Urea cycle disorders are characterized by hyperammonemia under catabolic conditions or under protein stress.
There are many types of Harnstoffzyklus- and related disorders (see table) and many other amino acid and organic acid metabolism disorders. See also approach in a patient with suspected congenital metabolic disorder
Urea cycle disorders are characterized by hyperammonemia under catabolic conditions or under protein stress. There are many types of Harnstoffzyklus- and related disorders (see table) and many other amino acid and organic acid metabolism disorders. See also procedure in a patient suspected of having a congenital metabolic disorder, The primary urea cycle disorders (UCDs) include a lack of carbamoyl Phosphatsynthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (Citrullinemia), argininosuccinate lyase (Argininosuccinurie) and arginase (argininaemia ) on. In addition, a lack of N-acetylglutamate synthetase (NAGS) is mentioned. Depending proximal to the enzyme deficiency, the more pronounced is the hyperammonemia. The following are the severity of the disease is classified by enzyme deficiency defects: lack of NAGS, CPS, OTC, Citrullinemia, Argininosuccinurie and Argininemia. Inheritance for all disorders of the urea change occurs autosomal recessive trait. An exception is the OTC deficiency, which is inherited X-linked. Urea cycle disorders and diseases related disease (OMIM number) Defective proteins or enzymes defective gene or genes (chromosomal location) Comments ornithine (OTC) deficiency (311250) OTC OTC (Xp21.1) * Biochemical Profile: Increased ornithine and glutamine, reduced citrulline and arginine significantly increased orotate in urine Clinical characteristics: in men, repeated vomiting, irritability, lethargy, hyperammonemisches coma, cerebral edema, spasticity, mental retardation, seizures, death in female carriers variable manifestations of wax stumsverzögerung, small stature, protein-aversion and postpartum hyperammonemia to symptoms that are so severe as in men with this deficiency treatment: hemodialysis for acute hyperammonämischer crisis, sodium benzoate, sodium phenylacetate, sodium phenylbutyrate, protein-calorie diet, supplementation with essential amino acids and arginine, citrulline; Experimental Experiments with gene therapy, liver transplantation (curative) NAcetylglutamat synthetase deficiency (237310) N-Acetylglutamatsynthetase NAGS (17q21.31) Biochemistry profile: Similar to OTC deficiency, except for the normal to low Orotatspiegel in urine Clinical features: Similar to OTC deficiency, except that the carriers are asymptomatic treatment: Similar to OTC deficiency, but also sodium Carbamylglutamat- supplementation Carbamoylphosphatsynthetasemangel (CPS) deficiency (237300) Carbamoylphosphatsynthetasemangel CPS1 (2q35) * Biochemical profile: Similar to O TC deficiency, except for the normal to low Orotatspiegel in urine Clinical features: Similar to OTC deficiency, except that the carriers are asymptomatic treatment: sodium benzoate and arginine Citrullinemia type I (215,700) Argininosuccinic synthetase ASA (9q34) * Biochemical profile: Increased citrulline and glutamine, Citrullinurie, orotische aciduria in blood Clinical features: episodic hyperammonemia, stunted growth, protein aversion, lethargy, vomiting, coma, seizures, cerebral edema, developmental delay treatment: as with OTC deficiency except that here a citrulline supplementation is not recommended liver transplantation Citrullinemia type II (603814, 603471) citrine SCL25A13 (7q21.3) * Biochemical Profile: Increased citrulline, methionine, galactose and bilirubin in the blood Clinical features: In the beginning in the neonatal period, disappears cholestasis after 3 months At the beginning of adulthood: enuresis, delayed menarche , sleep reversal, vomiting, delusions, hallucinations, psychosis, coma treatment: liver transplantation; otherwise no clear treatment Argininosuccinic aciduria (207900) argininosuccinate lyase ASL (7CEN-q11.2) * biochemical profile: Elevated citrulline and glutamine in the blood, increased argininosuccinate in urine Clinical features: Episodic hyperammonemia, hepatic fibrosis, elevated liver enzymes, hepatomegaly, protein-aversion, vomiting, seizures, mental retardation, ataxia, lethargy, coma, trichorrhexis nodosa Treatment: arginine substitution Argininemie (107830) arginase I ARG1 (6q23) * Biochemical profile: Increased arginine in the blood, Diaminoazidurie (Argininurie, Lysinurie, cystinuria, Or nithinurie) Orotsäureazidurie, Pyrimidinurie Clinical features: growth and development disorders, loss of appetite, vomiting, seizures, spasticity, irritability, hyperactivity, protein intolerance, hyperammonemia treatment: Protein poor diet, benzoate, phenylacetate Lysinurische Protein Intolerance (dibasic aminoaciduria II; 222700) dibasic amino acid transporter SLC7A7 (14q11.2) * Biochemical Profile: Increased lysine, ornithine and arginine in urine Clinical features: protein intolerance, episodic hyperammonemia, growth and developmental delays, diarrhea, vomiting, hepatomegaly, cirrhosis, leukopenia, osteopenia, bone fragility, coma treatment: protein diet, citrulline hyperornithinemia, hyperammonemia and Homocitrullinämie (238970) Mitochondrial Ornithintranslocase SLC25A15 (13q14) * biochemical profile: increased ornithine in the blood, Homocitrullinämie Clinical features: mental retardation, progressive spastic paraparesis, episodic confusion, hyperammonemia, dyspraxia, Kr ämpfe, vomiting, retinopathy, abnormal nerve and evoked potentials, leukodystrophy Treatment: supplementation with lysine, ornithine or citrulline Ornithinämie (258870) Ornithinaminotransferase OAT (10q26) * biochemical profile: increased ornithine in blood and urine, lysine and arginine in the urine; Low lysine, glutamic acid and glutamine in blood Clinical features: myopia, night blindness, blindness, progressive loss of peripheral vision, progressive atrophy of the choroid and retina, light proximal hypotonia, myopathy treatment: pyridoxine, arginine diet, lysine and the ?-Aminoisobutyrate, to increase a renal loss of ornithine; Proline or creatine supplementation hyperinsulinism-hyperammonemia syndrome (606,762) hyperactivity glutamate GLUD1 (10q23.3) * Biochemical Profile: Increased ?-ketoglutarate in urine Clinical features: seizures, recurrent hypoglycemia, hyperinsulinemia, asymptomatic hyperammonemia treatment: * avoid hypoglycaemia the gene was identified, and the molecular basis has been elucidated. OMIM = Online Mendelian Inheritance in Man (see OMIM database). Symptoms and signs The clinical manifestations range from mild (eg. As failure to thrive, mental retardation, episodic hyperammonemia) to severe symptoms (eg. As modified mental state, coma, death). The manifestations in women with OTC deficiency range from failure to thrive, growth retardation, psychiatric diseases and episodic (especially post partum) hyperammonaemia to a similar in affected men phenotype (eg recurrent vomiting. Irritability, lethargy; hyperammonämisches coma, cerebral edema , spasticity, mental retardation, seizures, death). Diagnostic serum amino acid profiles The diagnosis of disorders in the urea cycle is created due to the amino acid profiles. For example, increased Ornithinspiegel mean a lack of CPS or OTC, while increased Citrullinspiegel mean a Citrullinemia. In order to distinguish a CPS deficiency of a OTC deficiency, the orotic acid is determined, since in a OTC deficiency, the accumulation of carbamoyl result, it is converted to an alternative pathway in orotic acid. Therapy Low protein diet arginine or citrulline supplementation sodium phenylbutyrate Possible liver transplant Treatment of urea cycle disorders is in a restriction of oral intake of protein, but which ensures that sufficient amino acids for growth, development and normal protein turnover are available. A mainstay of treatment is arginine. Characterized provided sufficiently intermediates of the urea cycle, in order to facilitate the introduction of more nitrogen in the intermediates of the urea cycle, which can be easily eliminated all. Furthermore arginine is a positive regulator of Acetylglutamatsynthese. Recent studies suggest that oral citrulline is more effective in patients with OTC deficiency as arginine. The additional treatment is carried out with sodium benzoate, phenylacetate or phenylbutyrate, by the conjugation with glycine (sodium benzoate) and glutamine (phenylbutyrate and phenylacetate) is a so-called “nitrogen sink”. Despite these therapeutic advances many UCDs remain difficult to treat, and a liver transplant is ultimately required for many patients. The right time for a liver transplant is critical. Optimally, the infant should grow up to an age in which the transplant less risky (> 1 year), but it is also important not wait until an episode intercurrent hyperammonemia occur (which is often associated with disease) and resulting in irreparable damage to the CNS.