Neurological implications of urea cycle disorders

Abstract

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.

Fig. 1

Diagrammatic depiction of the major enzymatic reactions in the urea cycle

Fig. 2

CT scan demonstrating left-sided, posteriorly located area of decreased attenuation, consistent with infarction (arrow)

Fig. 3

The glutamate–glutamine cycle. Neuronal glutamate is released from the nerve terminal and taken up by the glial cell where it is converted into glutamine, a less toxic molecule. The glutamine can be transferred to the neuron and allow glutamate to be resynthesized

Fig. 4

T2-weighted MRI image, axial and coronal showing white-matter changes (arrows) seen in OTCD deficiency

Fig. 5

T1-weighted coronal (a) and autopsy specimen (b) of neonate with OTCD. Note the significant grey-matter involvement with severe cortical atrophy and cystic changes

Fig. 6

¹H MRS acquisition from the thalamus of control subject (black) and one with OTCD (red). Note the elevation of glutamine and decreased level of myoinositol in the subject relative to control. In addition, there are differences in other metabolites, including decreased choline in the subject relative to control