Of Ammonia and Orotic Acid and Their Importance for Clinical Neuropediatrics

Urea cycle defects (UCDs) are rare inherited diseases with an estimated overall incidence of approximately 1 in 35,000.[1] An impairment of the urea cycle results in hyperammonemia, which is the hallmark of UCDs, and is defined as an increase of the highly neurotoxic metabolite ammonia in plasma.[2] [3] UCDs can manifest at all ages but about half of all known patients present already within the first few days after birth.[4] The urea cycle is the only pathway in the human body, which is able to detoxify ammonia.[5] Acute hyperammonemia leads to encephalopathy and is always a life-threatening condition and an emergency because it may lead to irreversible brain damage depending on the extent and duration of the elevated ammonia levels.[6] The overall prognosis of UCD patients must generally be considered as poor because the disorder at the time of the initial presentation is often recognized too late to avoid neurological sequelae or death. In addition, current treatment strategies are far from being satisfactory as they offer no cure, but they determine an enormous burden of disease for patients and their families. In principle, treatment for a UCD is based on the following three modalities that are given in combination in most of the patients: (1) a low-protein diet with supplementation of essential amino acids, vitamins, and trace elements, (2) nitrogen scavenging drugs offering the possibility of nitrogen removal independent from the hampered urea cycle function, and (3) medication with intermediate metabolites, l-arginine and/or l-citrulline, to support residual urea cycle function.[7] This treatment remained largely unchanged over the last three decades with only minor improvement in drug formulation.

There are six different monogenic forms of UCD described with a defect in any of the six enzymes of the urea cycle. The most frequent UCD is the ornithine transcarbamylase deficiency (OTCD) which is the cause of over 50% of the cases of UCD. Depending on the mutation in the X-linked OTC gene (more than 340 are currently described[8]) and on the degree of X-inactivation in heterozygous females, the associated onset can vary from neonatal with a first hyperammonemic crisis within few days after birth to heterozygous females with only a subtle neurological phenotype.

OTCD is biochemically characterized by the increased excretion of orotic acid in urine. Orotic acid is a metabolite downstream the pyrimidine biosynthesis pathway and usually present in our urine in only low concentration. However, in OTCD, the impaired function of the OTC leads to the intramitochondrial accumulation of one of its substrates, carbamylphosphate, which then spills over to the cytosol to be degraded in the pyrimidine biosynthesis pathway.

Orotic acid in urine can also be increased in patients with other UCDs, but the concentrations are much smaller than in OTCD. Apart from UCDs, orotic acid in urine is found to be increased in yet another rare condition affecting the pyrimidine biosynthesis pathway. The enzyme uridine-5-monophosphate synthase (UMPS) is a bifunctional protein and catalyzes the final two pyrimidine nucleotide synthesis reactions (one domain catalyzes an orotate phosphoribosyltransferase step and the other enzyme domain an orotidine-5-monophosphate decarboxylase step). As orotic acid is the substrate of the first enzymatic reaction of UMPS, patients with a defect in UMPS excrete large amounts of orotic acid besides presenting other signs. In fact, when the first patient with this disease was described, the main phenotypic feature was a megaloblastic anemia which was unresponsive to vitamin B₁₂ and folic acid.[9] Remarkably, a treatment was then already suggested when anemia and orotic aciduria improved after administration of uridylic acid and cytidylic acid.

The disease hereditary orotic aciduria, caused by a defect UMPS, is excessively rare, but it is now clear that it is a pan-ethnic disease with a broad clinical heterogeneity. Every report of a new patient with this disease adds to our understanding of the clinical consequences of a blockage in pyrimidine nucleotide synthesis. In this issue of Neuropediatrics, the readers can learn about a unique presentation of hereditary orotic aciduria in the communication by Grohmann et al.[10] They reported a case of a 3-year-old boy with tonic–clonic seizures in whom a thorough metabolic screening revealed a marked increase of orotic acid in urine. Interestingly, this boy did not show megaloblastic anemia. The authors report the course of the disease during an 8-year follow-up and under treatment with uridine.

There are at least two lessons that can be learned from this report: one is related to the work-up of patients with newly developed epilepsy. Only the careful and extensive investigations performed in this case lead to the correct diagnosis in this patient. Another lesson is that the clinical presentation in a patient not always follows textbook chapters. In the present patient, absence of megaloblastic anemia as the “leading” clinical feature in hereditary orotic aciduria could well have distracted from the correct diagnosis. Finally, hyperammonemia should be regarded as an urgent differential diagnosis in any child or adult with an unclear compromise of consciousness and prompt diagnosis and start of treatment are vital for the patient's prognosis.

This article is an editorial on “Hereditary Orotic Aciduria with Epilepsy and without Megaloblastic Anemia” by Grohmann et al (Neuropediatrics 2015;46(2):123–125, doi: 10.1055/s-0035-1547341).

• References

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