Work

Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency

Year: 2026

Type: article

Abstract: ABSTRACT Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1 , encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the γ‐aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including γ‐hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10‐month‐old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left‐sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right > left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography–mass spectrometry revealed markedly elevated 4‐hydroxybutyric acid and 4,5‐dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous ALDH5A1 variants: c.278G>T p.(Cys93Phe) and c.612G>A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9 years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.

Source: JIMD Reports

DOI: 10.1002/jmd2.70071