Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

P. Malaspina, Jean-Baptiste Roullet, P. L. Pearl, G. R. Ainslie, K. R. Vogel, K. M. Gibson

Research output: Contribution to journalReview article

17 Citations (Scopus)

Abstract

Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

Original languageEnglish (US)
Pages (from-to)72-84
Number of pages13
JournalNeurochemistry International
Volume99
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Fingerprint

gamma-Aminobutyric Acid
Mitochondrial Degradation
GABA Agents
Hydroxybutyrates
Genes
Aldehyde Dehydrogenase
Autophagy
Research
Synaptic Transmission
Single Nucleotide Polymorphism
Neurotransmitter Agents
Epilepsy
Oxidative Stress
succinic semialdehyde dehydrogenase deficiency
Phenotype
Gene Expression

Keywords

  • Autophagy
  • Crystal structure
  • GABA (4-aminobutyric acid)
  • GABAergic neurotransmission
  • Genome wide association study
  • GHB (4-hydroxybutyric acid)
  • GWAS
  • Knockout mouse model
  • Mitophagy
  • Multifactorial traits
  • Neurological disease
  • Oxidative damage
  • Pathogenic mutations
  • Pathophysiology
  • Pathophysiology
  • Polymorphisms
  • SNP (single nucleotide polymorphism)
  • Succinic semialdehyde dehydrogenase deficiency (SSADHD)

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

Cite this

Succinic semialdehyde dehydrogenase deficiency (SSADHD) : Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. / Malaspina, P.; Roullet, Jean-Baptiste; Pearl, P. L.; Ainslie, G. R.; Vogel, K. R.; Gibson, K. M.

In: Neurochemistry International, Vol. 99, 01.10.2016, p. 72-84.

Research output: Contribution to journalReview article

Malaspina, P. ; Roullet, Jean-Baptiste ; Pearl, P. L. ; Ainslie, G. R. ; Vogel, K. R. ; Gibson, K. M. / Succinic semialdehyde dehydrogenase deficiency (SSADHD) : Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. In: Neurochemistry International. 2016 ; Vol. 99. pp. 72-84.
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AU - Roullet, Jean-Baptiste

AU - Pearl, P. L.

AU - Ainslie, G. R.

AU - Vogel, K. R.

AU - Gibson, K. M.

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N2 - Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

AB - Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.

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