Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations

Abstract

Background: Ornithine transcarbamylase deficiency (OTCD) is an X-linked recessive disorder and the most common error of the urea cycle, caused by the mutations in the OTC gene. Due to X-inactivation, 15-20% of female carriers present symptoms of OTCD at late onset. Early diagnosis of OTCD by molecular analysis in females is highly desirable. The aim of the study was to identify the mutations in two unrelated Vietnamese girls suspected with OTCD and the carriers in their families for definitive diagnosis and proper counseling. Case Presentation: Two patients presented with an acute encephalopathy at the first admission. Biochemical tests revealed hyperammonemia, hyperlactatemia, elevated glutamine level, elevated transaminase, elevated urinary orotic and uracil acid levels, and disorder of prothrombin time. Brain magnetic resonance imaging indicated cerebral edema. Based on the clinical and laboratory results, the two patients were diagnosed with urea cycle disorders. Therefore, the two patients were managed by stopping feeding, with infused glucose, l-carnitine, l-arginine, and sodium benzoate, and with hemofiltration. The two patients were alert and recovered with normal blood ammonia levels after 72 h of treatment. The family history of patient 1 showed that her brother died at 4 days of age due to a coma and dyspnea, while her parents were asymptomatic. Variable phenotypes were observed in three generations of the patient 2's family, including asymptomatic (mother), affected female adults dying at the first symptom (grandmother and aunt), and affected males dying in the first week of life (uncle, cousin, and siblings). Whole-exome sequencing showed two mutations in the OTC gene, including one novel missense mutation, c.365A>T, in the patient 1 and one previously reported splicing mutation, c.717+1G>A, in the patient 2. The two mutations are evaluated as likely pathogenic and pathogenic, respectively, according to the recommendations of the American College of Medical Genetics and Genomics (ACMG). Genetic analyses in the families indicated the mothers were heterozygous. Nguyen et al. Vietnamese Females With OTC Mutations Conclusion: Clinical, biochemical, and molecular findings accurately diagnosed the two patients with late-onset OTCD. Our results explained the genetic causes and proposed the risk in the patients' families, which could be useful for genetic counseling and monitoring in prenatal diagnosis.

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

“…More than 500 disease causing mutations have been reported in the OTC gene so far [ 44 ]. Of all, single base substitutions account for 70–84%, 12% are small-fragment deletions or insertions and the rest are large fragment deletions [ 14 , 44 ]. Several mutations have been reported in the promoter and enhancer region [ 41 ].…”

“…In general, the complete dysfunction of enzymes is due to the distortion of the reading frame of the coding sequence via nonsense, insertion and deletion. The substitution of an amino acid in either the active site or the hydrophobic core leads to the partial dysfunction of the enzyme [ 14 , 46 ]. Approximately 60% of hemizygous males with the severe neonatal form have mutation around the active site of the enzyme.…”

“…OTCD was first described in 1962 by Russell regarding two girls at the age of 1 year and 8 months and 6 years [ 3 ]. The estimated prevalence is between 1:14,000 and 80,000 [ 14 ]. The X-linked inheritance of OTCD is unique with the remaining UCDs inherited in an autosomal recessive manner.…”

Detection of c.G2194A mutation in \(\textit{AR}\) gene of a vietnamese patient with androgen insensitivity syndrome: a case report

“…The predictive results of the in silico analysis showed a significant level of damage of this mutation to AR protein function. These are also highly reliable bases that have been used by many studies to predict the impact of new mutations (Nguyen et al, 2020;Wang et al, 2017).…”

Effect of Ornithine Transcarbamylase (OTC) Deficiency on Pregnancy and Puerperium

“…The disease is bound to the X chromosome. In male individuals, hemyzygotes, the disease often manifests as a severe hyperammonemic crisis with a neurological symptomatology as early as in the neonatal period [ 4 ]. If not recognized correctly and left without treatment, the disease can progress to severe brain edema and lead to the death of the newborn [ 2 ].…”