Sudden unexpected fatal encephalopathy in adults with OTC gene mutations-Clues for early diagnosis and timely treatment

Abstract

BackgroundX-linked Ornithine Transcarbamylase deficiency (OTCD) is often unrecognized in adults, as clinical manifestations are non-specific, often episodic and unmasked by precipitants, and laboratory findings can be normal outside the acute phase. It may thus be associated with significant mortality if not promptly recognized and treated. The aim of this study was to provide clues for recognition of OTCD in adults and analyze the environmental factors that, interacting with OTC gene mutations, might have triggered acute clinical manifestations.MethodsWe carried out a clinical, biochemical and molecular study on five unrelated adult patients (one female and four males) with late onset OTCD, who presented to the Emergency Department (ED) with initial fatal encephalopathy. The molecular study consisted of OTC gene sequencing in the probands and family members and in silico characterization of the newly detected mutations.ResultsWe identified two new, c.119G>T (p.Arg40Leu) and c.314G>A (p.Gly105Glu), and three known OTC mutations. Both new mutations were predicted to cause a structural destabilization, correlating with late onset OTCD. We also identified, among the family members, 8 heterozygous females and 2 hemizygous asymptomatic males. Patients' histories revealed potential environmental triggering factors, including steroid treatment, chemotherapy, diet changes and hormone therapy for in vitro fertilization.ConclusionsThis report raises awareness of the ED medical staff in considering OTCD in the differential diagnosis of sudden neurological and behavioural disorders associated with hyperammonemia at any age and in both genders. It also widens the knowledge about combined effect of genetic and environmental factors in determining the phenotypic expression of OTCD.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype

“…However, mild clinical variants of IVA, argininosuccinate synthetase (ASS; EC 6.3.4.5; OMIM #215700) and lyase (ASL; EC 4.3.2.1; OMIM #207900) deficiency have been described and are thought to be common in female ornithine transcarbamylase (OTC; EC 2.1.3.3; OMIM #311250) carriers (Ensenauer et (Hörster et al 2007;Hörster et al 2009;Kölker et al 2006a;Rüegger et al 2014), the knowledge about the long-term outcome is still incomplete and there is uncertainty about the risk of developing (multiple) organ dysfunction with increasing age. Evidence is increasing that even patients who have been considered as Bmetabolically stable^or who have never developed a metabolic crisis might be at risk of developing (fatal) late-onset organ complications (Cavicchi et al 2014;Herskovitz et al 2013;Hörster et al 2007;Komatzusaki et al 2012;Marquard et al 2011;P e n ae ta l2012;R o m a n oe ta l 2010; Serrano et al 2010;Williams et al 2009).…”

Long-term outcomes in Ornithine Transcarbamylase deficiency: a series of 90 patients

“…However, presymptomatic therapy may improve neonatal survival (100% vs 40%, p = 0.06) and long-term survival (50-75% vs 10%, p = 0.11). It is also important to consider that some adults still die during their first metabolic coma because of a delayed diagnosis [ 16 ], thus emphasizing that adult intensive care unit physicians should have a greater awareness of the presentations of late-onset forms of inherited metabolic diseases.…”

Genotype–Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update

“…Individuals with sequence variants that allow residual OTC activity can present with hyperammonemia at any point in life, while others remain asymptomatic. In patients with late onset OTCD, acute hyperammonemia can be triggered by a high protein meals (Ben-Ari et al, 2010; Thurlow et al, 2010; Cavicchi et al, 2014), fasting (Marcus et al, 2008), infections (McGuire et al, 2013), invasive medical procedures (Chiong et al, 2007; Hu et al, 2007; Bezinover et al, 2010), chemotherapy (Lipskind et al, 2011; Cavicchi et al, 2014), or other environmental insults that result in increased protein catabolism and ammonia production (Seminara et al, 2010). Missense mutations that cause partial OTCD reduce OTC enzymatic activity or stability while mutations in the vicinity of consensus splice sites can potentially affect mRNA processing and result in decreased abundance of the OTC enzyme.…”