Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase

Boris M. Hogema, Maneesh Gupta, Henry Senephansiri, Terry G. Burlingame, Melissa Taylor, Cornelis Jakobs, Ruud B H Schutgens, Wolfgang Froestl, O. Carter Snead, Ramon Diaz-Arrastia, Teodoro Bottiglieri, Markus Grompe, K. Michael Gibson

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Succinate semialdehyde dehydrogenase (ALDHSA1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-1- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-1- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed treatment of mutant mice with the amino acid taurine rescued Aldh5a1-1- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

Original languageEnglish (US)
Pages (from-to)212-216
Number of pages5
JournalNature Genetics
Volume29
Issue number2
DOIs
StatePublished - 2001

Fingerprint

Succinate-Semialdehyde Dehydrogenase
Seizures
gamma-Aminobutyric Acid
Vigabatrin
Ataxia
Tonic-Clonic Epilepsy
Language Development Disorders
Deficiency Diseases
Muscle Hypotonia
Gliosis
Taurine
Phenytoin
Human Milk
Phenobarbital
Weaning
Nervous System Diseases
Nervous System
Hippocampus
Therapeutics
Urine

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Hogema, B. M., Gupta, M., Senephansiri, H., Burlingame, T. G., Taylor, M., Jakobs, C., ... Gibson, K. M. (2001). Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nature Genetics, 29(2), 212-216. https://doi.org/10.1038/ng727

Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. / Hogema, Boris M.; Gupta, Maneesh; Senephansiri, Henry; Burlingame, Terry G.; Taylor, Melissa; Jakobs, Cornelis; Schutgens, Ruud B H; Froestl, Wolfgang; Snead, O. Carter; Diaz-Arrastia, Ramon; Bottiglieri, Teodoro; Grompe, Markus; Gibson, K. Michael.

In: Nature Genetics, Vol. 29, No. 2, 2001, p. 212-216.

Research output: Contribution to journalArticle

Hogema, BM, Gupta, M, Senephansiri, H, Burlingame, TG, Taylor, M, Jakobs, C, Schutgens, RBH, Froestl, W, Snead, OC, Diaz-Arrastia, R, Bottiglieri, T, Grompe, M & Gibson, KM 2001, 'Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase', Nature Genetics, vol. 29, no. 2, pp. 212-216. https://doi.org/10.1038/ng727
Hogema BM, Gupta M, Senephansiri H, Burlingame TG, Taylor M, Jakobs C et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nature Genetics. 2001;29(2):212-216. https://doi.org/10.1038/ng727
Hogema, Boris M. ; Gupta, Maneesh ; Senephansiri, Henry ; Burlingame, Terry G. ; Taylor, Melissa ; Jakobs, Cornelis ; Schutgens, Ruud B H ; Froestl, Wolfgang ; Snead, O. Carter ; Diaz-Arrastia, Ramon ; Bottiglieri, Teodoro ; Grompe, Markus ; Gibson, K. Michael. / Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. In: Nature Genetics. 2001 ; Vol. 29, No. 2. pp. 212-216.
@article{bc0980a2007547b5a6ca352c8cbb2f3d,
title = "Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase",
abstract = "Succinate semialdehyde dehydrogenase (ALDHSA1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-1- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-1- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed treatment of mutant mice with the amino acid taurine rescued Aldh5a1-1- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.",
author = "Hogema, {Boris M.} and Maneesh Gupta and Henry Senephansiri and Burlingame, {Terry G.} and Melissa Taylor and Cornelis Jakobs and Schutgens, {Ruud B H} and Wolfgang Froestl and Snead, {O. Carter} and Ramon Diaz-Arrastia and Teodoro Bottiglieri and Markus Grompe and Gibson, {K. Michael}",
year = "2001",
doi = "10.1038/ng727",
language = "English (US)",
volume = "29",
pages = "212--216",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase

AU - Hogema, Boris M.

AU - Gupta, Maneesh

AU - Senephansiri, Henry

AU - Burlingame, Terry G.

AU - Taylor, Melissa

AU - Jakobs, Cornelis

AU - Schutgens, Ruud B H

AU - Froestl, Wolfgang

AU - Snead, O. Carter

AU - Diaz-Arrastia, Ramon

AU - Bottiglieri, Teodoro

AU - Grompe, Markus

AU - Gibson, K. Michael

PY - 2001

Y1 - 2001

N2 - Succinate semialdehyde dehydrogenase (ALDHSA1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-1- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-1- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed treatment of mutant mice with the amino acid taurine rescued Aldh5a1-1- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

AB - Succinate semialdehyde dehydrogenase (ALDHSA1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-1- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-1- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed treatment of mutant mice with the amino acid taurine rescued Aldh5a1-1- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

UR - http://www.scopus.com/inward/record.url?scp=0034795729&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034795729&partnerID=8YFLogxK

U2 - 10.1038/ng727

DO - 10.1038/ng727

M3 - Article

C2 - 11544478

AN - SCOPUS:0034795729

VL - 29

SP - 212

EP - 216

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -