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

Award Number: R01HD091142
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $649,604 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	002	7	8/25/2025	NON-COMPETING CONTINUATION	$649,604
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	6	3/20/2025	COMPETING CONTINUATION	$14,391
2025	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	5	3/20/2025	NON-COMPETING CONTINUATION	-$14,391
														Subtotal = $649,604

Issue Date FY: 2024 ( Subtotal = $738,814 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	002	6	9/24/2024	COMPETING CONTINUATION	$0
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	6	9/19/2024	COMPETING CONTINUATION	$124,998
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	6	9/20/2024	COMPETING CONTINUATION	$613,816
														Subtotal = $738,814

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	5	12/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $602,492 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	001	5	5/26/2022	NON-COMPETING CONTINUATION	$602,492
2022	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	4	5/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $602,492

Issue Date FY: 2021 ( Subtotal = $611,058 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	4	6/24/2021	NON-COMPETING CONTINUATION	$611,058
														Subtotal = $611,058

Issue Date FY: 2020 ( Subtotal = $633,886 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	3	6/23/2020	NON-COMPETING CONTINUATION	$633,886
														Subtotal = $633,886

Issue Date FY: 2019 ( Subtotal = $640,535 )
2019	2019	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	2	8/5/2019	NON-COMPETING CONTINUATION	$640,535
														Subtotal = $640,535

Issue Date FY: 2018 ( Subtotal = $686,980 )
2018	2018	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	1	7/23/2018	NEW	$686,980
														Subtotal = $686,980

Grand Total All Awards = $4,563,369

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

Award Number: R01HD091142

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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