Ornithine transcarbamylase deficiency diagnosed post-mortem

RaeLynn Forsyth, Ryan H. Peretz, Angela Dempsey, Jacquelyn Britton, Lisa Kratz, Ada Hamosh, Hilary Vernon, Mark L. Batshaw, David Valle. The remarkable journey of one female individual with ornithine transcarbamylase deficiency diagnosed post-mortem. JIMD reports. First published: 29 January 2023 https://doi.org/10.1002/jmd2.12361.  

Urea cycle disorders (UCDs) comprise a group of inborn errors of metabolism with impaired ammonia clearance and an incidence of ~1:35 000 individuals. First described in the 1970s, the diagnosis and management of these disorders has evolved dramatically. We report on a 59‐year‐old woman with a UCD who contributed to advances in the understanding and treatment of this group of disorders. This individual was diagnosed with carbamoyl phosphate synthetase 1 deficiency based on a biochemical assay under a research context predating genetic sequencing, treated longitudinally as having this metabolic disorder, and was among the first participants to trial UCD pharmaceutical therapies. She ultimately succumbed to a SARS‐CoV‐2 infection while maintaining unexpectedly normal ammonium levels. Postmortem genetic testing revealed ornithine transcarbamylase deficiency. This individual's contributions to the field of UCDs is discussed herein. 

From the article:

 

We report the natural history of a 59-year-old woman with a UCD. Her care and management paralleled the development of modern methods of UCD diagnosis and treatment, and she has been included in two previous publications describing these developments over the last 45 years. Together with her family, she was a participant in the clinical research that led to these developments. In an initial report, she was misdiagnosed with CPS1 deficiency based on biochemical and enzyme studies. Subsequent molecular testing obtained post-mortem revealed that her UCD was heterozygosity for OTC deficiency. Just as this patient contributed to the understanding of UCDs throughout her life, the events surrounding her death continue to promote our learning about these rare disorders.  

 

In retrospect, the diagnosis of OTC deficiency is more explanatory than CPS1 deficiency. First, OTC deficiency is more common than CPS1 deficiency, with prevalence of 1:56 500 compared to 1:1 300 000 individuals, respectively.3 Second, the maternal family history of migraines is suggestive of a possible X-linked disorder, and females who are heterozygous for pathogenic variants of OTC have a spectrum of symptoms related to impaired waste nitrogen excretion, including migraine headaches. Because of the variable pattern of X-chromosome inactivation, enzyme testing is not reliable for diagnosis of OTC heterozygosity in females. This is likely the explanation for failing to make an accurate diagnosis with an assay of OTC activity in her liver biopsy. Moreover, these assays were just being developed when performed on this patient and preanalytical handling of the liver biopsy sample was likely not as accurate as required for correct CPS1 enzyme analysis. The lack of orotic acid, a characteristic marker in OTC deficiency in blood and urine samples at times of hyperammonemia, is unusual, but orotic acid can be normal even in hemizygous male individuals with OTC deficiency. 

If this patient had been born today, prompt diagnosis of her OTC deficiency could have been made after her first presentation and effective therapies started before there was irreversible neurological damage. Given that OTC and CPS1 deficiencies are both proximal UCDs, medical management in this patient would not have been different had the correct diagnosis been known sooner. Accurate reproductive and familial risk counseling and testing, however, considering the X-linked inheritance pattern, would have been offered. 

Although she escaped the lethal complications of her genetic disorder, she ultimately succumbed to SARS-CoV-2 infection despite good metabolic control throughout this illness. This patient's relatively delayed presentation and good metabolic control with infrequent hyperammonemic episodes may have also been a clue to a partial defect and suggest that her pattern of X inactivation may have been favorable. Unfortunately, we have no data addressing this possibility. Elevated plasma ammonium levels are commonly seen in patients with UCDs during times of infection, and we would expect the SARS-CoV-2 virus to induce a profound catabolic state. The patient presented with hypothermia, bradycardia, and hypotension, and we hypothesize that this physiological state, in combination with the expeditious initiation of intravenous fluids with 10% dextrose to maintain a high glucose infusion rate and the introduction of enteral feeds upon patient rewarming, may have halted catabolism and prevented hyperammonemia. Hypothermia preventing hyperammonemia in the context of metabolic crises has previously been shown to be safe and feasible in neonates with UCDs, but no studies have been done in adults. This patient raises the notion of utilizing therapeutic hypothermia to help prevent catabolism and hyperammonemia among individuals affected by UCDs, which should be weighed against hemodynamic risks.