Diagnosis Of Urea Cycle Disorders Research Articles

Application of machine learning tools and integrated OMICS for screening and diagnosis of inborn errors of metabolism

Tandem mass spectrometry (TMS) has emerged an important screening tool for various metabolic disorders in newborns. However, there is inherent risk of false positive outcomes. Objective To establish analyte-specific cutoffs in TMS by integrating metabolomics and genomics data to avoid false positivity and false negativity and improve its clinical utility. TMS was performed on 572 healthy and 3000 referred newborns. Urine organic acid analysis identified 23 types of inborn errors in 99 referred newborns. Whole exome sequencing was performed in 30 positive cases. The impact of physiological changes such as age, gender, and birthweight on various analytes was explored in healthy newborns. Machine learning tools were used to integrate demographic data with metabolomics and genomics data to establish disease-specific cut-offs; identify primary and secondary markers; build classification and regression trees (CART) for better differential diagnosis; for pathway modeling. This integration helped in differentiating B12 deficiency from methylmalonic acidemia (MMA) and propionic acidemia (Phi coefficient=0.93); differentiating transient tyrosinemia from tyrosinemia type 1 (Phi coefficient=1.00); getting clues about the possible molecular defect in MMA to initiate appropriate intervention (Phi coefficient=1.00); to link pathogenicity scores with metabolomics profile in tyrosinemia (r2=0.92). CART model helped in establishing differential diagnosis of urea cycle disorders (Phi coefficient=1.00). Calibrated cut-offs of different analytes in TMS and machine learning-based establishment of disease-specific thresholds of these markers through integrated OMICS have helped in improved differential diagnosis with significant reduction of the false positivity and false negativity rates.

Organic Acidemias.

Organic Acidemias.

Hepatic Manifestations of Urea Cycle Disorders.

Content available: Author Interview and Audio Recording.

Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients.

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy-one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16-86). Eighty-nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD-6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life-threatening condition. Physicians working in adult care must be aware of late-onset presentations given the implications for patients and their families.

Two Novel Mutations in the Argininosuccinate Lyase Gene in Iranian Patients and Literature Review

Introduction: The argininosuccinate lyase (ASL) gene encodes argininosuccinate lyase (ASL), which is one of the six enzymes of the urea cycle that detoxifies blood ammonia. Argininosuccinate lyase deficiency impairs the function of the urea cycle and causes hyperammonemia, neurodevelopmental delay and hepatopathy. Case Presentation: Here we report two patients with argininosuccinate aciduria. They were treated with peritoneal dialysis and scavenger drugs. Molecular genetic testing showed two novel homozygous mutations, c.146T > G (p.Leu49Arg) in exon 3 and c.1144-1G > C in intron 15 of the ASL gene. Conclusions: This report intends to underline the importance of pediatricians being aware of the existence of a metabolic disease in any ill neonate. Diagnosis of urea cycle disorders is particularly important because of availability of effective treatment options.

Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting.

Disorders of the urea cycle are secondary to a defect in the system that converts ammonia into urea, resulting in accumulation of ammonia and other products. This results in encephalopathy, coma, and death if not recognized and treated rapidly. Late-onset urea cycle disorders may be precipitated by acute disease and can be difficult to recognize because patients are already ill. Diagnosis of urea cycle disorders is based on clinical suspicion and determination of blood ammonia in suspected patients with neurological symptoms in the intensive care setting. Treatment is based on the removal of ammonia by dialysis or hemofiltration, reduction of the catabolic state, abolishment of nitrogen administration, and use of pharmacological nitrogen scavenging agents.

Computational regulatory model for detoxification of ammonia from urea cycle in liver

A nondeterministic finite automaton was designed to monitor enzymatic regulation and detoxification of excess ammonia in the urea cycle and its disorders. The designed machine is used for the diagnosis of deficiency and for regulating the expression of any of the enzymes involved with acceptance and rejection states in the urea cycle. The urea cycle is the metabolism of excess nitrogen produced by the breakdown of protein and other nitrogen-containing molecules in liver. Disorder in the urea cycle may lead to the accumulation of toxic ammonia in the blood, which leads to hyperammonemia. The elevation of plasma ammonia concentration may ultimately lead to cerebral edema in infants and severe brain damage due to the toxicity of ammonia. The diagnosis of urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data. In this study, a new therapeutic approach for urea cycle disorders is developed based on a computational model. It is used to observe the normal process of the cycle through the state of acceptance. The state of rejection denotes a deficiency in the respective enzymatic activity. Subsequently, it assists in the creation of targeted treatment for brain damage and related enzymatic deficiency disorders.

Analysis of clinical features, biochemical analysis and gene mutations in one Chinese pedigree with neonatal-onset ornithine transcarbamylase deficiency

This study aimed at understanding clinical features, biochemistry and gene mutation in one Chinese pedigree which had a neonatal-onset ornithine transcarbamylase deficiency (OTCD) boy, and exploring the significance of ornithine transcarbamylase analysis in prenatal diagnosis. The clinical and biochemical data of one case were analyzed. The amino acids in blood and organic acids in urine were analyzed by mass spectrum technology. The OTC gene mutation was detected using polymerase chain reaction (PCR) and DNA direct sequencing for the case, his parents and the fetus amniocyte and her blood after birth. The age of onset was 3 days after birth, he began to have poor reaction, difficulty to feed, high blood ammonia, infection, slight metabolic acidosis, which were consistent with the clinical diagnosis of urea cycle disorders. The boy died at the age of 9 days. Citrulline of blood was detected twice, and were 0.86 µm and 1.06 µm, respectively. The orotic acid was elevated (124 µm/M Creatinine), and urine lactic acid was significantly elevated. The citrulline and orotic acid in his parents and their second baby were normal in DBS and urine. One nonsense mutation in the OTC gene was found at the exon 9 (C. 958 C > T) and his mother was the heterozygote, which caused an arginine to terminate the code at position 320 of the protein (R320X). Two other mutations were also detected at intron 9 (C.1005 + 132 InsT) and intron 5 (C.542 + 134 G > G/A). But the analysis of his father's DNA, the fetus amniocyte and her blood was normal. The mutation of C. 958 C > T in OTC gene may occur during neonatal period. This mutation would result in a very severe symptom, even die suddenly several days after birth, if it was a boy. It needs more researches to discuss whether the C.1005 + 132 InsT in intron 9 and C.542 + 134 G > G/A in intron 5 were associated with the neonatal-onset OTCD. The DNA analysis of OTC gene could be utilized for the prenatal diagnosis.

UREA CYCLE DISORDERS

Deficiency of any of the five enzymes in the urea cycle results in the accumulation of ammonia and leads to encephalopathy. Episodes of encephalopathy and associated symptoms are unpredictable and, if untreated, are lethal or produce devastating neurologic sequelae in long-term survivors. Although these disorders do not produce liver disease, the consequences of hyperammonemia resemble those seen in patients with hepatic failure or in a transient interference with the urea cycle, as seen in some forms of organic acidemias. Therefore, investigation for hyperammonemia in any infant or child with altered mental status (in the absence of obvious causes, such as trauma, infection, or poisoning) is essential for prompt diagnosis of urea cycle disorders and institution of treatment to avoid brain damage and death. This article addresses the function of the urea cycle and the diagnosis and management of urea cycle disorders.

Diagnosis of Urea Cycle Disorders

Hyperammonemia in pediatrics can be due to a number of causes (defects of urea cycle enzymes or transport of its metabolites, organic acidurias, acyl-CoA dehydrogenase or carnitine deficiency, liver bypass or nonspecific insufficiency) requiring differentiated rapid treatment for a satisfactory prognosis. The specific diagnosis cannot be established by clinical means. Thus the work-up rests on biochemical analyses. The methods used are detailed and their interpretation discussed. An algorithm for the interpretation of the data which can easily be computerized is presented. The procedure has proven practicable in 126 patients with urea cycle disorders.

Diagnosis of urea cycle disorders.

Diagnosis of urea cycle disorders.