PARADOXICAL CONVULSIVE SEIZURES IN SSADH DEFICIENCY, A HYPER-GABA[apos]ERGIC SYNDROME
Abstract number :
1.397
Submission category :
Year :
2003
Submission ID :
3692
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Phillip L. Pearl, K. Michael Gibson, Maria T. Acosta, Michael A. Rogawski, Edward J. Novotny, William D. Gaillard, Steven L. Weinstein, Joan A. Conry, Gerard Gioia, Laura Kenealy, Madison Berle, Sandra Cushner-Weinstein, Marian J. Kelodgnie, Nancy J. Elli
Convulsive seizures paradoxically occur in nearly half of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency, a syndrome with elevated gamma-aminobutyric acid (GABA) and gamma-hydroxybutyrate (GHB). This is contrary to the induction of absence seizures in animal models by GABA and GHB. Alterations of other neurotransmitter systems may underlie this observation.
We present systematic clinical and EEG findings in our new cohort of 14 SSADH patients and review another 51 reported in the literature. CSF studies on 13 patients were obtained for selected neurotransmitters, amino acids, and biogenic amines.
Over 75% of patients have developmental delay (language[gt]motor), hypotonia, and mental retardation. Slightly [lt]50% have nonprogressive ataxia, behavior problems, hyporeflexia, and seizures (GTCS, absence, partial, status). EEGs have been abnormal in18 of 34 (53%) patients, with epileptiform discharges in 9/34 (26%). CSF measurements show increased GABA (up to 3 fold), GHB (65-230 fold), and homocarnosine, decreased glutamine, and a correlation between GHB and both HVA and 5-HIAA.
Human CSF measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in GABA, GHB, and homocarnosine, and low glutamine. We previously demonstrated elevated brain parenchymal GABA by MR spectroscopy. The explanation for convulsive seizures in this hyper-GABA-ergic syndrome is unknown. Decreased glutamine, coupled with elevated GABA, suggests disruption of the [ldquo]glutamine-glutamate[rdquo] astrocyte-neuronal shuttle, leading to uncoupling of the GABA-glutamate axis. As GHB acts by inhibition of presynaptic dopamine release, correlations between increased GHB with HVA and 5-HIAA suggest increased turnover of dopamine and serotonin. As the murine model has shown elevated glutamate in regional measurements of hippocampus, a constellation of evidence suggests a glutamatergic mechanism for convulsive seizures in his hyper-GABA[rsquo]ergic syndrome. Therapies targeting antiglutamatergic strategies may be effective in this disorder.
[Supported by: In part by NIH NS-40270 and National March of Dimes Birth Defects Foundation Grant #1-FY00-352 (KMG).]