Succinic semialdehyde dehydrogenase deficiency

Phillip L Pearl MD (

Dr. Pearl of Boston Children's Hospital and Harvard Medical School received research funding from PTC Therapeutics.

Melissa DiBacco MD (

Dr. DiBacco of Boston Children’s Hospital has no relevant financial relationships to disclose.

Jasmine Gite BS (Ms. Gite of Oakland University William Beaumont School of Medicine has no relevant financial relationships to disclose.)
Madalyn N Brown (

Ms. Brown of Washington State University College of Pharmacy has no relevant financial relationships to disclose.

Jean-Baptiste Roullet PhD (

Dr. Roullet of Washington State University College of Pharmacy has no relevant financial relationships to disclose.

K Michael Gibson PhD (Dr. Gibson of Washington State University College of Pharmacy has no relevant financial relationships to disclose.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released November 28, 1994; last updated May 23, 2020; expires May 23, 2023


Succinic semialdehyde dehydrogenase 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. 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. In this article, the authors review the current literature on this topic.

Key points


• Succinic semialdehyde dehydrogenase deficiency is an autosomal recessive disorder caused by pathological variants in the ALDH5A1 gene; over 60 pathological variants have been identified.


• The clinical presentation is typically an infantile-onset nonprogressive encephalopathy with early hypotonia and developmental delay, and later profound expressive language impairment, intellectual deficiency, hypotonia, epilepsy, and psychiatric morbidity especially manifest by anxiety and obsessive-compulsive symptoms; choreoathetosis, exertional dyskinesias, and ataxia may be present.


• MR imaging shows T2-weighted hyperintensities in the globus pallidus, subthalamic nucleus, and cerebellar dentate nuclei, and spectroscopy shows elevated GABA as measured in voxels of basal ganglia and cerebral cortex.


• The major diagnostic criterion is persistently elevated GHB in physiologic fluids and is usually detected on urine organic acids and confirmed via gene sequencing.


• A focus on natural history studies has revealed a significant negative age correlation with GHB and GABA, as well as worsening of psychiatric symptoms and epilepsy during adolescence and adulthood.


• Therapy remains symptomatic, although clinical trials are in progress for more targeted treatments; vigabatrin will lower GHB levels but raise GABA further, and it has not shown a consistent benefit.

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., 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. 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.

Biochemical interrelationships in SSADH deficiency Image: Biochemical interrelationships in SSADH 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 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).

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).

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