Gene Mutation Analysis and Prenatal Diagnosis of the Ornithine Transcarbamylase (OTC) Gene in Two Families with Ornithine Transcarbamylase Deficiency

Li, Sitao; Cai, Yujun; Shi, Changhong; Liu, Mengxian; Bingqing, Liu; Lin, Lin; Xiao, Xueshan; Hu, Hao

doi:10.12659/msm.911295

Cited by 4 publications

(4 citation statements)

References 19 publications

(17 reference statements)

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“…Notably, P4 and P5 had brothers who died a few days after birth due to unknown causes, presumably related to OTCD. This mutation was also detected in a Chinese male patient with early-onset disease 27 . It is speculated that c.116G > T may result in early onset in male patients, whereas female individuals may experience late-onset disease with severe clinical symptoms.…”

Section: Discussionmentioning

confidence: 73%

“…P225L is a relatively common mutation in the Chinese OTCD population 6 . It has been identi ed in several male patients with early onset, all of whom experienced severe hyperammonemia and died during the neonatal period 11,[27][28][29][30] . Two female individuals from the same family with late-onset disease were diagnosed at 20 months and 28 years of age, with varying degrees of symptoms 11 .…”

Section: Discussionmentioning

confidence: 99%

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Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

Yuan,

Liu,

Chen

et al. 2023

Preprint

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BackgroundThis study aimed to investigate the clinical and molecular genetic characteristics of ten children with ornithine carbamoyltransferase deficiency (OTCD) in southeastern China, as well as the correlation between the genotype and phenotype of OTCD. MethodsThe clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 were analyzed retrospectively. ResultsFive boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. Five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all with hepatic impairment, and four with hepatic failure. Coagulopathy occurred in eight patients. Urinary orotic acid levels were elevated in all patients except in one who received blood purification therapy. Only six patients showed decreased serum citrulline levels. Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T>A(p.M56K). Despite active treatment, seven patients died, of whom five had early-onset disease. Three patients survived, and two underwent liver transplantation. ConclusionsThe clinical manifestations of OTCD lack specificity. Elevated blood ammonia is a diagnostic clue for OTCD, elevated urinary orotate is specific for its diagnosis, and genetic testing can help confirm the diagnosis. These two novel variants expand the mutational spectra of OTC, which may contribute to a better understanding of the clinical and genetic characteristics of patients with OTCD.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

Yuan,

Liu,

Chen

et al. 2023

Preprint

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“…Because OTCD symptoms are nonspecific, it can easily be mistaken for general digestive system infection or other neurological diseases. In addition, treatment and prognosis of OTCD and these other diseases are largely different; therefore, early diagnosis is particularly important to guide treatment and prognosis [5]. The liver is the only site of the complete urea cycle in the body, consisting of 9 enzymes that participate in the breakdown of protein to amino acids, depicted in Figure 1.…”

Section: Discussionmentioning

confidence: 99%

Management of Ornithine Carbamoyltransferase Deficiency with Underlying Hyperammonia Hyperinsulinemia Syndrome

Dhillon

Stevens

2019

Am J Case Rep

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Patient: Female, 66 Final Diagnosis: Ornithine carbamoyltransferase deficency with underlying hyperammonia hyperinsulinemia syndrome Symptoms: Seizure Medication: — Clinical Procedure: — Specialty: General and Internal Medicine Objective: Rare co-existance of disease or pathology Background: The urea cycle converts amino acids to urea and is excreted by the kidneys. Ornithine carbamoyltransferase (OTC) deficiency is a rare X-linked urea cycle disorder which results in hyperammonemia. Diagnosis is made based on a clinical presentation of poor feeding, hypotonia, biochemical profile, and genetic testing. Another genetic cause for hyperammonemia is hyperammonia hyperinsulinemia (HAHI) syndrome. A mutation coding for glutamate dehydrogenase (GDH) results in increased alpha-keto glutarate and ATP, triggering the secretion of pancreatic insulin. However, unlike OTC deficiency, these patients are asymptomatic but do have symptoms of hypoglycemia. The purpose of this article is to present the case of a 66-year-old woman with an unusual late-onset of OTC deficiency compounded with an underlying HAHI syndrome with co-disease management. Case Report: A 66-year-old female with a history significant for transient ischemic attack (TIA) and urea cycle disorder was admitted for new adverse symptoms. Further evaluation revealed hyperammonemia and hypoglycemia. Despite standard previous treatment for her underlying urea cycle disorder, high ammonia levels and hypoglycemia persisted. The contradicting values with continued hypoglycemia regardless of dextrose treatment was suspicious for underlying HAHI. Further genetic testing during her admission revealed a deletion in GLUD-1 gene concurrent with diagnosis of HAHI. After co-diagnosis was established, effective management required medications for both disorders in concordance with dietary restriction. Conclusions: This is an extremely rare case of OTC deficiency, with a vague presentation in an elderly female. Exploring compounding genetic disorders in the presence of one that is already established and early recognition are crucial for prompt diagnosis and management.

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“…To date, over 500 mutations have been recorded in the OTC gene (7). Single base substitutions account for about 70-84% of OTC mutations, small-fragment deletions or insertions represent about 12%, and 4% is represented by large-fragment deletions (8). The disease severity depends on the activity of OTC, which is affected by the type and the site of mutations (9,10).…”

Section: Introductionmentioning

confidence: 99%

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

Nguyen

et al. 2020

Front. Pediatr.

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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.

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Gene Mutation Analysis and Prenatal Diagnosis of the Ornithine Transcarbamylase (OTC) Gene in Two Families with Ornithine Transcarbamylase Deficiency

Cited by 4 publications

References 19 publications

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

Clinical characteristics and molecular genetic analysis of ten cases of ornithine carbamoyltransferase deficiency in southeastern China

Management of Ornithine Carbamoyltransferase Deficiency with Underlying Hyperammonia Hyperinsulinemia Syndrome

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

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