2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Screening for disorders of GABA metabolism: Integration of sequencing and metabolomic screening supports early diagnosis and expands access to care

Pdf Summary

This article discusses the integration of sequencing and metabolomic screening to support early diagnosis and expand access to care for disorders of GABA metabolism. GABA is a neurotransmitter and metabolic intermediate in the brain that plays a role in inhibitory neuronal activity. Defects in the enzymes involved in GABA metabolism, GABA-transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH), can lead to rare neurologic disorders.<br /><br />Currently, diagnosing these disorders is challenging due to the lack of accessible biomarkers and limited genomic variant curation. The exact prevalence of these disorders is also unknown, making efforts to incorporate them into newborn screening panels and develop treatments difficult.<br /><br />The integrated approach used in this study involved molecular and biochemical testing, as well as the analysis of clinical data. Molecular testing identified significant variants, while biochemical testing revealed specific biomarkers in plasma that distinguish patients with GABA-T deficiency and SSADH deficiency from a control reference population.<br /><br />The analysis of patient data suggested that deleterious variants in the genes ABAT and ALDH5A1 may be more common than previously recognized, indicating that these disorders may be more prevalent than believed. The authors estimate that the actual disease incidence in the United States may be as high as approximately 1 in 1000 individuals.<br /><br />Metabolomic screening proved to be a reliable method for assaying GABA metabolites in non-invasive samples and providing specific biomarkers for screening. The increased usage of metabolomic screening and a broader approach to gene variant curation can help to better understand the clinical spectrum of these disorders.<br /><br />Early diagnosis through the integrated analysis of molecular, biochemical, and clinical data is essential in connecting affected individuals and their families to appropriate services and support groups. It can also facilitate the development of more effective targeted therapies for these disorders.<br /><br />Overall, the integration of these various approaches improves the efficiency of diagnosing disorders of GABA metabolism, reduces the burden on families, and allows for earlier access to care and support.

Asset Subtitle

Presenting Author - Kevin E. Glinton, MD, PHD; Co-Author - Charul Gijavanekar, PhD; Co-Author - Kirt A. Martin, PhD; Co-Author - Theresa A. Wilson, MS, RD; Co-Author - Vernon R. Sutton, MD; Co-Author - Sarah H. Elsea, PhD, FACMG;

Meta Tag

Biochemical genetics

Cognitive Disorders

Genome sequencing

Metabolic Disorder

NextGen Sequencing

Population Genetics

Sequencing

Co-Author Charul Gijavanekar, PhD

Co-Author Kirt A. Martin, PhD

Co-Author Theresa A. Wilson, MS, RD

Co-Author Vernon R. Sutton, MD

Co-Author Sarah H. Elsea, PhD, FACMG

Presenting Author Kevin E. Glinton, MD, PHD

Keywords

sequencing

metabolomic screening

early diagnosis

access to care

disorders of GABA metabolism

GABA neurotransmitter

inhibitory neuronal activity

GABA-T deficiency

SSADH deficiency

newborn screening panels