A 36-year-old Man with Repeated Short-term Transient Hyperammonemia and Impaired Consciousness with a Confirmed Carbamoyl Phosphate Synthase 1 Gene Monoallelic Mutation.

A 36-year-old man experienced severely impaired consciousness twice after drinking because of hyperammonemia. No abnormal blood tests were found other than ammonia levels. However, magnetic resonance imaging (MRI) showed atrophy of the brain parenchyma. One the second occasion, the patient suffered severe impairment of consciousness, and because of seizures and glossoptosis, mechanical ventilation was started. Urea cycle disorders (UCDs) were assumed to be involved. Genetic testing revealed a monoallelic mutation of the carbamoyl phosphate synthase 1 (CPS1) gene. When transient hyperammonemia of unknown cause occurs repeatedly in adults, an active investigation for UCDs should be conducted.

A constitutive knockout of murine carbamoyl phosphate synthetase 1 results in death with marked hyperglutaminemia and hyperammonemia.

The enzyme carbamoyl phosphate synthetase 1 (CPS1; EC 6.3.4.16) forms carbamoyl phosphate from bicarbonate, ammonia, and adenosine triphosphate (ATP) and is activated allosterically by N-acetylglutamate. The neonatal presentation of bi-allelic mutations of CPS1 results in hyperammonemia with reduced citrulline and is reported as the most challenging nitrogen metabolism disorder to treat. As therapeutic interventions are limited, patients often develop neurological injury or die from hyperammonemia. Survivors remain vulnerable to nitrogen overload, being at risk for repetitive neurological injury. With transgenic technology, our lab developed a constitutive Cps1 mutant mouse and reports its characterization herein. Within 24 hours of birth, all Cps1 -/- mice developed hyperammonemia and expired. No CPS1 protein by Western blot or immunostaining was detected in livers nor was Cps1 mRNA present. CPS1 enzymatic activity was markedly decreased in knockout livers and reduced in Cps1+/- mice. Plasma analysis found markedly reduced citrulline and arginine and markedly increased glutamine and alanine, both intermolecular carriers of nitrogen, along with elevated ammonia, taurine, and lysine. Derangements in multiple other amino acids were also detected. While hepatic amino acids also demonstrated markedly reduced citrulline, arginine, while decreased, was not statistically significant; alanine and lysine were markedly increased while glutamine was trending towards significance. In conclusion we have determined that this constitutive neonatal mouse model of CPS1 deficiency replicates the neonatal human phenotype and demonstrates the key biochemical features of the disorder. These mice will be integral for addressing the challenges of developing new therapeutic approaches for this, at present, poorly treated disorder.

Two novel CPS1 mutations in a case of carbamoyl phosphate synthetase 1 deficiency causing hyperammonemia and leukodystrophy.

BACKGROUND: Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CPS1D can be at any age, and the clinical manifestations are variable and atypical. Genetic tests are indispensable for accurate diagnosis of CPS1D on the basis of biochemical tests. METHODS: Blood tandem mass spectrometric analysis and urea organic acidemia screening were performed on a Chinese neonatal patient with low activity, recurrent seizures, and hyperammonemia. Next-generation sequencing and Sanger sequencing were followed up for making a definite diagnosis. Bioinformatics tools were used for the conservation analysis and pathogenicity predictions of the identified mutations. RESULTS: Increased lactate in urea and decreased citrulline in blood were detected in the patient. Two novel mutations (c.173G>T, p.G58V in exon 2 and c.796G>A, p.G266R in exon 8) in CPS1 identified in the neonatal patient were found through coseparation verification. Both of the two mutations were predicted to be deleterious, and the two relevant amino acids exerted highly evolutionarily conserved. The final diagnosis of the patient was compound heterozygous CPS1D. CONCLUSION: This study described the specific clinical characteristics and the variations of physiological and biochemical indices in a Chinese neonatal patient with CPS1D, which facilitated the diagnosis and mechanism research of the disease. Two novel causative missense mutations were identified, which enriched the mutation spectrum of CPS1D in China and worldwide. Advice of prenatal diagnosis was given to the family for a new pregnancy.

Errores innatos del metabolism en un hospital pediátrico. Diferencias sustanciales entre la era pre y postcribado neonatal ampliado / Innate errors of metabolism in a pediatric hospital. Substantial differences between the extended neonatal pre- and post screening era

Introducción. Las aminoacidopatías son enfermedades metabólicas hereditarias (EMH) que sin diagnóstico ni tratamiento precoz pueden producir consecuencias graves, llegando incluso a la muerte. La introducción del programa de cribado neonatal mediante espectrometría de masas en tándem (MS/MS) pretende mejorar el pronóstico. El objetivo del estudio es comparar la evolución clínica de pacientes diagnosticados de aminoacidopatías en fase clínica frente a los resultantes del cribado neonatal. Material y métodos. Estudio descriptivo retrospectivo de pacientes diagnosticados de metabolopatías entre Enero de 2002 y Junio de 2015. El cribado ampliado de EIM mediante MS/MS se está empleando en nuestro centro desde abril de 2010. Resultados. Han sido diagnosticados en nuestra unidad en estos 13 años 245 casos de EMH. Agrupándolos por patologías: 152 trastornos del metabolismo de las proteínas, 27 trastornos del metabolismo de los carbohidratos, 33 trastornos del metabolismo lipídico, 12 enfermedades lisosomales, 2 enfermedades peroxisomales, 4 defectos congénitos de glicosilación de proteínas, 10 casos de enfermedad de Wilson y 5 de deficiencia de alfa-1 antitripsina. Del total de la serie, 19 pacientes son de origen magrebí (7,7%) y un 52 % de sexo femenino. De los casos que debutaron en cuidados intensivos pediátricos la mayoría de los pacientes requirieron apoyo agresivo, incluyendo ventilación mecánica y terapia de eliminación extracorpórea (7 diálisis peritoneal, 6 hemofiltración veno-venosa continua), así como fármacos vasoactivos. De todos los pacientes, sufrieron datos de shock 15 niños, fallo multiorgánico 6, grave insulto neurológico 8, coagulopatía 3 y fallo hepático agudo 3. Discusión. La descompensación aguda de una metabolopatía, como en otros EIM, es una emergencia metabólica que debemos diagnosticar y tratar precozmente, por su elevada morbimortalidad. La instauración del cribado ampliado ha logrado el tratamiento en fase presintomática y la identificación precoz de las descompensaciones agudas, lo cual ha contribuido al descenso de las mismas y a una clara reducción de mortalidad. Hay niños ya diagnosticados por cribado que pueden necesitar ingreso por descompensación y otros sin posibilidad de cribado que pueden requerir ingreso por debut (AU)

Introduction. Amino acid disorders are hereditary metabolic diseases (HMD) that may cause serious consequences, even death, without diagnosis or early treatment. The introduction of the neonatal screening program using tandem mass spectrometry (MS/MS) aims to improve the prognosis. This study has aimed to compare the clinical course of patients diagnosed of amino acid disorders in the clinical phase versus the results of neonatal screening. Material and methods. Retrospective descriptive study of patients diagnosed of metabolic disorders between January 2002 and June 2015. The extended screening of EIM by MS/ MS has been used in our center since April 2010. Results. A total of 245 cases of HMD has been diagnosed in our unit during these 13 years. Grouped by conditions: 152 protein metabolism disorders, 27 carbohydrate metabolism disorders, 33 lipid metabolism disorders, 12 lysosomal diseases, 2 peroxisomal diseases, 4 protein glycosylation congenital defects, 10 cases of Wilson disease and 5 alpha-1 antitrypsin deficiency. Nineteen out of the entire series were of origin Maghreb (7.7%) and 52% were women. Of the cases initiating in pediatric intensive care, most of the patients required aggressive support, including mechanical ventilation and extracorporeal elimination therapy (7 peritoneal dialysis, 6 continuous venovenous hemofiltration) and vasoactive drugs. Fifteen of all the patients suffered shock data, 6 multiorgan failure, 8 severe neurological insult, 3 coagulopathy, and 3 severe liver failure. Discussion. Acute decompensation of a metabolic disorder, as in other EIM is a metabolic emergency that should be diagnosed and treated early, due to its elevated morbidity- mortality. Initiation of extended screening has achieved treatment in the presymptomatic phase and early identification of acute decompensations, which has contributed to their decrease and to a clear reduction of mortality. There are children who have already been diagnosed by screening that may need hospitalization due to decompensations and others without possibility of screening that may require admission due to debut (AU)

Urea cycle disorders: a case report of a successful treatment with liver transplant and a literature review.

The urea cycle is the final pathway for nitrogen metabolism. Urea cycle disorders (UCDs) include a variety of genetic defects, which lead to inefficient urea synthesis. Elevated blood ammonium level is usually dominant in the clinical pattern and the primary manifestations affect the central nervous system. Herein, we report the case of a 17-year-old girl who was diagnosed with UCD at the age of 3. Despite a controlled diet, she was hospitalized several times for acute attacks with recurrent life risk. She came to our attention for a hyperammonemic episode. We proposed an orthotopic liver transplant (OLT) as a treatment; the patient and her family were in complete agreement. On February 28, 2007, she successfully received a transplant. Following the surgery, she has remained well, and she is currently leading a normal life. Usually for UCDs diet plays the primary therapeutic role, while OLT is often considered as a last resort. Our case report and the recent literature data on the quality of life and prognosis of traditionally treated patients vs OLT patients, support OLT as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment.

Encefalopatía hiperamoniémica; valoración y manejo nutricional a propósito de un caso / Hyperammonemic encephalopathy; nutritional assessment and management of a case

El déficit de Ornitintranscarbamilasa (OTC) es un trastorno del ciclo de la urea ligado al cromosoma X. Se manifiesta en el varón como hiperamoniemia severa en los primeros días de vida. En la mujer la enfermedad esmás leve. Diversas situaciones pueden provocar una descompensación con hiperamoniemia que puede ser letal o provocar daños neurológicos permanentes. Presentamos una mujer de 36 años que ingresó para cirugía y que sufrió una descompensación coincidiendo con infección de la herida quirúrgica. La hiperamoniemia provocó un deterioro neurológico con disminución del nivel de conciencia, tetraparesia y disfagia neurógena. Con tratamiento, que consistió en dieta hipoproteica, quelantes de amonio y medidas dialíticas, se consiguió controlar la hiperamoniemia y mejorar el estado neurológico. Este caso ilustra la importancia del soporte nutricional especializado de los pacientes con trastornos del ciclo de laurea en el ámbito hospitalario por darse frecuentemente situaciones que favorecen las descompensaciones (AU)

OTC deficiency is a disorder of the urea cycle X-linked. It is manifested in men as severe hyperammonemia in the first days of life. In women the disease is milder severity. Various conditions cause de compensation with hyperammonemia. It could be fatal or cause permanent neurological damage. We report a 36 years old woman admitted forsurgery, she suffered a de compensation in conjunction with surgical wound infection. Hyperammonemia caused neurological deterioration with decreased level of consciousness, tetraparesis and neurogenic dysphagia. The treatment consisting of low-protein diet, ammonium chelating drugs and dialytic measures, was effective incontrolling hyperammonaemia and improving neurological status. This case illustrates the importance of nutritional support of patients with disorders of the urea cyclein the hospital because the descompensations are more frecuent here (AU)

Neuropsychiatric manifestations in late-onset urea cycle disorder patients.

Inherited urea cycle disorders represent one of the most common groups of inborn errors of metabolism. Late-onset urea cycle disorders caused by partial enzyme deficiencies may present with unexpected clinical phenotypes. We report 9 patients followed up in our hospital presenting late-onset urea cycle disorders who initially manifested neuropsychiatric/neurodevelopmental symptoms (the most prevalent neuropsychiatric/neurodevelopmental diagnoses were mental retardation, attention-deficit hyperactivity disorder [ADHD], language disorder, and delirium). Generally, these clinical pictures did not benefit from pharmacological treatment. Conversely, dietary treatment improved the symptoms. Regarding biochemical data, 2 patients showed normal ammonium but high glutamine levels. This study highlights the fact that neuropsychiatric/neurodevelopmental findings are common among the initial symptomatology of late-onset urea cycle disorders. The authors recommend that unexplained or nonresponsive neuropsychiatric/neurodevelopmental symptoms appearing during childhood or adolescence be followed by a study of ammonia and amino acid plasmatic levels to rule out a urea cycle disorder.

Ammonia detoxification by continuous venovenous haemofiltration in an infant with urea cycle defect.

We report the case of a newborn baby with carbamoyl phosphate synthetase deficiency. He presented at 2 weeks of life, deteriorating to a state of hyperammonaemic coma and respiratory failure. Rapid detoxification was successfully achieved by continuous venovenous haemofiltration while a definitive diagnosis and treatment were determined. The ammonia clearance achieved by continuous venovenous haemofiltration was greater than 20 mL/min/m(2), which is superior to that achieved by peritoneal dialysis and arteriovenous haemofiltration in this age-group.

[A case of late-onset carbamoyl phosphate synthetase I deficiency, presenting periodic psychotic episodes coinciding with menstrual periods].

Carbamoyl phosphate synthetase I deficiency (CPSID) is a rare metabolic disorder affecting the first enzymatic step of urea cycle. We report clinical manifestations of a female case of late-onset CPSID in Japan. An 18-year-old girl was admitted to emergency room due to acute comatose state. Her parents had no apparent consanguineous history. She had suffered from intermittent psychotic episodes (excitation, aggressive behavior and insomnia) with nausea and vomiting from the age of 13, mostly coinciding with menstrual period. She had minor learning disability without major neurological deficits and convulsions. Her mental status was estimated as normal in her intermenstrual period. She had been diagnosed as having hysteria and premenstrual syndrome. Her neurological findings on admission showed deep coma and hypotonic tetraparesis. Plasma ammonia level was markedly elevated (684 micrograms/dl) without significant liver dysfunction. Blood urea nitrogen decreased to 6 mg/dl. Continuous venovenous filtration with subsequential administration of sodium benzoate and l-arginine was started to eliminate blood ammonia. Although the plasma ammonia level decreased to 300 mu/dl in next 10 hours, severe cerebral edema was observed in head computed tomography subsequently, followed by marked cerebral atrophy. Finally, her consciousness status became almost alert a month after the onset, but her mental status was severely retarded. CPSI activity of her biopsied liver markedly decreased and she was diagnosed as having CPS ID. CPSI cDNA analysis of her biopsied liver demonstrated a V1149G mutation. Genomic DNA analysis showed that she was heterozygous in V1149G mutation. The mutation allele was derived from her father. The causative factor for absence or very low level of maternal CPSI mRNA will require further analysis.