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Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1 −/− mice and characterization of γ-hydroxybutyric acid pharmacology

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Summary

We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (γ-hydroxybutyric aciduria, OMIM 271980, 610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of γ-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH−/− (e.g. Aldh5a1 −/−) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1 −/− mice accumulate GHB and γ-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (Gln), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1 −/− mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease.

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Abbreviations

5-HIAA:

5-hydroxyindoleacetic acid

ALLO:

allopregnanolone; 3α-hydroxy-5α-tetrahydroprogesterone

AMPA:

α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid

BBB:

blood–brain barrier

BHB:

β-hydroxybutyrate

D-2-HG:

d-2-hydroxyglutarate

DHA:

docosahexaenoic acid

DHHA:

dihydroxyhexanoic acid

GABA:

γ-aminobutyric acid

GABA(B)R:

GABA(B) receptor

GABA-T:

GABA transaminase

GBL:

γ-butyrolactone

GHB:

γ-hydroxybutyric acid

GHBR:

GHB receptor

HMG-CoA:

3-hydroxy-3-methylglutaryl-CoA synthase

HOT:

hydroxyacid–oxoacid transhydrogenase

HVA:

homovanillic avid

MAO:

monoamine oxidase

MAP:

mitogen-activated protein

NMDA:

N-methyl-d-aspartate

PPAR:

peroxisome proliferator-activated receptor

SSA:

succinic semialdehyde

SSADH:

succinate semialdehyde dehydrogenase

T-HCA:

trans-4-hydroxycrotonic acid

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Authors and Affiliations

  1. Children’s and Adolescents’ Hospital, University of Erlangen-Nuremberg, Erlangen, Germany

    I. Knerr

  2. Department of Neurology, Children’s National Medical Center, George Washington University School of Medicine, Washington, DC, USA

    P. L. Pearl

  3. Clinical Epilepsy Branch, NINDS, NIH, Bethesda, Maryland, USA

    P. L. Pearl

  4. Baylor University Medical Center, Institute of Metabolic Disease, Dallas, Texas, USA

    T. Bottiglieri

  5. Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada

    O. Carter Snead

  6. VU University Medical Center, Amsterdam, The Netherlands

    C. Jakobs

  7. Biochemical Genetics Laboratory, Children’s Hospital Pittsburgh, Departments of Pediatrics, Pathology and Human Genetics, Division of Medical Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    I. Knerr & K. M. Gibson

  8. Division of Medical Genetics, Rangos Research Building Room 2111, Children’s Hospital of Pittsburgh, 3460 Fifth Avenue, Pittsburgh, PA, 15213, USA

    K. M. Gibson

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  1. I. Knerr
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  2. P. L. Pearl
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  3. T. Bottiglieri
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  4. O. Carter Snead
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  5. C. Jakobs
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  6. K. M. Gibson
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Correspondence to K. M. Gibson.

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Communicating editor: Jaak Jaeken

Competing interests: None declared

References to electronic databases: γ-Hydroxybutyric aciduria, OMIM 271980, 610045. Succinate-semialdehyde dehydrogenase, EC 1.2.1.24.

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Knerr, I., Pearl, P.L., Bottiglieri, T. et al. Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1 −/− mice and characterization of γ-hydroxybutyric acid pharmacology. J Inherit Metab Dis 30, 279–294 (2007). https://doi.org/10.1007/s10545-007-0574-2

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