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

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $738,814

## Abstract

SUMMARY – Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disease caused by
impaired γ-aminobutyric acid (GABA) neurotransmission. Since SSADHD was first identified in 1983, research
has focused on identifying the spectrum of pathogenic ALDH5A1 mutations, understanding the molecular and
biochemical bases of disease presentation, and testing promising therapeutics. To date, however, there remain
significant knowledge gaps that are barriers to early detection and prognosis of the disease, and to the
assessment of the efficacy of novel promising therapeutics. These gaps include a comprehensive description of
the natural course of the clinical severity of the disease, an in-depth assessment of the neurophysiology of the
disease, and the prognostic value of biochemical markers. We began to address these knowledge gaps four
years ago with our currently funded natural history study (NHS) of SSADHD and have already demonstrated
significant correlations between age of the patients, severity of the disease, blood biomarkers, and
neurophysiological parameters. However, the 4-5 year span of the current study and varying age and clinical
severity of the study participants has mostly afforded a cross-sectional perspective on disease progression and
the prognostic value of biomarkers. In order to gain the longitudinal insight needed to assess the predictive power
of disease markers at study intake on prognosis, a longer follow-up of the participants is needed. The purpose
of this application is to extend this natural history study for five years. We propose the following aims: 1) to
determine patient-specific changes over time in the clinical severity of SSADHD, 2) to determine patient-specific
changes over time in neurophysiological markers known to be dependent on GABA homeostasis, and 3) to
determine patient-specific changes over time in biochemical markers known to be abnormal in SSADHD. To
accomplish these aims, the study will follow ~70 patients representing ~30% of all known cases worldwide. The
project will be led by research teams at three academic institutions and is supported by patient advocacy groups
and families from all over the world. The research will provide the clinical and biochemical information needed
to predict the natural course of the disease, monitor the success of future therapeutic trials, and provide a strong
rationale for adding SSADHD screening to existing NBS panels.

## Key facts

- **NIH application ID:** 10804091
- **Project number:** 2R01HD091142-06A1
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Phillip Lawrence Pearl
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $738,814
- **Award type:** 2
- **Project period:** 2018-08-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804091

## Citation

> US National Institutes of Health, RePORTER application 10804091, Natural History of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD), a Heritable Disorder of GABA Metabolism (2R01HD091142-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10804091. Licensed CC0.

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