The
urea cycle disorders constitute a group of rare
congenital disorders caused by a deficiency of the
enzymes or
transport proteins required to remove
ammonia from the body. Via a series of biochemical steps,
nitrogen, the
waste product of
protein metabolism, is removed from the blood and converted into
urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema,
seizures,
coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of
neurotransmitter systems. In acute hyperammonaemia, activation of the
NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in
protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular (1)H MRS, can reveal markers of impaired metabolism such as elevations of
glutamine and reduction of
myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the
NMDA receptor and impairments in the
glutamate-
nitric oxide-cGMP pathway, leading to alterations in cognition and learning.
Therapy of acute hyperammonaemia has relied on
ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with
phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human
urea cycle disorders.