# Natural History of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a Heritable Disorder of GABA Metabolism

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2021 · $611,058

## Abstract

SUMMARY – Extensive basic research in the last 15 years has significantly extended our understanding of the
pathophysiology and potential treatment strategies for succinic semialdehyde dehydrogenase deficiency
(SSADHD), a rare heritable disorder of GABA metabolism. Yet, significant knowledge gaps remain as barriers
to early detection and prognosis of the disease, and to the assessment of the efficacy of novel therapeutics.
These gaps include a comprehensive description of the natural disease course, an understanding of the
prognostic value of neurophysiological and biochemical markers of the disease and a validated GABA assay
suitable for high-throughput NBS platforms. Thus, we propose a natural history study of SSADHD with the
following 3 aims: 1) to determine the natural course of the clinical presentation of SSADHD with comprehensive
yearly assessments. We hypothesize that disease presentation will worsen with age and propose to use a novel
semi-quantitative clinical severity score to quantify the most prominent clinical features of the disease; 2) to
determine the natural evolution of neurophysiological and biochemical indices known to be abnormal in
SSADHD, including: cerebral volume, brain GABA concentration (MRS), brain myelination (DTI), indices of
cortical GABAergic function measured with EEG and transcranial magnetic stimulation (TMS), and blood and
urine levels of GABA and GABA-related metabolic derivatives such as GHB and others. Embedded in this aim
is the validation of a dried bloodspot assay for GABA suitable for NBS; 3) to identify neurophysiological and
biochemical predictors of clinical severity, framed by the hypothesis that higher plasma and brain GABA
concentrations at first visit predict more severe clinical outcomes in later years. The study will follow 30 patients
with yearly assessments: 20 patients enrolled at Boston Children's Hospital, and 10 patients enrolled at foreign
academic sites participating in the International Working Group of Neurotransmitter Related Diseases (iNTD). In
addition, we will collected standard-of-care data from approximately 25 patients followed by an international
network of rare disease specialists also related to iNTD. Cumulatively, we will obtain longitudinal data from up
to 55 patients over the course of 5 years (~25% of reported cases). Biospecimens will be analyzed by the WSU
laboratory and banked for future testing (biorepository). Brain imaging scans, EEG and TMS recordings will be
analyzed by the BCH Imaging Core. Data will be managed by the RDCRN Data Management & Coordinating
Center at University of South Florida. The DMCC will also provide biostatistics support. On-line data entry forms
will be developed to facilitate standardized world-wide entry of relevant disease information, thus creating a truly
international SSADHD registry that will outlive the funding years of the study. The project is enthusiastically
supported by several patient advocacy groups representing over 125 patie...

## Key facts

- **NIH application ID:** 10200868
- **Project number:** 5R01HD091142-04
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** K Michael GIBSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $611,058
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200868

## Citation

> US National Institutes of Health, RePORTER application 10200868, Natural History of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a Heritable Disorder of GABA Metabolism (5R01HD091142-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200868. Licensed CC0.

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