Succinic semialdehyde dehydrogenase deficiency in children and adults.
Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.
Pearl
Phillip L
PL
Department of Neurology, Children's National Medical Center, The George Washington University School of Medicine, Washington, DC 20010-2970, USA. ppearl@cnmc.org
Novotny
Edward J
EJ
Acosta
Maria T
MT
Jakobs
Cornelis
C
Gibson
K Michael
KM
D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000172:deficiency*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D002648:Child; D004569:Electroencephalography; D006801:Humans; D008279:Magnetic Resonance Imaging; D050644:Succinate-Semialdehyde Dehydrogenase
D000445:Aldehyde Oxidoreductases; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase