Inherited hyperammonemias: a Contemporary view on pathogenesis and diagnosis

INTRODUCTION: Hyperammonemia is a marker for a disturbance either in the ammonia detoxification or less likely in the ammonia production. The symptoms are due mainly to ammonia’s effect on the brain. The prognosis depends on several factors, including the developmental stage, the magnitude and duration of exposure. A prompt ascertainment is crucial at any age for a good prognosis. AREAS COVERED: This review article will briefly summarize the most recent advances in the understanding of hyperammonemia due to disorders of the urea cycle and related enzymes. Major focus will be on the neuropathological mechanisms and new diagnostic approaches. Evidence shows that ammonium central nervous system exposure alters several amino acid pathways and neurotransmitter production, nitric oxide synthesis, signal transduction, cerebral energy metabolism, oxidative/nitrosative stress, and channels and transporters activity. Newborn screening programs for inherited hyperammonemias and next-generation sequencing panels of genes associated with hyperammonemia are already established diagnostic tools. EXPERT OPINION: In the light of the recent discovery of the role of the amino acid arginine in ammonia metabolism, urea cycle disorders may reveal new insights. In the absence of a method to achieve a genetic correction of the defective metabolic pathways, new therapeutic strategies for the neurological complications of hyperammonemia are still an urgent need and deserve further investigation.