Natural History Study of Patients With Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
2 other identifiers
observational
55
4 countries
4
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for all trials
Started Jan 2019
Longer than P75 for all trials
4 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 16, 2018
CompletedFirst Posted
Study publicly available on registry
November 29, 2018
CompletedStudy Start
First participant enrolled
January 15, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
May 31, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 1, 2029
January 13, 2026
January 1, 2026
10.4 years
November 16, 2018
January 12, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (4)
Clinical Severity Score
A composite score ranging from 5 (profound impairment) to 25 (no impairment) will be calculated using scores from five clinically significant subdomains (cognition, communication, motor skills, psychiatric presentation, and epilepsy), each scored from 1 (worse) to 5 (no impairment).
5 Years
Biochemical - GABA measurement
GABA is measured by electron-capture negative-ion mass fragmentography. The level will be measured in the different bio-specimens.
5 Years
Biochemical - GHB measurement
GHB is measured using gas chromatography-mass spectrometry (GCMS). GHB will be measured in the different bio-specimens.
5 Years
Quantification of GABA related signals on the MRI spectroscopy
MRI spectroscopy with special editing for GABA-related peaks in multi-voxel MRS. Concentrations will be analyzed.
5 Years
Other Outcomes (6)
Quantification of EEG abnormalities (%)
5 Years
Extent of altered signal hyperintensities on structural MRI (%)
5 years
Degree of myelination on structural MRI (%)
5 years
- +3 more other outcomes
Study Arms (3)
BCH Cohort
Patients enrolled at BCH will travel to BCH every 2 years at a minimum for comprehensive evaluation taking place over a 48 hour period. Visits to BCH may occur within ± 2 months of the scheduled visit date. Electronic surveys will be sent out every 6 months.Visits will consist of clinical assessments (demographics, medical history, physical examination, neurological exam, medication history, neuropsychological assessments, and clinical severity score), neurophysiological assessments (Brain Magnetic resonance imaging \[MRI/MRS/DTI\], Electroencephalogram \[EEG\], and Transcranial magnetic stimulation \[TMS\]), and yearly bio-specimen collection.
iNTD Cohort
Patients enrolled at iNTD sites will travel to their iNTD site according to standard of care requirements. Data collection includes clinical history and relevant laboratory-chemical, therapeutic, instrumental and neuropsychological parameters by the study centers. Data collection takes place within the framework of elective outpatient visits. The collected parameters are congruent with the current standard investigations. Electronic surveys will be sent out every 6 months. Imaging and neurophysiological data will be collected if performed during the clinical visit or if performed as part of the site's ongoing research. Yearly bio-specimen collection will be attempted after consent is obtained from the family.
Standard of Care Cohort
Patients enrolled at other sites will attend their visit at their regular clinical site as mandated by standard of care. Data collection includes medical history, family history, medications, and all clinical and neuropsychological assessments listed. Imaging and neurophysiological data will be collected if performed during the clinical visit or if performed as part of the clinical site's ongoing research. Yearly bio-specimen collection will be attempted.
Interventions
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.
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.
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.
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.
Eligibility Criteria
Children and adults diagnosed with Succinic Semialdehyde Dehydrogenase (SSADH) deficiency.
You may qualify if:
- hydroxybutyric aciduria (γ-hydroxybutyric aciduria)
- documented pathogenic ALDH5A1 (aldehyde dehydrogenase 5A1 gene) mutation
- years
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Boston Children's Hospitallead
- Washington State Universitycollaborator
- University of South Floridacollaborator
- University Hospital Heidelbergcollaborator
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)collaborator
Study Sites (4)
Boston Children's Hospital
Boston, Massachusetts, 02115, United States
University Children's Hospital
Heidelberg, Heidelberg, Germany
Sant Joan de Deu Hospital Barcelona
Barcelona, Spain
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, United Kingdom
Related Publications (2)
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: 40741980DERIVEDTokatly 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: 10.1186/s11689-024-09538-9.
PMID: 38658850DERIVED
Biospecimen
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.
MeSH Terms
Conditions
Interventions
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY CHAIR
Phillip L Pearl, MD
Boston Children's Hospital/Harvard Medical School
- STUDY CHAIR
K. Michael Gibson, PhD
Washington State University
Central Study Contacts
Study Design
- Study Type
- observational
- Observational Model
- COHORT
- Time Perspective
- PROSPECTIVE
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Director of Epilepsy and Clinical Neurophysiology, William G. Lennox Chair, Boston Children's Hospital
Study Record Dates
First Submitted
November 16, 2018
First Posted
November 29, 2018
Study Start
January 15, 2019
Primary Completion (Estimated)
May 31, 2029
Study Completion (Estimated)
June 1, 2029
Last Updated
January 13, 2026
Record last verified: 2026-01