Female heterozygotes for the hypomorphic R40H mutation can have ornithine transcarbamylase deficiency and present in early adolescence: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal.</p> <p>Case presentation</p> <p>A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range <500 μmol/mmol creatinine) highly suggestive of ornithine transcarbamylase deficiency. She was treated with intravenous sodium benzoate and arginine and made a rapid full recovery. She was discharged on a protein-restricted diet. She has not required ongoing treatment with arginine, and baseline ammonia and serum amino acid concentrations are within normal ranges. She has had one further episode of hyperammonemia associated with intercurrent infection after one year of follow up. An R40H (c.119G>A) mutation was identified in the ornithine transcarbamylase gene (<it>OTC</it>) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens.</p> <p>Conclusions</p> <p>This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H <it>OTC </it>mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history.</p

Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins. © 2018 The Author(s)

A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice

Many genetic liver diseases present in newborns with repeated, often lethal, metabolic crises. Gene therapy using non-integrating viruses such as AAV is not optimal in this setting because the non-integrating genome is lost as developing hepatocytes proliferate1,2. We reasoned that newborn liver may be an ideal setting for AAV-mediated gene correction using CRISPR/Cas9. Here we intravenously infuse two AAVs, one expressing Cas9 and the other expressing a guide RNA and the donor DNA, into newborn mice with a partial deficiency in the urea cycle disorder enzyme, ornithine transcarbamylase (OTC). This resulted in reversion of the mutation in 10% (6.7% – 20.1%) of hepatocytes and increased survival in mice challenged with a high-protein diet, which exacerbates disease. Gene correction in adult OTC-deficient mice was lower and accompanied by larger deletions that ablated residual expression from the endogenous OTC gene, leading to diminished protein tolerance and lethal hyperammonemia on a chow diet

Intellectual, Adaptive, and Behavioral Functioning in Children With Urea Cycle Disorders

Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain, and result in high rates of mortality and neurodevelopmental disability. The current study seeks to characterize the cognitive, adaptive, and emotional/behavioral functioning of children with Urea Cycle Disorders (UCDs). These domains were measured through testing and parent questionnaires in 92 children with UCDs (33 neonatal onset, 59 late onset). Results indicate that children who present with neonatal onset have poorer outcome than those who present later in childhood. Approximately half of the children with neonatal onset performed in the range of intellectual disability (ID), including a substantial number (~30%) who were severely impaired. In comparison, only a quarter of the late onset group were in the range of ID. There is also evidence that the UCD group has difficulties in aspects of emotional/behavioral and executive skills domains. In conclusion, children with UCDs present with a wide spectrum of cognitive outcomes. Children with neonatal onset disease have a much higher likelihood of having an intellectual disability, which becomes even more evident with increasing age. However, even children with late onset UCDs demonstrate evidence of neurocognitive and behavioral impairment, particularly in aspects of attention and executive functioning