Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
 ...
PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

Congenital ornithine transcarbamylase (OTC) deficiency in humans results in failure to thrive, hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals significant cerebral cortical atrophy, delayed myelination and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, studies reveal convincing evidence of a loss of forebrain cholinergic neurons in this condition. Evidence includes (i) reduced activities of the cholinergic nerve terminal enzyme choline acetyltransferase (ChAT), (ii) a 25% loss of ChAT immunostaining, (iii) reduced high affinity transport of [3H]choline by cortical synaptosomes and (iv) a selective reduction in densities of presynaptic muscarinic M2 binding sites, in spf mouse brain compared to controls. A partial correction of the cholinergic deficit was observed following treatment with acetyl-L-carnitine. Possible mechanisms responsible for cholinergic neuronal loss in congenital OTC deficiency include decreased synthesis of the ChAT substrate acetyl CoA, impaired cerebral energy metabolism and NMDA receptor-mediated excitotoxicity. Loss of forebrain cholinergic neurons is consistent with the severe cognitive impairment characteristic of congenital OTC deficiency.
 ...
PMID:Evidence for forebrain cholinergic neuronal loss in congenital ornithine transcarbamylase deficiency. 1088 42