Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders.

OBJECTIVE: In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes. METHODS: We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model. RESULTS: Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes. INTERPRETATION: The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA. CLINICAL TRIAL REGISTRATION: The UCDC database is recorded at the US National Library of Medicine (https://clinicaltrials.gov).

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

BACKGROUND: This 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. METHODS: A retrospective analysis was performed on the clinical manifestations, laboratory testing, and genetic test findings of ten children with OTCD admitted between August 2015 and October 2021 at Quanzhou Maternity and Children's Hospital of Fujian Province in China. RESULTS: Five boys presented with early-onset symptoms, including poor appetite, drowsiness, groaning, seizures, and liver failure. In contrast, five patients (one boy and four girls) had late-onset gastrointestinal symptoms as the primary clinical manifestation, all presenting with hepatic impairment, and four with hepatic failure.Nine distinct variants of the OTC gene were identified, including two novel mutations: c.1033del(p.Y345Tfs*50) and c.167T > A(p.M56K). Of seven patients who died, five had early-onset disease despite active treatment. Three patients survived, and two of them underwent liver transplantation. CONCLUSIONS: The clinical manifestations of OTCD lack specificity. However, elevated blood ammonia levels serve as a crucial diagnostic clue for OTCD. Genetic testing aids in more accurate diagnosis and prognosis assessment by clinicians. In addition, we identified two novel pathogenic variants and expand the mutational spectrum of the gene OTC, which may contribute to a better understanding of the clinical and genetic characteristics of OTCD patients.

Variant analysis and PGT-M of OTC gene in a Chinese family with ornithine carbamoyltransferase deficiency.

BACKGROUND: Ornithine carbamoyltransferase deficiency (OTCD) is a kind of X-linked metabolic disease caused by a deficiency in ornithine transcarbamylase leading to urea cycle disorders. The main reason is that the OTC gene variants lead to the loss or decrease of OTC enzyme function, which hinders the ammonia conversion to urea, resulting in hyperammonemia and severe neurological dysfunction. Here, we studied one Chinese family of three generations who consecutively gave birth to two babies with OTCD. This study aims to explore the pathogenicity of two missense variants in the OTC gene and investigate the application of preimplantation genetic testing for monogenic (PGT-M) for a family troubled by Ornithine carbamoyltransferase deficiency (OTCD). METHODS: The retrospective method was used to classify the pathogenicity of two missense variants in the OTC gene in a family tortured by OTCD. Sanger sequencing was used to validate the variants in the OTC gene, and then the pathogenicity of variants was confirmed through family analysis and bioinformatics software. We used PGT-M to target the OTC gene and select a suitable embryo for transplantation. Prenatal diagnosis was recommended to confirm previous results using Sanger sequencing and karyotyping at an appropriate gestational stage. Tandem mass spectrometry (MS-MS) and gas chromatography-mass spectrometry (GC-MS) were used to detect fetal metabolism after birth. The number of the study cohort is ChiCTR2100053616. RESULTS: Two missense variants, c.959G > C (p.Arg320Pro) and c.634G > A (p.Gly212Arg), were validated in the OTC gene in this family. According to the ACMG genetic variation classification criteria, the missense variant c.959G > C can be considered as "pathogenic", and the missense variant c.634G > A can be regarded as "likely benign." PGT-M identified a female embryo carrying the heterozygous variant c.959G > C (p.Arg320Pro), which was selected for transplantation. Prenatal diagnosis revealed the same variant in the fetus, and continued pregnancy was recommended. A female baby was born, and her blood amino acid testing and urine organic acid testing were regular. Follow-up was conducted after six months and indicated the girl was healthy. CONCLUSION: Our research first validated the segregation of both c.959G > C and c.634G > A variants in the OTC gene in a Chinese OTCD family. Then, we classified variant c.959G > C as "pathogenic" and variant c.634G > A as "likely benign", providing corresponding theoretical support for genetic counseling and fertility guidance in this family. PGT-M and prenatal diagnosis were recommended to help the couple receive a female baby successfully with a six-month follow-up.

Corticosteroid-induced hyperammonaemic encephalopathy in a woman with late-onset ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is a rare, X linked disorder that can manifest in late adulthood in heterozygous females as severe hyperammonaemia following environmental stressors. We present a case of hyperammonaemic encephalopathy that was triggered by glucocorticoid administration in an adult woman with heterozygous OTCD with clinical response to haemodialysis, ammonia scavengers and a high-calorie, low-protein diet.

[Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate]. / è‹¯ä¸é ¸ç”˜æ²¹é ¯æ²»ç–—å„¿ç«¥é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡1例.

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

Sensory ataxic polyneuropathy unmasking late-onset urea cycle defect.

A 63-year-old man with type 2 diabetes mellitus, alcohol consumption in moderation, and three episodes of hepatic encephalopathy presented with symmetrical lower limb distal weakness, sensory ataxia, thickened palpable nerves, mood disturbances for seven years, and a family history of schizophreniform disorders. Nerve conduction studies showed demyelinating sensorimotor polyradiculoneuropathy. CSF analysis showed mild albumino-cytological dissociation. MRI brain and lumbosacral plexus showed thickened fifth cranial nerves and lumbosacral roots. He was treated with steroids for a provisional diagnosis of chronic inflammatory polyneuropathy and became encephalopathic. EEG showed triphasic waves. Serum ammonia was 201 micrograms/dL. Further evaluation suggested ornithine transcarbamylase (OTC) deficiency. The patient underwent hemodialysis with a low protein diet, rifaximin, and sodium benzoate, with subsequent recovery.

Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. METHODS: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. RESULTS: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 µM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. CONCLUSIONS: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

[Genetic analysis and prenatal diagnosis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency and MECP2 duplication syndrome].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with co-morbid Ornithine carbamoyl transferase deficiency (OTCD) and MECP2 duplication syndrome. METHODS: A proband who was admitted to the Neonatal Intensive Care Unit of Gansu Provincial Maternal and Child Health Care Hospital on December 19, 2017 was selected as the study subject. High-throughput sequencing and multiplex ligation-dependent probe amplification (MLPA) were carried out for her pedigree, and short tandem repeat-based linkage analysis and chromosome copy number variation sequencing (CNV-seq) were used for the prenatal diagnosis. RESULTS: The proband, a 3-day-old female, was found to harbor heterozygous deletion of exons 7-9 of the OTC gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PVS1+PM2_Supporting+PP4). The proband was diagnosed with OTCD , which was in keeping with her acute encephalopathy and metabolic abnormalities (manifesting as hyperammonemia, decreased blood citrulline, and increased urine orotic acid). Prenatal diagnosis was carried out for the subsequent pregnancy. The fetus did not harbor the exons 7-9 deletion of the OTC gene, but was found to carry a duplication in Xq28 region (which encompassed the whole region of MECP2 duplication syndrome) and was positive for the SRY sequence. The same duplication was also found in the proband and her mother. Considering the possible existence of X-chromosome inactivation, the proband was diagnosed with two X-linked recessive disorders including OTCD and MECP2 duplication syndrome, and the fetus was determined as a male affected with the MECP2 duplication syndrome. CONCLUSION: Discoveries of the pathogenic variants underlying the OTCD and MECP2 duplication syndrome have enabled clinical intervention, treatment, genetic counseling and prenatal diagnosis for this pedigree.

Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease.

BACKGROUND: Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked urea cycle disorder characterized by acute hyperammonemic episodes. Hemizygous males are usually affected by a severe/fatal neonatal-onset form or, less frequently, by a late-onset form with milder disease course, depending on the residual enzymatic activity. Hyperammonemia can occur any time during life and patients could remain non- or mis-diagnosed due to unspecific symptoms. In heterozygous females, clinical presentation varies based on the extent of X chromosome inactivation. Maternal transmission in X-linked disease is the rule, but in late-onset OTCD, due to the milder phenotype of affected males, paternal transmission to the females is possible. So far, father-to-daughter transmission of OTCD has been reported only in 4 Japanese families. RESULTS: We identified in 2 Caucasian families, paternal transmission of late-onset OTCD with severe/fatal outcome in affected males and 1 heterozygous female. Furthermore, we have reassessed the pedigrees of other published reports in 7 additional families with evidence of father-to-daughter inheritance of OTCD, identifying and listing the family members for which this transmission occurred. CONCLUSIONS: Our study highlights how the diagnosis and pedigree analysis of late-onset OTCD may represent a real challenge for clinicians. Therefore, the occurrence of paternal transmission in OTCD should not be underestimated, due to the relevant implications for disease inheritance and risk of recurrence.

Two pregnancies of an ornithine carbamoyltransferase deficiency disease carrier and review of the literature.

Introduction: Background: the underlying cause of the deficiency of ornithine carbamoyltransferase (OTCD) is a gene mutation on the X chromosome. In females, the phenotype is highly variable, ranging from asymptomatic to neurologic compromise secondary to hyperammonemia and it can be prompted by numerous triggers, including pregnancy. Objective: the objective of this article is to report a case of two pregnancies of an OTCD-carrier, and to review the literature describing OTCD and pregnancy, parturition and postpartum. Methods: an extensive search in PubMed in December 2021 was conducted using different search terms. After screening all abstracts, 23 papers that corresponded to our inclusion criteria were identified. Results: the article focuses on the management of OTCD during pregnancy, parturition, and the postpartum period in terms of clinical presentation, ammonia levels and treatment. Conclusions: females with OTCD can certainly plan a pregnancy, but they need a careful management during delivery and particularly during the immediate postpartum period. If possible, a multidisciplinary team of physicians, dietitians, obstetrician-gynecologist, neonatologists, pharmacists, etc. with expertise in this field should participate in the care of women with OTCD and their children during this period and in their adult life.

Introducción: Antecedentes: la causa subyacente de la deficiencia de ornitina transcarbamilasa (OTC) es una mutación genética en el cromosoma X. En las mujeres, el fenotipo es muy variable, desde asintomático hasta presentar un compromiso neurológico secundario a hiperamonemia, y puede ser provocado por numerosos factores desencadenantes, incluido el embarazo. Objetivo: el objetivo de este artículo es reportar un caso de dos embarazos de una portadora de OTC, y revisar la literatura que describe OTC y embarazo, parto y posparto. Métodos: se realizó una búsqueda exhaustiva en PubMed en diciembre de 2021 utilizando diferentes términos de búsqueda. Después de examinar todos los resúmenes, identificamos 23 artículos que correspondían a nuestros criterios de inclusión. Resultados: el artículo se centra en el manejo de la OTC durante el embarazo, el parto y el posparto en términos de presentación clínica, niveles de amonio y tratamiento. Conclusiones: las mujeres con OTC pueden planificar un embarazo, pero necesitan un manejo cuidadoso durante el parto, y particularmente, durante el posparto inmediato. Si es posible, un equipo multidisciplinar de médicos, dietistas, ginecólogos-obstetras, neonatólogos, farmacéuticos, etc., con experiencia en este campo, debe participar en el cuidado de las mujeres con OTC y sus hijos durante este periodo y en su vida adulta.

Gene therapy for urea cycle defects: An update from historical perspectives to future prospects.

Urea cycle defects (UCDs) are severe inherited metabolic diseases with high unmet needs which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life-long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of UCDs, improve quality of life and long-term outcomes: adenoviral vectors, adeno-associated viral vectors, gene editing, genome integration and non-viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.

Adult presentation of ornithine transcarbamylase deficiency: a possible cause of hyperammonemia after high-dose chemotherapy and stem cell transplantation.

Hyperammonemia is a rare and often fatal complication following the conditioning therapy in autologous and allogeneic stem cell transplant recipients. It is characterized by anorexia, vomiting, lethargy and coma without any other apparent cause. The diagnosis is often delayed because symptoms can be subtle and ammonia is usually not included among the routine analyzes. Previous reports have not identified the molecular mechanisms behind hyperammonemia in stem cell transplant recipients. Urea cycle disorders (UCDs) are inborn errors of metabolism leading to hyperammonemia that usually presents in early childhood, whereas first presentation in adults is less common. Here we describe an adult woman with hyperammonemia following autologous stem cell transplantation for multiple myeloma. No apparent cause of hyperammonemia was identified, including portosystemic shunting, liver dysfunction or recent hyperammonemia-inducing chemotherapy. Hyperammonemia, normal blood glucose as well as anion gap and a previous history of two male newborns that died early after birth, prompted biochemical and genetic investigations for a UCD. A heterozygous variant in the X-linked gene encoding ornithine transcarbamylase (OTC) was identified and was regarded as a cause of UCD. The patient improved after treatment with nitrogen scavengers and high caloric intake according to a UCD protocol. This case report suggests that UCD should be considered as a possible cause of hyperammonemia following stem cell transplantation.

[Preliminary study of glyceryl phenylbutyrate therapy for Ornithine transcarbamylase deficiency and a literature review].

OBJECTIVE: To evaluate the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy for patients with Ornithine transcarbamylase deficiency (OTCD). METHODS: Two children with OTCD were selected as the study subjects, and their clinical manifestations, blood ammonia, liver enzymes, growth and development information following the treatment with GPB were retrospectively analyzed. A literature review was also carried out by searching the PubMed database for studies on the GPB treatment for urea cycle disorders. RESULTS: With the GPB treatment, the blood ammonia and liver enzyme level in both patients have decreased to the normal range within 3 months. Motor development in child 2 has improved. No adverse reaction was noted, except for transient palmar greasy smell and loss of appetite in child 1. Analysis of the literature showed that patients had lower ammonia exposure, lower annual incidence of hyperammonemic crisis, more actual protein intake and fewer adverse events during GPB treatment. CONCLUSION: GPB is safe and effective for the treatment of OTCD.

Anesthesia management protocol for liver transplantation as treatment for ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase deficiency is an X-linked genetic disorder that induces accumulation of ammonia in the liver and is the most common urea cycle disorder. The clinical manifestation of ornithine transcarbamylase deficiency is hyperammonemia that causes irreversible neurological damage. Liver transplantation is a curative therapy for ornithine transcarbamylase deficiency. The aim of this study is to suggest, from our previous experience, an anesthesia management protocol of liver transplantation for ornithine transcarbamylase deficiency, particularly focused on liver transplantation for cases with uncontrolled hyperammonemia. METHOD: We retrospectively reviewed our anesthesia-related experience in all cases of liver transplantation for ornithine transcarbamylase deficiency in our center. RESULTS: Twenty-nine liver transplantation cases for ornithine transcarbamylase deficiency were found between November 2005 and March 2021 in our center. Of these, 25 cases were stable through the perioperative period. However, 2 cases with carrier donor graft had hyperammonemia after liver transplantation. Another two cases had uncontrolled hyperammonemia before liver transplantation, even with continuous hemodialysis. They underwent life-saving liver transplantation. Their metabolic status stabilized after the anhepatic phase. CONCLUSION: Liver transplantation for cases with uncontrolled hyperammonemia can be performed with proper management. Second, liver transplantation with carrier donors should be avoided because of the risk of postoperative recurrence.

Recapitulation of Skewed X-Inactivation in Female Ornithine Transcarbamylase-Deficient Primary Human Hepatocytes in the FRG Mouse: A Novel System for Developing Epigenetic Therapies.

Realization of the immense therapeutic potential of epigenetic editing requires development of clinically predictive model systems that faithfully recapitulate relevant aspects of the target disease pathophysiology. In female patients with ornithine transcarbamylase (OTC) deficiency, an X-linked condition, skewed inactivation of the X chromosome carrying the wild-type OTC allele is associated with increased disease severity. The majority of affected female patients can be managed medically, but a proportion require liver transplantation. With rapid development of epigenetic editing technology, reactivation of silenced wild-type OTC alleles is becoming an increasingly plausible therapeutic approach. Toward this end, privileged access to explanted diseased livers from two affected female infants provided the opportunity to explore whether engraftment and expansion of dissociated patient-derived hepatocytes in the FRG mouse might produce a relevant model for evaluation of epigenetic interventions. Hepatocytes from both infants were successfully used to generate chimeric mouse-human livers, in which clusters of primary human hepatocytes were either OTC positive or negative by immunohistochemistry (IHC), consistent with clonal expansion from individual hepatocytes in which the mutant or wild-type OTC allele was inactivated, respectively. Enumeration of the proportion of OTC-positive or -negative human hepatocyte clusters was consistent with dramatic skewing in one infant and minimal to modest skewing in the other. Importantly, IHC and fluorescence-activated cell sorting analysis of intact and dissociated liver samples from both infants showed qualitatively similar patterns, confirming that the chimeric mouse-human liver model recapitulated the native state in each infant. Also of importance was the induction of a treatable metabolic phenotype, orotic aciduria, in mice, which correlated with the presence of clonally expanded OTC-negative primary human hepatocytes. We are currently using this unique model to explore CRISPR-dCas9-based epigenetic targeting strategies in combination with efficient adeno-associated virus (AAV) gene delivery to reactivate the silenced functional OTC gene on the inactive X chromosome.

The functional impact of 1,570 individual amino acid substitutions in human OTC.

Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases.

Acute onset of ornithine transcarbamylase deficiency after total anomalous pulmonary venous connection repair to a 2-day-old neonate.

Ornithine transcarbamylase deficiency is an X-linked disorder which results in the accumulation of ammonia causing irritability and vomiting. Acute hyperammonemia requires rapid and intensive intervention. However, as those clinical features are non-specific and commonly seen in peri-operative situation, ornithine transcarbamylase deficiency could be difficult to diagnose prior to and post-emergency cardiac surgery. We report a 2-day-old male neonate who was diagnosed with ornithine transcarbamylase deficiency presenting hyperammonemia and severe heart failure after total anomalous pulmonary venous connection repair.

[Neonate-onset ornithine transcarbamylase deficiency]. / æ–°ç”Ÿå„¿é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡.

The male neonate in this case study was admitted to the hospital at 15 hours of age due to respiratory distress for 15 hours and poor response for 3 hours after resuscitation from asphyxia. The neonate was highly unresponsive, with central respiratory failure and seizures. Serum ammonia was elevated (>1 000 µmol/L). Blood tandem mass spectrometry revealed a significant decrease in citrulline. Rapid familial whole genome sequencing revealed OTC gene mutations inherited from the mother. Continuous hemodialysis filtration and other treatments were given. Neurological assessment was performed by cranial magnetic resonance imaging and electroencephalogram. The neonate was diagnosed with ornithine transcarbamylase deficiency combined with brain injury. He died at 6 days of age after withdrawing care. This article focuses on the differential diagnosis of neonatal hyperammonemia and introduces the multidisciplinary management of inborn error of metabolism.

Delayed recognition of autism spectrum disorder and attention-deficit/hyperactivity disorder in a girl with ornithine transcarbamylase deficiency: A case report.

RATIONALE: Ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder, is a rare congenital metabolic error that leads to hyperammonemia. Psychiatric symptoms of hyperammonemia are nonspecific and can cause autism spectrum disorder (ASD)-like symptoms and attention-deficit/hyperactivity disorder (ADHD)-like symptoms. Some studies report that OTC deficiency is often initially diagnosed as ASD or ADHD. However, there are no reports of OTC deficiency comorbid with ASD and ADHD. PATIENT CONCERNS: The patient is 17-year-old girl diagnosed with OTC deficiency at 3 years of age. She had behavioral problems since childhood, including depressed mood, irritability, and impulsive behavior; however, they were considered OTC-mediated nonspecific psychiatric symptoms. Therefore, the patient had not been appropriately assessed for ASD and ADHD. She presented with depressed mood and self-harm at 17 years of age. DIAGNOSES: We diagnosed her with ASD and ADHD based on her medical history and semistructured interviews. INTERVENTIONS: We focused her ASD and ADHD traits and discussed strategies with her for better adaptive living. OUTCOMES: Our interventions resulted in her better social adjustment. LESSONS: Physicians should consider the possibility of comorbid ASD and ADHD in individuals with OTC, facilitating appropriate and intervention for better outcomes.