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  • Updated 02.18.2021
  • Released 11.28.1994
  • Expires For CME 02.18.2024

Succinic semialdehyde dehydrogenase deficiency

Introduction

Overview

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 (52). 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. 1.2.1.24), 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. 1.1.1.61). 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
The enzyme defect is marked by the hatched arrow. Abbreviations: GABA, gamma-aminobutyric acid; GHB, gamma-hydroxybutyric acid; TCA, tricarboxylic acid. (Contributed by Dr. Phillip Pearl.)

GHB, whose role is unclear, is an agonist towards both GHB and GABAB receptors (03) and has been considered to be a potential neurotoxic agent that contributes to the clinical manifestations of succinic semialdehyde dehydrogenase deficiency (79).

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 (36). Sensitive fluorometric and isotope dilution mass spectrometric methods have since then been developed to improve diagnostic accuracy in identifying succinic semialdehyde dehydrogenase deficiency (23; 33).

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 (103).

Molecular studies have enabled the elucidation of the complete succinic semialdehyde dehydrogenase amino acid sequence and its localization to chromosome 6p22 (106). 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 (15).

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