Journal of Inherited Metabolic Disease

, Volume 30, Issue 3, pp 279–294

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

  • I. Knerr
  • P. L. Pearl
  • T. Bottiglieri
  • O. Carter Snead
  • C. Jakobs
  • K. M. Gibson
Review

DOI: 10.1007/s10545-007-0574-2

Cite this article as:
Knerr, I., Pearl, P.L., Bottiglieri, T. et al. J Inherit Metab Dis (2007) 30: 279. doi:10.1007/s10545-007-0574-2

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.

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

Copyright information

© SSIEM and Springer 2007

Authors and Affiliations

  • I. Knerr
    • 1
    • 7
  • P. L. Pearl
    • 2
    • 3
  • T. Bottiglieri
    • 4
  • O. Carter Snead
    • 5
  • C. Jakobs
    • 6
  • K. M. Gibson
    • 7
    • 8
  1. 1.Children’s and Adolescents’ HospitalUniversity of Erlangen-NurembergErlangenGermany
  2. 2.Department of Neurology, Children’s National Medical CenterGeorge Washington University School of MedicineWashingtonUSA
  3. 3.Clinical Epilepsy Branch, NINDS, NIHBethesdaUSA
  4. 4.Baylor University Medical Center, Institute of Metabolic DiseaseDallasUSA
  5. 5.Division of NeurologyThe Hospital for Sick ChildrenTorontoCanada
  6. 6.VU University Medical CenterAmsterdamThe Netherlands
  7. 7.Biochemical Genetics Laboratory, Children’s Hospital Pittsburgh, Departments of Pediatrics, Pathology and Human Genetics, Division of Medical GeneticsUniversity of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Division of Medical Genetics, Rangos Research Building Room 2111Children’s Hospital of PittsburghPittsburghUSA

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