Clinical trial NCT03758521: Natural History Study of Patients with Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
Official title: Natural History Study of Patients with Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Succinic Semialdehyde Dehydrogenase Deficiency
Keywords: SSADHD
SSADH deficiency
Lead sponsor: Boston Children's Hospital
Sponsor class: OTHER
Collaborators: name: Washington State University
name: University of South Florida
name: University Hospital Heidelberg
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2018-11-29
Enrollment: 55
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children and adults diagnosed with Succinic Semialdehyde Dehydrogenase (SSADH) deficiency.

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Clinical Severity Score
timeFrame: 5 Years
measure: Biochemical - GABA measurement
timeFrame: 5 Years
measure: Biochemical - GHB measurement
timeFrame: 5 Years
measure: Quantification of GABA related signals on the MRI spectroscopy
timeFrame: 5 Years
Secondary outcomes:
Other outcomes:
measure: Quantification of EEG abnormalities (%)
timeFrame: 5 Years
measure: Extent of altered signal hyperintensities on structural MRI (%)
timeFrame: 5 years
measure: Degree of myelination on structural MRI (%)
timeFrame: 5 years
measure: Total cerebral volume on structural MRI (cm3)
timeFrame: 5 years
measure: Amplitudes of motor evoked potentials (mm)
timeFrame: 5 years
measure: Durations of cortical silent period (ms)
timeFrame: 5 years
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Heidelberg
country: Germany
facility: University Children's Hospital
city: Barcelona
country: Spain
facility: Sant Joan de Deu Hospital Barcelona
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital NHS Foundation Trust
Study officials:
affiliation: Boston Children's Hospital/Harvard Medical School
name: Phillip L Pearl, MD
role: STUDY_CHAIR
affiliation: Washington State University
name: K. Michael Gibson, PhD
role: STUDY_CHAIR
References: