Late‐onset ornithine transcarbamylase deficiency: a rare cause of recurrent abnormal behavior in adults

Abstract

Background Ornithine transcarbamylase is an enzyme of the urea cycle, which produces urea from ammonia. Although ornithine transcarbamylase deficiency mainly occurs as a severe neonatal‐onset disease, a late‐onset form that could become symptomatic from infancy to adulthood is also known. Case presentation A 34‐year‐old man presented with sudden onset of abnormal behavior, lethargy, and hyperammonemia (108 µmol/L). He had recently increased daily protein intake, which suggested urea cycle disorder. After initiation of protein‐restricted diet and treatment with arginine and sodium phenylbutyrate, his symptoms resolved, along with a decrease in the ammonia level. An R40H(c.119G > A) mutation in the OTC gene was identified. Conclusion Awareness of adult onset ornithine transcarbamylase deficiency in a patient with acute psychiatric symptoms due to hyperammonemia is important.

Common polymorphic OTC variants can act as genetic modifiers of enzymatic activity

“…Although significantly reduced by comparison with wild-type, the level of enzymatic activity associated with the various versions of OTC harboring the p.Arg40His mutation may well be enough to F I G U R E 4 Structural analysis of Site 2 in OTC homology models. OTC, ornithine transcarbamylase sustain quasi-normal metabolic status as several OTC deficiency patients have been reported in the literature as presenting symptoms at distinct ages (Cavicchi et al, 2014;Hidaka et al, 2020;Koya et al, 2019;Matsuda et al, 1996;Pinner et al, 2010;Ploechl et al, 2001;Tuchman et al, 1994;Yoshino et al, 1990;Zhou et al, 2020). The interplay between rare disease-causing mutations and common polymorphic variants has been documented for only a very limited number of genes/proteins involved in human genetic disease (Chan et al, 2006;Cheng et al, 2011;Cooper et al, 2010;Gonzalez & Ostermeier, 2019;Lage et al, 2014;Li et al, 2018;Matsumura et al, 2017;Niu et al, 2006;Poelzing et al, 2006;Raef et al, 2008;Silva et al, 2004;Zhang et al, 2008).…”

“…This concurs with literature records reporting similar levels of enzymatic activity in liver samples obtained post mortem from patients carrying the p.Arg40His mutation (Matsuda et al, 1996 ) and with previous studies that characterized this mutation in vitro (Matsuda et al, 1996 ; Nishiyori et al, 1997 ). Although significantly reduced by comparison with wild‐type, the level of enzymatic activity associated with the various versions of OTC harboring the p.Arg40His mutation may well be enough to sustain quasi‐normal metabolic status as several OTC deficiency patients have been reported in the literature as presenting symptoms at distinct ages (Cavicchi et al, 2014 ; Hidaka et al, 2020 ; Koya et al, 2019 ; Matsuda et al, 1996 ; Pinner et al, 2010 ; Ploechl et al, 2001 ; Tuchman et al, 1994 ; Yoshino et al, 1990 ; Zhou et al, 2020 ).…”

“…The majority of these lesions are private or found in very few families (Yamaguchi et al, 2006 ). One exception is the p.Arg40His replacement (NM_000531.5:c.119G>A [p.Arg40His]) which has been reported in a number of distinct families as a consequence of both recurrent and identical‐by‐descent mutation (Hidaka et al, 2020 ; Koya et al, 2019 ; Matsuda et al, 1996 ; Nishiyori et al, 1997 ; Zhou, Huang, Ma & Zhu, 2020 ). OTC activity measured from the necropsied liver of five deceased patients with a confirmed p.Arg40His mutation has been found to be between 1.3% and 12% of the wild‐type OTC level (Matsuda et al, 1996 ) whereas the mutant (p.Arg40His‐harboring) OTC enzyme expressed in vitro in COS‐1 cells exhibited 10.2% (Matsuda et al, 1996 ) to 28% (Nishiyori et al, 1997 ) of wild‐type activity.…”

“…OTC activity measured from the necropsied liver of five deceased patients with a confirmed p.Arg40His mutation has been found to be between 1.3% and 12% of the wild‐type OTC level (Matsuda et al, 1996 ) whereas the mutant (p.Arg40His‐harboring) OTC enzyme expressed in vitro in COS‐1 cells exhibited 10.2% (Matsuda et al, 1996 ) to 28% (Nishiyori et al, 1997 ) of wild‐type activity. The p.Arg40His mutation has been associated with both the early onset and the late‐onset phenotype in both females and males (Hidaka et al, 2020 ; Koya et al, 2019 ; Zhou et al, 2020 ). In a few cases, the sudden appearance of metabolic distress in otherwise apparently healthy carriers of the p.Arg40His mutation has been suggested to be associated with specific acute dietary changes (Cavicchi et al, 2014 ; Hidaka et al, 2020 ; Koya et al, 2019 ; Pinner et al, 2010 ).…”

“…The p.Arg40His mutation has been associated with both the early onset and the late‐onset phenotype in both females and males (Hidaka et al, 2020 ; Koya et al, 2019 ; Zhou et al, 2020 ). In a few cases, the sudden appearance of metabolic distress in otherwise apparently healthy carriers of the p.Arg40His mutation has been suggested to be associated with specific acute dietary changes (Cavicchi et al, 2014 ; Hidaka et al, 2020 ; Koya et al, 2019 ; Pinner et al, 2010 ).…”