ALDH5A1 – Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1, encoding mitochondrial SSADH. Clinically, SSADH deficiency presents in infancy or childhood with global developmental delay, hypotonia, and epilepsy characterized by generalized and tonic-clonic seizures, often accompanied by ataxia and behavioral disturbances (Pediatrics • 1997 • The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. [PMID:9093300]).

Extensive genetic studies have identified over 44 unique ALDH5A1 mutations across more than 180 patients from 54 families worldwide. These include missense, nonsense, frameshift, splice-site, and small indel variants. A recurrent pathogenic allele, c.1226G>A (p.Gly409Asp), has been observed in multiple unrelated cohorts and co-segregates with disease in sibships (Human mutation • 2003 • Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. [PMID:14635103]).

Functional assays demonstrate that most missense variants abolish or severely reduce SSADH enzymatic activity, leading to accumulation of GABA and γ-hydroxybutyrate (GHB). Electrophysiological studies in Aldh5a1–/– mice reveal desensitization of postsynaptic GABA(B) receptors and decreased GIRK channel currents, correlating with seizure susceptibility (Experimental neurology • 2010 • Plasticity of postsynaptic, but not presynaptic, GABAB receptors in SSADH deficient mice. [PMID:20570675]). Mitochondrial and redox dysregulation, astrocyte dysfunction, and myelin lipid depletion further contribute to neuropathology (Glia • 2024 • Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function. [PMID:38899762]).

Therapeutically, the ketogenic diet prolongs lifespan and normalizes EEG and motor deficits in SSADH-deficient mice by restoring GABAergic inhibition and mitochondrial bioenergetics (Experimental neurology • 2008 • A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. [PMID:18199435]). Clinical use of vigabatrin shows variable efficacy in reducing GHB levels and improving neurodevelopmental outcomes.

No studies have refuted the loss-of-function mechanism or the AR inheritance model. Taken together, genetic, biochemical, and animal model data establish a definitive gene–disease relationship. Key take-home: ALDH5A1 testing should be included in the genetic evaluation of infants and children with unexplained developmental delay, hypotonia, and epilepsy, and functional assays of novel missense variants can guide diagnostic interpretation.

References

• Pediatrics • 1997 • The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients. PMID:9093300
• Human mutation • 2003 • Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. PMID:14635103
• Experimental neurology • 2010 • Plasticity of postsynaptic, but not presynaptic, GABAB receptors in SSADH deficient mice. PMID:20570675
• Glia • 2024 • Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function. PMID:38899762

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