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
alpha-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.