Murine succinate semialdehyde dehydrogenase deficiency.
Inherited succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is one of the few neurogenetic disorders of GABA metabolism, and one in which tonic-clonic seizures associate with increased central nervous system GABA and gamma-hydroxybutyrate (GHB). To explore pathomechanisms and develop new preclinical treatment approaches, we developed a murine knockout model of SSADH deficiency. In the absence of intervention, SSADH(-/-) mice suffer 100% mortality at week 3 to 4 of life from generalized tonic-clonic seizures. In this report, we summarize earlier studies indicating disruption of the GABA/glutamine axis in SSADH(-/-) mouse brain, effective pharmacotherapeutic approaches, preliminary gene-therapy results, and electrophysiological analyses of mutant mice. We also present new evidence for oxidative stress in SSADH(-/-) mice, significant alterations of dopamine metabolism, and abnormal neurosteroid levels in brain, potentially implicating the GABA(A) receptor in pathogenesis. In SSADH deficiency, the accumulation of two neuroactive species, GABA and GHB, is significant because GABA is one of the earliest transmitters expressed in mammals, with key roles in synaptogenesis and myelination, whereas GHB displays a vast array of pharmacological actions. The SSADH(-/-) mouse may represent a useful model in which to explore the effect of GABA and GHB accumulation on central nervous system development and function.
Gupta
Maneesh
M
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97201, USA.
Hogema
Boris M
BM
Grompe
Markus
M
Bottiglieri
Teodoro G
TG
Concas
Alessandra
A
Biggio
Giovanni
G
Sogliano
Cristiana
C
Rigamonti
Antonello E
AE
Pearl
Phillip L
PL
Snead
O Carter
OC
Jakobs
Cornelis
C
Gibson
K Michael
KM
D000445:Aldehyde Oxidoreductases / Q000172:deficiency* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D051379:Mice; D050644:Succinate-Semialdehyde Dehydrogenase
D000445:Aldehyde Oxidoreductases; D050644:Succinate-Semialdehyde Dehydrogenase