Three-Country Snapshot of Ornithine Transcarbamylase Deficiency

Abstract

X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle defect. The disease severity ranges from asymptomatic carrier state to severe neonatal presentation with hyperammonaemic encephalopathy. We audited the diagnosis and management of OTCD, using an online 12-question-survey that was sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres responded and 495 patients were reported in total. A total of 208 French patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51 (25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%) males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic females. A total of 19%, 12% and 7% of the patients presented with a neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting, altered mental status and encephalopathy were the most common initial symptoms in all three countries. While 69% in France and 79% in Turkey were receiving protein restriction, 42% were on a protein-restricted diet in the UK. A total of 76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey, France and the UK, respectively. The findings of our audit emphasize the differences and similarities in manifestations and management practices in three countries.

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database

“…While approximately 80% of heterozygous females remain apparently “asymptomatic” (Batshaw et al., 1986 ), about 20% are thought to manifest symptoms, the risk of which is related to the time of onset, type of OTC variant, and severity of OTCD in their offspring (McCullough et al., 2000 ). The variability of the nature and onset of symptoms makes risk factor evaluation in heterozygous females especially challenging due, in part, to the unpredictability of skewed X‐inactivation (Lichter‐Konecki et al., 1993 ; Seker Yilmaz et al., 2022 ; Yorifuji et al., 1998 ) as well as the imperfect predictability of severity based on enzyme activity in liver biopsies (Musalkova et al., 2018 ). Genotype–phenotype correlations with the functional impact of 1570 individual amino acid substitutions in OTC using a yeast‐based functional complementation assay for human OTCD have been evaluated (Caldovic et al., 2015 ; Lo et al., 2023 ).…”

Diagnostic and Management Issues in Patients with Late-Onset Ornithine Transcarbamylase Deficiency

“…Common complications of UCD include the accumulation of ammonia, which is neurotoxic [ 3 , 4 , 5 , 6 , 7 ], and hepatic dysfunction. The most prevalent UCD is an ornithine transcarbamylase deficiency (OTCD) [ 8 , 9 , 10 , 11 ]. The anabolic OTC enzyme is responsible for the transfer of a carbamoyl group from carbamoyl phosphate to the amino group of L-ornithine, producing citrulline in an early step of the urea cycle [ 12 , 13 ].…”

“…The X-linked inheritance of OTCD is unique with the remaining UCDs inherited in an autosomal recessive manner. Due to its X-linked recessive inheritance, OTCD tends to present earlier, and more severely, in males [ 11 ]. However, patient phenotype can vary due to random X inactivation in females and hypomorphic variants in OTC that cause a partial enzyme deficiency and later onset of symptoms in males [ 7 , 15 ].…”

Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency

“…A recent study revealed that 19%, 12% and 7% of the patients had a neonatal-onset phenotype in France, Turkey, and the UK, respectively. In contrast, the most frequent primary symptoms were vomiting, altered mental status and encephalopathy in all countries [ 10 ]. In addition to the neurological presentation, liver presentation with acute liver failure or chronic liver disease is also common in OTCD [ 11 ].…”