Adult Presentation of Ornithine Transcarbamylase Deficiency: 2 Illustrative Cases of Phenotypic Variability and Literature Review

Pizzi, Michael; Alejos, David; Hasan, Tasneem F.; Atwal, Paldeep S.; Krishnaiengar, Suparna; Freeman, William D.

doi:10.1177/1941874418764817

Cited by 15 publications

(25 citation statements)

References 37 publications

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“…Ornithine transcarbamylase catalyzes the formation of citrulline from ornithine and carbamyl phosphate. [ 2 ]. Thereby, OTCD leads to excess carbamoyl phosphate production, which then reacts with aspartate generating excess orotic acid.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

Feng

Qiu

et al. 2020

Orphanet J Rare Dis

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Background This study aimed to describe the clinical and biochemical features of Chinese patients with ornithine transcarbamylase deficiency (OTCD), and to investigate the mutation spectrum of OTC gene and their potential correlation with phenotype. Methods Sixty-nine patients with OTCD were enrolled between 2004 and 2019. Clinical and laboratory data were reviewed retrospectively from medical records. Results Fifteen cases (13 males, 2 females) presented with early onset; 53 cases (21 males, 32 females) had late onset, and one female was asymptomatic. The median onset age was 1.5 years (range 1 day–56 years). Urine orotic acid levels were increased in all patients tested, while only 47.6% of patients showed decreased serum levels of citrulline. The peak plasma ammonia levels were higher in early-onset patients than in late-onset patients (P < 0.01). Fifty-four different mutations of OTC gene were identified and 18 of them were novel. R277W (10.6%) was the most common mutation, followed by G195R (4.6%) and A209V (3.0%). By June 2019, 41 patients had survived, 24 were deceased, and 4 were lost to follow-up. Among the survivors, 13 patients had received liver transplantation at a median age of 3 years, with a one-year survival rate of 100%. The mortality of OTCD is extremely high among patients with early onset (80.0% versus 24.5% in patients with late onset). Conclusions The evaluation of serum citrulline level is of limited value in diagnosis of OTCD, while urine orotic acid detection and genetic testing are more helpful.

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Section: Introductionmentioning

confidence: 99%

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

Feng

Qiu

et al. 2020

Orphanet J Rare Dis

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“…Specifically, one male OCD patient was found to have pathogenic variants in both SCN1A and OTC, while a female SSD patient was found to have pathogenic variants in SCN1A and PDHA1. Interestingly, OTC deficiency patients can present with cerebellar ataxia, seizures and epilepsy, all of which are phenotypes also prevalent amongst channelopathies (Barkovich et al, 2020;Crowe et al, 2018;Hidaka et al, 2020;Im et al, 2018;Pizzi et al, 2019;B. Wu et al, 2018).…”

Section: Prevalence Of Treatable Genetic Disorder Variants Within the Study Cohortmentioning

confidence: 99%

When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population

Sriretnakumar

Harripaul

Kennedy

et al. 2021

Preprint

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Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is non-responsive to standard medications and therapies. There has not been a comprehensive study to date examining the burden and impact of treatable genetic disorders (TGDs) that can present with neuropsychiatric features in psychiatric patient populations. In this study, we test the hypothesis that TGDs that present with psychiatric symptoms are more prevalent within psychiatric patient populations compared to the general population by performing targeted next-generation sequencing (NGS) of 129 genes associated with 108 TGDs in a cohort of 2301 psychiatric patients. In total, 72 putative affected and 293 putative carriers for TGDs were identified, with known or likely pathogenic variants in 78 genes. Despite screening for only 108 genetic disorders, this study showed an approximately four-fold (4.13%) enrichment for genetic disorders within the psychiatric population relative to the estimated 1% cumulative prevalence of all single gene disorders globally. This strongly suggests that the prevalence of these, and most likely all, genetic diseases are greatly underestimated in psychiatric populations. Increasing awareness and ensuring accurate diagnosis of TGDs will open new avenues to targeted treatment for a subset of psychiatric patients.

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“…Hyperammonemic comas may reveal the disease from the neonatal period. Chronic manifestations include protein aversion, recurrent vomiting, developmental delay, and psychiatric disorders 8‐11,13 . This high clinical heterogeneity is thought to be related to inter‐individual variability of mutant X chromosome inactivation, as observed in other X‐linked metabolic disorders (Danon, Fabry, Hunter…).…”

Section: Introductionmentioning

confidence: 99%

OTC deficiency in females: Phenotype‐genotype correlation based on a 130‐family cohort

Gobin-Limballe¹,

Ottolenghi²,

Reyal³

et al. 2021

J of Inher Metab Disea

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OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X‐linked OTC gene. Phenotype‐genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and OTC gene sequencing to genetic counseling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11%), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60%, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra‐hepatic variability of OTC activity and X inactivation profile (range of variability: 30% and 20%, respectively) without correlation between both parameters for 3 of the 4 livers. Ninety disease‐causing variants were found, 27 of which were novel. Mutations were classified as “mild” or “severe,” based on male phenotypes and/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio = 1.365; P = 1.6e‐06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing.

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Adult Presentation of Ornithine Transcarbamylase Deficiency: 2 Illustrative Cases of Phenotypic Variability and Literature Review

Cited by 15 publications

References 37 publications

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency

When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population

OTC deficiency in females: Phenotype‐genotype correlation based on a 130‐family cohort

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