Late-onset Ornithine Transcarbamylase Research Articles

Long-term safety and efficacy of DTX301 in adults with late-onset ornithine transcarbamylase (OTC) deficiency: A Phase 1/2 trial

Long-term safety and efficacy of DTX301 in adults with late-onset ornithine transcarbamylase (OTC) deficiency: A Phase 1/2 trial

Design of a Phase 3 study of AAV-mediated gene transfer of ornithine transcarbamylase (OTC) in patients with late-onset OTC deficiency

Design of a Phase 3 study of AAV-mediated gene transfer of ornithine transcarbamylase (OTC) in patients with late-onset OTC deficiency

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

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

A case with late-onset Ornithine Transcarbamylase Deficiency as a possible cause of osteoporosis

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Benefits of tailored disease management in improving tremor, white matter hyperintensities, and liver enzymes in a child with heterozygous X-linked ornithine transcarbamylase deficiency

We report the case of a 19-month-old girl with late-onset ornithine transcarbamylase (OTC) deficiency initially referred to gastroenterology for intermittent vomiting lasting a year and abnormal liver enzymes (AST 730 U/L [reference range 26–55 U/L]; ALT 1213 U/L [reference range 11–30 U/L]) without hepatomegaly. While the patient was hospitalized for liver biopsy, intermittent tremors of the upper extremities with varying severity were noted. The patient was presumed to have hyperammonemia secondary to acute liver failure and was discharged after 5 days; follow-up monitoring led to readmission 7 days later. A brain MRI showed nonspecific bilateral pericallosal and bifrontal white matter FLAIR hyperintensities. These findings raised suspicion for a metabolic disease and prompted a genetics consultation. After inconclusive biochemical testing and worsening clinical status, rapid whole genome sequencing results were obtained identifying a novel, de novo, likely pathogenic, variant c.608C > T (p.Ser203Phe) in the OTC gene. The patient was promptly started on an oral nitrogen scavenger, citrulline supplementation, and protein restriction. Ammonia and glutamine levels normalized within 1 month of treatment and have stayed within the goal ranges with continued tailoring of treatment. Her parents noted resolution of vomiting and improved mood stability. Liver enzymes normalized after 2 months of treatment. The tremor, identified as asterixis, improved and a repeat brain MRI 3 months after the initial imaging showed near-complete resolution of previous white matter hyperintensities.

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Ornithine transcarbamylase deficiency: A diagnostic odyssey

Whole exome sequencing make a definitive diagnosis of a Vietnamese patient with a late onset urea cycle disorder

Our report describes a female presenting with vomiting, fever, coma and right hemiplegia at 26 months of age. Biochemical tests revealed hyperammonemia, hyperlactatemia, elevated glutamine level, elevated transaminase and disorder of prothrombin time. She was priory diagnosed with urea cycle disorders (UCDs). UCDs are caused by mutations in eight genes that regulate the synthesis of enzymes and cofactors involved in urea metabolism. Singleton whole exome sequencing was applied to screen causative variants in these genes in the patient at 6 years of age. The result showed one heterozygous stop loss mutation c.1065A>G in the OTC gene as a potential disease causing in the patient. The mutation c.1065A>G leads to alternation of stop codon to tryptophan, resulting in elongation of fourteen amino acids in ornithine transcarbamylase (OTC) protein (p.Ter355TrpextTer14). Sanger sequencing in the family revealed the mutation c.1065A>G was not present in healthy parents and brother. Therefore, this mutation is considered as a de novo mutation in the patient. The mutation c.1065A>G was conferred to pathogenic according to the standards and guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology with 1 strong (PS2), 3 moderate (PM2, PM4 and PM5) and 1 support criteria (PP2). Although OTC deficiency is an X-linked recessive inheritance, approximately 15% of females carrying heterozygous variants showed the late onset OTC deficiency. Therefore, in combination of clinical presentations, laboratory findings and molecular genetic analyses, we made a definitive diagnosis of the patient with late onset OTC deficiency, a disorder of UCDs.

Retrospective evaluations revealed pre-symptomatic citrulline concentrations measured by newborn screening were significantly low in late-onset ornithine transcarbamylase deficiency patients

IntroductionOrnithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Late-onset OTCD manifests after the neonatal period; therefore, if pre-symptomatic diagnosis and treatment are performed, it can improve the prognosis by preventing hyperammonemia. However, pre-symptomatic diagnosis is unreliable as the specific screening marker of OTCD has not been established yet. This retrospective study aimed to evaluate the pre-symptomatic blood citrulline levels in patients with late-onset OTCD. MethodsPatients with late-onset OTCD who were born after the newborn screening based on tandem mass spectrometry (MS/MS-NBS) was started and were referred to Hyogo College of Medicine Hospital between 2014 and 2018 were included. Pre-symptomatic blood citrulline levels measured by MS/MS-NBS were retrospectively evaluated. ResultsFour patients were included in this study. The pre-symptomatic blood citrulline levels were 2.02, 4.50, 4.97, and 3.75 µmol/l, respectively. Compared with the citrulline levels in all newborns in Hyogo prefecture, these values were significantly low. ConclusionsThese results suggest the possibility that hypocitrullinemia detected by the MS/MS-NBS can be used as a screening marker for some patients with late-onset OTCD. Further retrospective evaluation of pre-symptomatic citrulline levels in patients with late-onset OTCD, as well as prospective monitoring of hypocitrullinemia on the MS/MS-NBS should be conducted.

A mutation-independent CRISPR-Cas9-mediated gene targeting approach to treat a murine model of ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder associated with high mortality. Although a promising treatment for late-onset OTC deficiency, adeno-associated virus (AAV) neonatal gene therapy would only provide short-term therapeutic effects as the non-integrated genome gets lost during hepatocyte proliferation. CRISPR-Cas9-mediated homology-directed repair can correct a G-to-A mutation in 10% of OTC alleles in the livers of newborn OTC spfash mice. However, an editing vector able to correct one mutation would not be applicable for patients carrying different OTC mutations, plus expression would not be fast enough to treat a hyperammonemia crisis. Here, we describe a dual-AAV vector system that accomplishes rapid short-term expression from a non-integrated minigene and long-term expression from the site-specific integration of this minigene without any selective growth advantage for OTC-positive cells in newborns. This CRISPR-Cas9 gene-targeting approach may be applicable to all patients with OTC deficiency, irrespective of mutation and/or clinical state.

Undiagnosed Late-onset Ornithine transcarbamylase (OTC) Deficiency Presenting With Psychiatric Symptoms (P4.6-067)

Undiagnosed Late-onset Ornithine transcarbamylase (OTC) Deficiency Presenting With Psychiatric Symptoms (P4.6-067)

Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency.

Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5cm2. X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X-inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver.

Late-onset ornithine transcarbamylase deficiency associated with hyperammonemia

The urea cycle converts ammonia and produces urea. One form of urea cycle abnormality is ornithine transcarbamylase (OTC) deficiency. This hereditary disorder is associated with hyperammonemia. OTC deficiency commonly appears during neonatal and early childhood life and is rare in adults. We report a 69-year-old man who presented at the local hospital with 3-day loss of appetite, early morning vomiting, and state of confusion. Blood ammonia was 293μg/dl. At 2-3h after admission, the patient went into a deep coma. He was intubated and admitted immediately to the intensive care unit. Treatment, including sustained hemodialysis, failed to lower blood ammonia level. His grandchild died of OTC deficiency at 6year of age. Computed tomography, magnetic resonance imaging and esophagogastroduodenoscopy showed no abnormalities. On admission to our hospital, he complained of vomiting and disturbance of consciousness, hyperammonemia, and normal anion gap. Genetic analysis showed A208T mutation. The deceased grandchild with OTC deficiency also had the same mutation. Long-term hemodialysis coupled with administration of L-arginine and lactulose resulted in improvement of blood ammonia level. Early diagnosis and treatment of adult-onset OTC deficiency are essential to avoid serious complications.

Hyperammonemia: What Urea-lly Need to Know: Case Report of Severe Noncirrhotic Hyperammonemic Encephalopathy and Review of the Literature.

Purpose. A 66-year-old man who presented with coma was found to have isolated severe hyperammonemia and diagnosed with a late-onset urea-cycle disorder. He was treated successfully and had full recovery. Methods. We report a novel case of noncirrhotic hyperammonemia and review the literature on this topic. Selected literature for review included English-language articles concerning hyperammonemia using the search terms “hyperammonemic encephalopathy”, “non-cirrhotic encephalopathy”, “hepatic encephalopathy”, “urea-cycle disorders”, “ornithine transcarbamylase (OTC) deficiency”, and “fulminant hepatic failure”. Results. A unique case of isolated hyperammonemia diagnosed as late-onset OTC deficiency is presented. Existing evidence about hyperammonemia is organized to address pathophysiology, clinical presentation, diagnosis, and treatment. The case report is discussed in context of the reviewed literature. Conclusion. Late-onset OTC deficiency presenting with severe hyperammonemic encephalopathy and extensive imaging correlate can be fully reversible if recognized promptly and treated aggressively.

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype.

The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.

Late onset ornithine transcarbamylase deficiency in a 61 year old male

Ornithine transcarbamylase (OTC) deficiency is the most frequent innate urea cycle disorder (UCD) and is the only one with an X-linked inheritance. OTC deficiency leads to hyperammonemia and subsequent elevated cerebral pressure and brain damage. Most often, UCDs are described as acute onset hyperammonemia in the newborn; however, rare, it can present in adulthood. We present the case of a 61-year old Caucasian man with unexplained coma. He developed an acute hyperammonemic encephalopathy leading to mental problems, seizures and coma. Despite the classical treatment with hemodialysis and the administration of a combination of sodium phenylacetate and sodium benzoate, the patient unfortunately died of cerebral herniation. Postmortem, genetic analysis confirmed the presence of a c.662G > A (p.Ala208Thr) pathogenic mutation in the OTC gene in a hemizygous state. Synopsis: The association of neuropsychiatric symptoms or encephalopathy of unknown origin should lead, even in the absence of liver disease and even in late adulthood, to a high level of suspicion of hyperammonemia secondary to UCDs to ensure a timely diagnosis and life-saving treatment. UCD, an inborn error of metabolism, can present itself at an advanced age; attenuated phenotypes probably remain under-ascertained.

Severe hyperammonemia in late-onset ornithine transcarbamylase deficiency triggered by steroid administration.

Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked disorder of urea synthesis leading to hyperammonemia. Several late-onset cases have been reported. Undiagnosed and untreated patients are at the risk of death or suffering from irreversible sequelae. We describe a 56-year-old patient who presented with acute encephalopathy after steroid treatment. Hyperammonemia due to OTCD was diagnosed and a mutation was found. This allowed us to diagnose two other family members with unexplained encephalopathy who are now asymptomatic on a low-protein diet. OTCD should be considered in any patient with hyperammonemic encephalopathy and immediate treatment should be given to avoid a fatal outcome. We emphasize the need to examine other family members if the diagnosis is confirmed, in order to prevent further life-threatening episodes of encephalopathy or neonatal coma of newborn.

Late-Onset Ornithine Transcarbamylase Deficiency: Treatment and Outcome of Hyperammonemic Crisis

Hyperammonemic crises in ornithine transcarbamylase deficiency (OTC) can be associated with devastating cerebral edema resulting in severe long-term neurologic impairment and death. We present an 8-year-old boy who had late-onset OTC deficiency in which early and aggressive management of hyperammonemia and associated cerebral edema, including therapeutic hypothermia and barbiturate-induced coma, resulted in favorable neurologic outcome. Our patient presented with vomiting and altered mental status, and was found to have a significantly elevated serum ammonia level of 1561 μmol/L. Hyperammonemia was managed with hemodialysis, 10% sodium phenylacetate, 10% sodium benzoate, L-arginine, intravenous 10% dextrose, intralipids, and protein restriction. He developed significant cerebral edema with intracranial pressures >20 mm Hg, requiring treatment with 3% saline and mannitol. Despite this treatment our patient continued to have elevated intracranial pressures, which were treated aggressively with non-conventional modalities including therapeutic hypothermia, barbiturate-induced coma, and external ventricular drainage. This therapy resulted in stabilization of hyperammonemia and resolution of cerebral edema. Molecular testing later revealed a hemizygous mutation within the OTC gene. Neuropsychological testing 1 year after discharge showed normal intelligence with no visual-motor deficits, minor deficits in working memory and processing speed, and slightly below average processing speed and executive functioning.

Histopathological findings in livers of patients with urea cycle disorders

BackgroundUrea cycle disorders (UCD) are caused by genetic defects in enzymes that constitute the hepatic ammonia detoxification pathway. Patients may present with variable clinical manifestations and with hyperammonaemia. Liver abnormalities have been associated with UCD, but only a few reports on the histopathological findings in the liver of UCD patients have been published. MethodsWe conducted a retrospective review of liver biopsies, ex-planted livers and livers at post-mortem of patients with UCD. A single pathologist reviewed all specimens. ResultsThere were 18 liver samples from 13 patients with confirmed UCD: four ex-planted livers from patients with Ornithine Transcarbamylase (OTC) (n=3) and Carbamoyl Phosphate Synthetase 1 (CPS 1) (n=1) deficiencies, eight post-mortem samples from patients with CPS 1 (n=2), OTC (n=4), Argininosuccinate Synthetase (ASS) (n=1) and Argininosuccinate Lyase (ASL) (n=1) deficiencies, and six liver biopsies, three of which came from one patient with ASL deficiency. The other three liver biopsies were from patients who subsequently received liver transplantation. Histopathological findings in samples from neonates were non-specific. Samples from three late onset OTC deficient and one ASL deficient patients showed thin fibrous septa with portal to portal bridging fibrosis and focal marked enlargement and pallor of the hepatocytes due to accumulation of glycogen particles, resembling glycogenosis and resulting in a prominent nodular pattern. Serial liver biopsies in four UCD patients with interval between samples ranging from 1year 2months to 17years showed progression in fibrosis in one OTC and one ASL deficient patients. Moderate fatty changes to no progression in liver disease were noted in the two patients (OTC=1 and CPS=1). A variety of non-specific features such as fatty change, mild inflammation, cholestasis and focal necrosis were seen in the other UCD patients. ConclusionsHistopathological changes in livers from neonates with UCD are non-specific. Older patients with UCD seem to show variable hepatic fibrosis compared to those who died early. Some of these patients also show focal and superficial resemblance to a glycogen storage disorder and cirrhosis. However, progression of these changes seems to be slow. To clarify the long term consequence of these changes, more extensive periods of follow up in a larger population series is needed.

Coagulopathy in Patients With Late-Onset Ornithine Transcarbamylase Deficiency in Remission State: A Previously Unrecognized Complication

The late-onset type of ornithine transcarbamylase (OTC) deficiency is almost asymptomatic before an abrupt onset of metabolic crisis in adolescence. This study focused on coagulopathy in OTC deficiency. We collected laboratory data regarding coagulation from OTC-deficient patients in Kyushu University Hospital in Japan or from cases reported from previous articles. Five patients with late-onset OTC deficiency, admitted to Kyushu University Hospital at the first metabolic attack or who presented at the outpatient clinic in the hospital, were analyzed, and 3 additional cases of OTC deficiency with coagulopathy in previous articles were included. As a result, the blood ammonia levels in these patients were remarkably high at the time of the metabolic attack, and prothrombin times were far below the normal level. The prothrombin times remained significantly abnormal on remission, despite almost normal levels of blood ammonia, serum aspartate aminotransferase, and alanine aminotransferase. Coagulation abnormality is a previously unidentified complication of OTC deficiency in remission state. This information will aid in the identification of patients with OTC deficiency before a lethal metabolic crisis occurs during adolescence.

Recurrent somnolence in a 17-month-old infant: Late-onset ornithine transcarbamylase (OTC) deficiency due to the novel hemizygous mutation c.535C > T (p.Leu179Phe)

Herein, we describe a case of a now 28-month-old boy who presented at the age of 17 months with four episodes of recurrent vomiting and somnolence during a period of four months with increasing severity. A comprehensive clinical and metabolic evaluation revealed normal blood pH and blood glucose, normal cerebral computed tomography and electroencephalogram but an elevated plasma ammonia concentration, which raised the suspicion of a urea cycle disorder. The combination of elevated urinary orotic acid and plasma glutamine with normal citrulline suggested the diagnosis of ornithine transcarbamylase (OTC) deficiency, which was confirmed by molecular genetic testing revealing the novel hemizygous mutation c.535C > T (p.Leu179Phe) of the OTC gene. After restitution of anabolism by administration of parenteral glucose, substitution of citrulline and detoxification of ammonia with sodium benzoate, the patient recovered rapidly and is in a stable metabolic and neurological state since then. This case underlines that the diagnosis of a urea cycle defect should be considered in the differential diagnosis of recurrent idiopathic vomiting in combination with unexplained neurological symptoms also beyond the neonatal period due to the possibility of mild or atypical late-onset presentation (e.g. OTC deficiency in hemizygous males).