Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.
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PMID:Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency. 1289 56

The succinic semialdehyde dehydrogenase (SSADH) null mouse (SSADH(-/-)) represents a viable animal model for human SSADH deficiency and is characterized by markedly elevated levels of both gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acid (GABA) in brain, blood, and urine. In physiological concentrations, GHB acts at the GHB receptor (GHBR), but in high concentrations such as those observed in the brains of children with SSADH deficiency, GHB is thought to be a direct agonist at the GABABR receptor (GABABR). We tested the hypothesis that both GHBR and GABABR-mediated function are perturbed in SSADH deficiency. Therefore, we examined the high affinity binding site for GHB as well as the expression and function of the GABABR in mutant mice made deficient in SSADH (SSADH(-/-)). There was a significant decrease in binding of the specific GABABR antagonist, [3H]CGP-54626A at postnatal day (PN)7 and PN14 in SSADH(-/-) when compared to wild type control animals (SSADH(+/+)), particularly in hippocampus. GABABR-mediated synaptic potentials were decreased in SSADH(-/-). Immunoblot analysis of GABABR1a, R1b, and R2 in SSADH(-/-) indicated a trend towards a region-specific and time-dependent decrease of GABABR subunit protein expression. There was no difference between SSADH(-/-) and wild type in binding of either [3H]GHB or a specific GHBR antagonist to the GHBR. These data suggest that the elevated levels of GABA and GHB that occur in SSADH(-/-) lead to a use-dependent decrease in GABABR-mediated function and raise the possibility that this GHB- and GABA-induced perturbation of GABABR could play a role in the pathogenesis of the seizures and mental retardation observed in SSADH deficiency.
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PMID:Succinic semialdehyde dehydrogenase deficiency: GABAB receptor-mediated function. 1664 90