This article includes discussion of succinic semialdehyde dehydrogenase deficiency, 4-Hydroxybutyric acidemia, 4-Hydroxybutyric aciduria, 4-Hydroxybutyricaciduria, gamma-hydroxybutyric acidemia, and gamma-hydroxybutyric aciduria. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively inherited disorder that interferes with the catabolism of the brain's major inhibitory neurotransmitter, gamma-amino butyric acid (GABA). The absence of succinic semialdehyde dehydrogenase results in the accumulation of GABA and its neurotoxic metabolite, gamma hydroxybutyric acid (GHB) (Parviz et al 2014). Succinic semialdehyde dehydrogenase deficiency is caused by homozygous or compound heterozygous mutations in the ALDH5A1 gene. The clinical presentation is nonspecific, with clinical hallmarks including a nonprogressive course, ataxia, hypotonia, developmental delay, intellectual disability, behavioral dysregulation, hyporeflexia, and epilepsy (Pearl et al 2015). In this article, the authors review the current literature on this topic.
Historical note and terminology
In 1981, the index patient was described with 4-hydroxybutyric aciduria, a previously unrecognized organic aciduria (Jakobs et al 1981). Although definitive enzyme studies were lacking, these investigators hypothesized that 4-hydroxybutyric aciduria resulted from an inherited deficiency of succinic semialdehyde dehydrogenase, or SSADH (E.C. 220.127.116.11), an enzyme involved in the metabolism of the inhibitory neurotransmitter GABA. GABA is metabolized to succinic acid by the sequential action of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid). Jakobs and colleagues suggested that in response to an inherited deficiency of succinic semialdehyde dehydrogenase, accumulated succinic semialdehyde would undergo reduction to 4-hydroxybutyric acid in a reaction catalyzed by 1 or more 4-hydroxybutyrate dehydrogenases (E.C. 18.104.22.168). At that time it was believed that eventual diagnosis of putative succinic semialdehyde dehydrogenase deficiency would be dependent on the availability of autopsied brain tissue. It is now understood that in the absence of succinic semialdehyde dehydrogenase, transamination of GABA to succinic semialdehyde is followed by its reduction to 4-hydroxybutyrate (gamma hydroxybutyrate, GHB), a short monocarboxylic fatty acid that accumulates in the urine, serum, and CSF of patients with succinic semialdehyde dehydrogenase deficiency.GHB, whose role is unclear, is an agonist towards both GHB and GABAB receptors (Ainslie 2015) and has been considered to be a potential neurotoxic agent that contributes to the clinical manifestations of succinic semialdehyde dehydrogenase deficiency (Pearl et al 2003a).
The identification of succinic semialdehyde dehydrogenase activity in peripheral leukocytes and Epstein-Barr virus-transformed lymphoblasts allowed Gibson and colleagues to document succinic semialdehyde dehydrogenase deficiency in patients with 4-hydroxybutyric aciduria (Gibson et al 1983). Sensitive fluorometric and isotope dilution mass spectrometric methods have since then been developed to improve diagnostic accuracy in identifying succinic semialdehyde dehydrogenase deficiency (Gibson et al 1990b; Gibson et al 1991).
The Jakobs Laboratory has developed a stable-isotope dilution liquid chromatography-tandem mass spectrometry method for the determination of succinic semialdehyde, an unstable metabolite, in urine and cerebrospinal fluid samples (Struys et al 2005).
Since the description of the index patient, the authors are aware of approximately 450 patients worldwide with succinic semialdehyde dehydrogenase deficiency (Pearl et al 2011). Subsequently identified patients were published as case reports or small series (De Vivo et al 1988; Pattarelli et al 1988; Gibson et al 1989; Gibson et al 1997; Gibson et al 1998; Onkenhout et al 1989; Jakobs et al 1990; Jakobs et al 1993; Shih et al 1990; Scriver and Gibson 1995; Ishiguro et al 2001; Pearl et al 2003; Jung et al 2006; Knerr et al 2007a; Crutchfield et al 2008; Knerr et al 2010; Puttmann et al 2012; Yamakawa et al 2012). Consanguinity in many families and gene dosage effect in the parents verified that succinic semialdehyde dehydrogenase deficiency is inherited in an autosomal recessive fashion. Molecular studies have enabled the elucidation of the complete succinic semialdehyde dehydrogenase amino acid sequence and its localization to chromosome 6p22 (Trettel et al 1997). The genomic structure of the succinic semialdehyde dehydrogenase gene has been identified, the promoter region sequenced, and the first inherited mutations responsible for succinic semialdehyde dehydrogenase deficiency were identified by Chambliss and colleagues in 1998 (Chambliss et al 1998).
The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.
If you are a subscriber, please log in.
If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.