title: SSADH deficiency possibly associated with enzyme activity-reducing SNPs.
abstract: BACKGROUND
  Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific.
  
  
  METHODS
  The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range).
  
  
  CONCLUSIONS
  Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.
authors.affiliation: Department of Child Neurology, Okayama University Hospital, Japan. Electronic address: takiyama@okayama-u.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Department of Pediatrics, Jichi Medical University, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Division of Neurology, Kanagawa Children's Medical Center, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimbo
authors.affiliation: Japan Clinical Metabolomics Institute, Japan.
authors.forename: Tomiko
authors.initials: T
authors.lastname: Kuhara
authors.affiliation: Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Division of Genetics, Kanagawa Children's Medical Center, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Yoshinaga
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D060005:Genotyping Techniques; D006801:Humans; D007564:Japan; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics
chemical_list: C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase
keywords: ALDH5A1 gene; Gamma-aminobutyric acid; Gamma-hydroxybutyric acid; Metabolome analysis