5. Signs and symptoms of hyperammonaemic patients and how they can be explained by pathomechanisms (looking forward to module 3)

You have already learned a lot about the complex neuro-pathophysiology of hyperammonaemia. Now we will try to elucidate how these mechanisms can be translated into clinical and neuro-radiological observations in patients with urea cycle defects.

These symptoms can be explained by previously identified mechanisms. Although this still remains a bit speculative and although there is some overlap between single mechanisms, it helps to understand the severity of an acute hyperammonaemic decompensation and to consider an appropriate therapeutic strategy.

As with many other diseases, the vulnerability of the brain to hyperammonaemia is age-dependent. This has consequences for the clinical presentation and brain pathology.

This MRI was performed on a girl with symptomatic heterozygous OTC deficiency at age 2 weeks. She presented at age 2 days with lethargy, anorexia, respiratory distress, coma, and generalized tonic-clonic seizures. Plasma ammonia (1700 µmol/L) and glutamine (1268 µmol/L) levels were massively elevated.

The T1 weighted MRI shows bilateral lentiform nuclei shortening (globi pallidi more than putamina) and the signal change in the insular cortex. The T2 weighted image shows low signal intensity in the left globus pallidus and high signal intensity in the corpora striata. This is characteristic of neonatal hyperammonaemic decompensation in patients with proximal urea cycle defects.

Further details explanations are given in reference 13

The authors explained this characteristic pattern as follows:

"In general, the most metabolically active and mature regions of the premature brain, those that have the most advanced myelination, perfusion and glucose uptake, are regions that are damaged first in the setting of nearly complete cessation of brain perfusion. At 40 weeks after conception, the basal ganglia and peri-rolandic region have the highest metabolic activity; this is in addition to the brain stem and thalamus, which also have high activity beginning in the third trimester."

Hyperammonaemia causes different MRI abnormalities at different ages. In children, hyperammonaemia typically leads to extensive infarct-like lesions, often resulting in hemiplegia. Presumably ischaemic lesions are located in the cerebral inter-vascular boundary zones. In contrast, MRI in adults following hyperammonaemia often reveals reversible symmetric cortical involvement of the cingulate gyri, temporal lobes, and insular cortex with sparing of the peri-rolandic cortex. The symptoms of hyperammonaemia also vary with age. Accordingly, in patients with partial urea cycle defects who may present in adolescence or adulthood, the clinical features are often less obvious than in younger patients and, therefore, many of these patients are diagnosed and treated far too late (if at all). In this age group, learning disorders, behavioural abnormalities (e.g. self-injury, hyperactivity, aggressiveness), recurrent vomiting, stroke-like episodes, protein aversion, and psychiatric symptoms (e.g. psychosis, major depression) may be observed. In patients with partial urea cycle defects, the symptoms may be even more subtle and might only be elucidated by systematic testing.

References 14 and 15 give further details on OTC female carriers and partial OTC deficient patients.

This is an interesting and somewhat complex area of metabolic medicine and references 16-19 are strongly recommended as further reading