufficiency Syndrome (SPLIS)
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Survival
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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:
- •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.
排除标准
- •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
结局指标
主要结局
Survival
时间窗: 3 years
The primary outcome of this study is survival (age at death).
Proteinuria
时间窗: 3 years
Proteinuria will be measured as urine albumin/creatinine ratio (ACR) determined with a 24 hour urine collection.
Thyroid function
时间窗: 3 years
Free thyroxine (T4) and thyroid stimulating hormone by blood sample will be measured over time.
Height
时间窗: 3 years
Standing height, sitting height and knee height in centimeters will be performed by stadiometer over time.
Weight
时间窗: 3 years
Weight in kilograms will be measured by weight scale over time.
Head circumference
时间窗: 3 years
Head circumference in centimeters will be measured by insertion tape over time.
Triceps skin fold measurement
时间窗: 3 years
Skin fold in centimeters by skinfold calipers will be measured at the mid-triceps region over time.
Subscapular skin fold measurement
时间窗: 3 years
Skin fold in centimeters by skinfold calipers will be measured at the subscapular region over time.
Upper arm muscle circumference
时间窗: 3 years
Upper arm muscle circumference in centimeters will be measured using a tape measure over time.
Sitting height
时间窗: 3 years
Sitting height in centimeters will be measured using a stadiometer over time.
Knee height
时间窗: 3 years
Knee height in centimeters will be measured using a knee height caliper over time.
Tibial length
时间窗: 3 years
Tibial length in centimeters will be measured using a tape measure over time.
Skin condition
时间窗: 3 years
Appearance of acanthoses, ichthyosis, skin barrier function will be performed by a Tewameter instrument over time.
Renin
时间窗: 3 years
Blood renin measured in nanograms/milliliter/hour will be measured over time.
Estradiol
时间窗: 3 years
Estradiol will be measured in picograms per milliliter by blood sample over time.
Inhibin B
时间窗: 3 years
Inhibin B will be measured in picograms per milliliter by blood sample over time.
Follicle stimulating hormone (FSH)
时间窗: 3 years
Follicle stimulating hormone will be measured in milli international units per milliliter (mIU/ml) by blood sample over time.
Luteinizing hormone (LH)
时间窗: 3 years
Luteinizing hormone will be measured in international units per liter (IU/L) by blood sample over time.
Blood glucose
时间窗: 3 years
Blood glucose will be measured in milligrams per deciliter by blood sample over time.
Serum sodium
时间窗: 3 years
Serum sodium will be measured in milliequivalents per liter by blood sample over time.
Serum carbon dioxide (CO2)
时间窗: 3 years
Serum CO2 will be measured in milliequivalents per liter by blood sample over time.
Complete blood count
时间窗: 3 years
A complete automated blood count will be performed by blood sample over time.
Serum immunoglobulins
时间窗: 3 years
Serum immunoglobulins (IgG, IgA, IgM) will be measured by blood sample over time.
Antibodies to vaccine
时间窗: At baseline
Antibodies to childhood vaccinations by blood sample will be measured.
Blood urea nitrogen (BUN)
时间窗: 3 years
BUN will be measured in mg/dL by blood sample over time.
Insulin-like growth factor 1 (IGF-1)
时间窗: 3 years
IGF-1 will be measured in nanograms/mL by blood over time.
Nutritional intake assessment
时间窗: 3 years
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
时间窗: 3 years
Retinal condition will be assessed using a non-dilated eye exam.
Serum potassium
时间窗: 3 years
Serum potassium will be measured in milliequivalents per liter by blood sample over time.
Serum chloride
时间窗: 3 years
Serum chloride will be measured in milliequivalents per liter by blood sample over time.
Charcot Marie Tooth Neuropathy Score (CMTNS)
时间窗: 3 years
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.
Abdominal ultrasound
时间窗: At baseline
An abdominal ultrasound will be performed to evaluate kidney and adrenal gland structure.
Audiology testing
时间窗: 3 years
Hearing will be tested over time using standard audiology testing methods.
Cognitive function
时间窗: 3 years
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.
Tanner stage
时间窗: 3 years
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.
Testosterone
时间窗: 3 years
Testosterone will be measured in nanograms/deciliter by blood sample over time.
Anti-mullerian hormone (AMH)
时间窗: 3 years
Anti-mullerian hormone will be measured in nanograms/milliliter by blood sample over time.
Serum creatinine
时间窗: 3 years
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.
Cortisol
时间窗: 3 years
Morning cortisol level in micrograms/deciliter by blood sample will be measured over time.
Adrenocorticotropin hormone (ACTH)
时间窗: 3 years
ACTH in picograms per milliliter will be measured by blood sample over time.
Patient journey questionnaire
时间窗: At baseline
A patient journey questionnaire capturing timing of disease feature onset and progression will be completed by the patient/family.
Pediatric Quality of Life (PedsQL) Questionnaires
时间窗: At baseline
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.
Cholesterol panel
时间窗: 3 years
A cholesterol profile including high, low, and very low density lipoprotein (HDL, LDL, VLDL) and total cholesterol by blood sample will be measured.
Pre- and Post-Kidney Transplant Questionnaire
时间窗: 3 years
A questionnaire capturing pre- and post-kidney transplant clinical information will be completed by the patient's physician (if applicable).
Echocardiography
时间窗: 3 years
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.
Edema-Related Quality of Life
时间窗: 3 years
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.
Patient-Reported Outcomes Measurement Information System (PROMIS)
时间窗: 3 years
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
时间窗: 3 years
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
时间窗: 3 years
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 uingTewameter, Sebumeter, and Corneometer
时间窗: 3 years
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).
次要结局
- 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)