Evidence for a Central Cholinergic Deficit in Congenital Ornithine Transcarbamylase Deficiency

Abstract

Congenital ornithine transcarbamylase (OTC) deficiency is the most common inborn error of urea cycle enzymes in humans. A large percentage of survivors of neonatal OTC deficiency suffer severe developmental disorders, including seizures, mental retardation and cerebral palsy. Neuropathological studies reveal ventricular enlargement, cerebral atrophy and delayed myelination, as well as Alzheimer type II astrocytosis. Using the sparse-fur (spf) mouse model of congenital OTC deficiency, studies of central cholinergic integrity revealed a developmental delay in choline acetyltransferase activity and of high-affinity [³H]-choline uptake in several brain structures. Subsequent studies of muscarinic cholinergic binding site distribution showed a widespread loss of M₁ sites, consistent with cholinergic cell loss. These alterations are similar to those reported in Alzheimer’s disease, suggesting that the severe cognitive dysfunction in congenital OTC deficiency may at least partly result from a muscarinic cholinergic lesion. Possible mechanisms involved in the pathogenesis of cholinergic cell loss in congenital OTC deficiency include ammonia-induced inhibition of pyruvate and α-oxoglutarate oxidation, resulting in decreased synthesis of acetyl CoA and a cerebral energy deficit, as well as NMDA receptor-mediated excitotoxicity. Treatment of spf mice with acetyl-L-carnitine (ALCAR) results in partial recovery of the developmental choline acetyltransferase deficit, suggesting a potential therapeutic benefit of ALCAR in congenital OTC deficiency. Other therapies currently used include ammonia-lowering strategies (using sodium benzoate or sodium phenylacetate) and, in severe cases, liver transplantation.

The Lycopodium alkaloids

“…The degree of cholinergic cell loss in the central nervous system relates to the level of neuropathologic alteration, memory impairment and cognitive lesion. [206][207][208][209] AChE and choline levels in patients' cerebrospinal fluid have a close relationship to the severity of dementia. [210][211][212][213] Recent studies have shown that HupA possesses additional pharmacological actions other than affecting the hydrolysis of synaptic ACh described directly above.…”

Ornithine transcarbamylase deficiency in a girl with hyperkinetic behaviour

“…This can lead to impaired cerebral energy metabolism. Further explanations may relate to the toxic effects of metabolites and NMDA (glutamate) receptormediated excitotoxicity caused by energy depletion ("slow onset excitotoxicity") (3)(4)(5).…”

“…There is evidence for osmotic effects of glutamine generated in astrocytes as a consequence of ammonia removal leading to brain swelling (6). Another explanation may be alterations of serotonin synthesis and turnover in brain (3,4). Increased glutamine synthesis in brain may have deleterious effects, including a role in the stimulation of aromatic amino acid transport across the blood brain barrier.…”

“…The aim of treatment is to control the hyperammonaemia, improve survival, prevent mental retardation and to ensure maintenance of cognitive function, normal psychomotor development and growth (11). New therapeutic approaches aim at the correction of neurotransmitter (excitotoxicity) and cerebral energy deficits (Lcarnitin, NMDA receptor-antagonists) to improve cognitive function (3,11,12).…”

Impaired novelty acquisition and synaptic plasticity in congenital hyperammonemia caused by hepatic glutamine synthetase deficiency

“…Until recently, the only available animal model of congenital hyperammonemia was the sparse-fur ( spf ) mouse carrying a point mutation in the ornithine transcarbamoylase (OTC) gene1516. Spf mice have blood ammonia levels that are 2–3fold higher than normal; they show cerebral atrophy, significant alterations in neurotransmitter systems, behavioral abnormalities, and a decreased life span161718192021. As OTC is central for the mitochondrial portion of the urea cycle, it is not surprising that spf mice also show adaptive alterations in other mitochondrial enzyme activities and deficits in energy metabolism making a clear deduction of findings from mere hyperammonemia rather difficult.…”