Natural History Study of Patients With Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency

Обзор

Succinic Semialdehyde Dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disease that interferes with the catabolism of the major inhibitory neurotransmitter gamma-amino butyric acid (GABA) and furthermore leads to accumulation of various potential toxic metabolites, most prominently gamma hydroxybutyric acid (GHB). Current research indicates that there is developmental delay and significant neurophysiological and biochemical alterations in SSADHD patients, but whether disease presentation varies with age is not known. The investigators propose to determine the natural course of the clinical presentation of SSADHD; to determine the natural course of neurophysiological and biochemical indices known to be altered in SSADHD; and to identify neurophysiological and biochemical predictors of clinical severity. The overall objective is to define the natural course of the clinical, neurophysiological and biochemical spectrum of SSADHD. Secondary objectives include the identification of biomarkers that correlate with disease phenotype and predict clinical outcomes, and the creation of an international SSADHD data repository for future investigation of pathogenesis and therapy.

Подробное описание

The study will be conducted by 4 academic institutions: Washington State University (WSU), Boston Children's Hospital (BCH), University of South Florida (USF), and University Children's Hospital Heidelberg (iNTD). The design of the study is mixed, with longitudinal and cross-sectional assessments over a period of 5 years.

Patients will be separated into three cohorts. The Boston Children's cohort will be a total of 20 patients evaluated at Boston Children's Hospital in the United States. These patients will be followed for five years, and attend a visit to the hospital in years 1,3 and 5 where assessments including history/physical, neuropsychological testing, EEG, TMS, and bio-specimen collection will be completed. Each patient will have an MRI of the brain done with special GABA sequencing one time over the five years. Each visit will take place over the course of two days. At BCH, the goal will be to schedule visits every other year with questionnaires and surveys sent out up to every 6 months, and bio-specimen collection every year. The BCH team will also ask for two follow up phone calls occurring 12 months after each onsite visit. Visits will consist of clinical assessments (demographics, medical history, physical examination, neurological exam, medication history, neuropsychological assessments, and clinical severity score), neurophysiological assessments (Brain MRI/MRS/DTI, Electroencephalogram, and Transcranial magnetic stimulation), and yearly bio-specimen collection (blood, urine, saliva, hair, stool, and skin biopsy). Bio-specimens will be sent to Washington State University for testing and addition to a biorepository. The iNTD (international NeuroTransmitters Disorders) cohort will be comprised of 15 patients who are seen at European sites who will have approval through their ethics committee to share de-identified information. Bio-specimens will be attempted to be collected at each visit from patients and sent to Washington State University. At the iNTD sites and for patients followed outside of iNTD, visits and bio-specimen collections will depend on the patients' follow-up schedules with electronic, web-based survey sent on a regular schedule (every 6 months). The standard of care cohort will be comprised of 10 patients throughout the world who provide consent to share de-identified information to the database.

The data will be stored in a database on the University of South Florida server. The server is password protected, and each member of the study personal will have a unique log in to have access to the site. Subjects will also be given specialized access to complete follow up electronic web based surveys twice a year over the course of 5 years. The team at USF will assist with data analysis.

Вмешательства

• Устройство Transcranial magnetic stimulation (TMS)
  Transcranial magnetic stimulation (TMS) is a method for noninvasive electrical cortical stimulation, where small intracranial currents are generated by a powerful, fluctuating, extracranial magnetic field. TMS is unique in its capacity for experimental, diagnostic, and therapeutic utility. Single pulse (spTMS) and paired-pulse TMS (ppTMS) have been used extensively to study, measure, and modulate cortical excitability and plasticity.
• Устройство Magnetic resonance imaging (MRI)
  These will be outpatient MRI studies that are planned without sedation. Subjects enrolled at BCH will undergo brain MRI, including volumetric MRI, MRS, and diffusion tensor imaging (DTI). The data will help define the natural history of brain volume, brain myelination and spectroscopic (e.g. GABA) abnormalities.
• Устройство Electroencephalogram (EEG)
  These will be outpatient EEG recordings that span 20-60 minutes and done without sedation. Recordings will be performed using electrode locations specified by the international 10-20 system for standard clinical practice.
• Процедура Bio-specimen Collection
  Bio-specimen collection will include blood, urine, saliva, hair, stool, and a skin biopsy. Blood, urine, saliva, blood spots, and hair samples will also be banked for to-be-determined (TBD) studies.

Первичные конечные точки

• Clinical Severity Score [Срок оценки: 5 Years]
• Biochemical - GABA measurement [Срок оценки: 5 Years]
• Biochemical - GHB measurement [Срок оценки: 5 Years]
• Quantification of GABA related signals on the MRI spectroscopy [Срок оценки: 5 Years]

Критерии участия

Критерии включения

• 4-hydroxybutyric aciduria (γ-hydroxybutyric aciduria)
• documented pathogenic ALDH5A1 (aldehyde dehydrogenase 5A1 gene) mutation
• 0-99 years

Критерии исключения

• active or recent substance abuse or dependence within the past year.
• inability to participate in the study procedures.
• any condition that makes the study subject, in the opinion of the investigator, unsuitable for the study.
• patients will be excluded from the MRI section of the study if they have: implanted cardiac pacemaker or autodefibrillators, implanted neural pacemakers, cochlear implants, metallic foreign bodies in the eye or Central Nervous System (CNS), any implanted wire or metal device that may concentrate radio frequency fields.
• patients less than age two years will be excluded from the TMS procedure.

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

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 1 центр

• Boston Children's Hospital — Boston

Германия · 1 центр

• University Children's Hospital — Heidelberg

Испания · 1 центр

• Sant Joan de Deu Hospital Barcelona — Barcelona

Великобритания · 1 центр

• Birmingham Children's Hospital NHS Foundation Trust — Birmingham

Публикации

• Tokatly Latzer I, Lee HHC, Yang E, Alves C, Bertoldi M, Fung C, Steele SV, Kule E, Jin Z, Rotenberg A, Roullet JB, Pearl PL. Central Dysmyelination in SSADH-Deficient Humans and Mice. Ann Clin Transl Neurol. 2025 Nov;12(11):2193-2205. doi: 10.1002/acn3.70148. Epub 2025 Jul 31. PMID 40741980
• Tokatly Latzer I, Roullet JB, Afshar-Saber W, Lee HHC, Bertoldi M, McGinty GE, DiBacco ML, Arning E, Tsuboyama M, Rotenberg A, Opladen T, Jeltsch K, Garcia-Cazorla A, Julia-Palacios N, Gibson KM, Sahin M, Pearl PL. Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder. J Neurodev Disord. 2024 Apr 24;16(1):21. doi: 1 PMID 38658850

Идентификаторы

NCT: NCT03758521 · IRB-P00029917 · 1R01HD091142-01A1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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