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  • Updated 08.04.2019
  • Released 11.28.1994
  • Expires For CME 08.04.2022

Ornithine transcarbamylase deficiency

Introduction

This article includes discussion of ornithine transcarbamylase deficiency, OTCD, and OTC deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited urea cycle disorder and the only one to be transmitted as an X-linked trait. It causes hyperammonemia, intellectual disability, (severe) developmental disabilities, and fluctuating neurologic and psychiatric symptoms, and it may be fatal unless treated with liver transplantation. Complete enzyme deficiency in affected hemizygous males almost invariably results in hyperammonemic coma within the first weeks of life (≤ 28 days; neonatal or early onset), whereas partial deficiency in males or manifesting heterozygous females can result in hyperammonemia at any age (> 28 days; late onset). Biochemical markers include elevated plasma glutamine and reduced or absent L-arginine and L-citrulline concentrations on amino acid analysis and elevated concentrations of urinary orotic acid. Diagnosis is established by identifying the mutation or by enzyme analysis of liver tissue or intestinal mucosa. Treatment consists of a protein-restricted diet, ammonia scavenger drugs, and L-citrulline or L-arginine substitution. Liver transplantation cures recurrent hyperammonemic episodes, but will not restore neurologic sequelae.

Currently, international networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more completely describe the initial and evolving clinical phenotype of urea cycle disorders (UCD) such as ornithine transcarbamylase deficiency. Furthermore, they want to determine if the natural disease course can be favorably modulated by diagnostic and therapeutic interventions. These networks collect systematic data to improve clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestation and complications, as well as long-term outcomes of urea cycle disorders. These networks include the Urea Cycle Disorders Consortium (UCDC), established in 2006, the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), established in 2011, and the Japanese Urea Cycle Disorders Consortium (JUCDC), established in 2012 (104).

Key points

• Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder as well as the only X-linked urea cycle disorder.

• Deleterious mutations cause severe male neonatal-onset type disease and mild to severe disease in females (depending on lyonization). Less severe mutations with partial enzyme deficiency cause mild to moderate late-onset type disease in males and females.

• Clinical presentation of heterozygous female OTC carriers is highly variable, even within the same family because of different X-inactivation.

• Female carriers are at special risk of severe metabolic decompensation after birth.

• Male OTC patients may be underrepresented in statistical analyses because many patients die early (within 48 to 72 hours) and are potentially undiagnosed.

• Neurologic outcome depends primarily on noninterventional parameters, eg, intrinsic disease severity (reflected by onset type and initial peak plasma ammonium concentration during first metabolic decompensation). The impact of interventional parameters on clinical outcome, eg, diagnostic and therapeutic interventions, remains to be elucidated.

Historical note and terminology

Ornithine transcarbamylase deficiency (OTCD) was first reported in 1962 in 2 girls, aged 20 months and 6 years, who were found to have hyperammonemia associated with episodic vomiting, delirium, stupor, failure to thrive, and mental retardation (94). The mothers were sisters, and both showed evidence of a similar but less marked metabolic disorder. Both girls died before the age of 8 years. Several years later, this disorder was identified in males (100), and the delayed recognition was attributable to the almost total lack of enzyme activity and rare survival of affected males beyond the newborn period at that time. The reason for this difference between males and females was subsequently determined in the X-linked trait (92).

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