Ornithine transcarbamylase deficiency: A diagnostic odyssey

Abstract

Iceland have further elucidated the molecular pathophysiology in a subgroup of predominantly male patients with late-onset ornithine transcarbamylase deficiency (OTCD), an X-linked urea cycle disorder. The authors put the spotlight on pathogenic variants affecting the regulatory regions of the OTC gene, specifically the OTC promoter variant c.-106C>A. This leads to impaired promoter function of the OTC gene and may present as late-onset OTCD in apparently healthy individuals; however, when metabolic stress is increased, impaired upregulation of OTC gene activity can then be followed by hyperammonaemia.Parallel to both of these reports, two additional males (16 and 20 years of age, respectively) with, thus far, clinically very mild late-onset OTCD, were diagnosed in Ireland by our group. They had been under surveillance with "sick day" management and L-arginine supplements due to a positive family history of hyperammmonaemia with a biochemical diagnosis of OTCD in their older brother. This Irish family had extensive genetic testing done, including OTC gene sequencing in different diagnostic laboratories, which came back negative. The two younger brothers' diagnosis was based on an allopurinol load performed 10 years previously. Further to diagnostic findings of Jang et al. 3 which describe the pathogenic variant c.-106C>A in the promoter region of the OTC gene, a diagnosis of OTCD could be genetically confirmed for the two Irish patients. Whole exome sequencing also verified that no other pathogenic variant was identifiable relating to their biochemical findings. These biochemical results include, for example, normal plasma ammonia measurements to date and, intermittently, marginally raised transaminases.The difficult diagnostic journey with its serendipitous outcome, described by Hertzog and collaborators, underscores how metabolic medicine is sometimes not unlike detective work, particularly when confirmatory testing

Intronic variants in inborn errors of metabolism: Beyond the exome

“…This was consistent with the milder clinical features of affected males. Provision of timely genetic diagnosis would have assisted with family planning: for many individuals, the diagnostic odyssey can lead families to disengage detrimentally with services ( Knerr and Cassiman, 2022 ), in the false belief that there is no risk of recurrence.…”