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Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients - PubMed

Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients

Ina Knerr et al. CNS Spectr. 2008 Jul.

Abstract

Introduction: Succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disorder of gamma-aminobutyric acid degradation. While neurological manifestations, such as developmental delay, are typical during infancy, limited data are available on adolescent and adult symptomatology.

Methods: We overview the phenotype of 33 adolescents and adults (10.1-39.5 years of age, mean: 17.1 years, 48% females) with SSADH deficiency. For this purpose, we applied a database with systematic questionnaire-based follow-up data.

Results: Sixty-six percent of patients (n=21) presented by 6 months of age, 14% from 6-12 months of age, 5% from 1-2 years of age, and 14% from 2-4 years of age, mean age at first symptoms was 11+/-12 months. However, mean age at diagnosis was 6.6+/-6.4 years of age. Presenting symptoms encompassed motor delay, hypotonia, speech delay, autistic features, seizures, and ataxia. Eighty-two percent demonstrated behavioral problems, such as attention deficit, hyperactivity, anxiety, or aggression, and 33% had >or=3 behavior problems. Electroencephalograms showed background slowing or epileptiform discharges in 40% of patients. Treatment approaches are then summarized.

Conclusion: The variable phenotype in SSADH deficiency suggests the likelihood that this disease may be under-diagnosed. Families of patients with SSADH deficiency should be counseled and supported regarding the anticipated persistence of various neuropsychiatric symptoms into adulthood.

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Figures

**FIGURE. GABA metabolic interrelationships and conversion to succinate in the mitochondria**
The site of the defect in patients with SSADH deficiency (and Aldh5a1^−/− mice) is depicted by the hatched box. GABA is synthesized primarily from glutamate via glutamic acid decarboxylase, an irreversible reaction that releases CO₂. GABA is transaminated to SSA by the action of GABA-transaminase. The NH₄+ of GABA condenses with α-KG from the Krebs cycle to generate glutamate for each GABA molecule consumed (the “GABA shunt”). In the central nervous system, this ensures balance between production of inhibitory and excitatory neurotransmitters. SSA that accumulates is most likely the metabolic precursor of GHB, produced by AKR7a5. Another key glutamate precursor is glutamine (synthesized in glial cells via glutamine synthase). In neurons, glutamine is converted to glutamate by the action of glutaminase. GABA=TK; CO₂=carbon dioxide; α-KG=α-ketoglutarate; NH₄+=nitrogen; SSA=succinic semialdehyde; GHB=γ-hydroxybutyrate; SSADH=succinic semialdehyde dehydrogenase; AKR7a5=aldo-keto reductase 7a5.

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Neuropsychiatric morbidity in adolescent and adult succinic semialdehyde dehydrogenase deficiency patients - PubMed