RESUMEN

La hiperamonemia constituye una emergencia médica. No existen publicaciones que hagan referencia a la disponibilidad de recursos, insumos y conocimientos necesarios para el manejo inicial de esta por parte del pediatra en nuestro país, pero, según la experiencia de los autores, los recursos necesarios no se encuentran disponibles los 365 días del año en una gran porción de nuestro territorio. Sobre la base de este estado de situación, de una revisión bibliográfica internacional sobre el tema y de la experiencia de los autores, se elaboraron una serie de recomendaciones para el manejo pediátrico inicial de esta emergencia, que tienen como objetivo poder reducir las deficiencias, permitir una sospecha clínica adecuada que lleve a un diagnóstico y tratamiento de emergencia oportunos, con utilización racional de recursos farmacológicos (algunos de ellos de alto costo), para reducir la morbimortalidad que asocia la patología.

Hyperammonemia is a medical emergency. There are no publications regarding the availability of resources, supplies, and knowledge necessary for the initial management of hyperammonemia by pediatricians in Argentina; however, according to the authors' experience, the necessary resources are not available all year round in a large portion of our territory. Based on such state of affairs, an international bibliographic review on this topic and the authors' experience, we developed a series of recommendations for the initial pediatric management of this emergency, with the objective of reducing deficiencies, allowing adequate clinical suspicion leading to a timely diagnosis and emergency management and a rational use of pharmacological resources (some of which are costly) to reduce the morbidity and mortality associated with hyperammonemia.

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RESUMEN

Hyperammonemia is a medical emergency. There are no publications regarding the availability of resources, supplies, and knowledge necessary for the initial management of hyperammonemia by pediatricians in Argentina; however, according to the authors' experience, the necessary resources are not available all year round in a large portion of our territory. Based on such state of affairs, an international bibliographic review on this topic and the authors' experience, we developed a series of ecommendations for the initial pediatric management of this emergency, with the objective of reducing deficiencies, allowing adequate clinical suspicion leading to a timely diagnosis and emergency management and a rational use of pharmacological resources (some of which are costly) to reduce the morbidity and mortality associated with hyperammonemia.

La hiperamonemia constituye una emergencia médica. No existen publicaciones que hagan referencia a la disponibilidad de recursos, insumos y conocimientos necesarios para el manejo inicial de esta por parte del pediatra en nuestro país, pero, según la experiencia de los autores, los recursos necesarios no se encuentran disponibles los 365 días del año en una gran porción de nuestro territorio. Sobre la base de este estado de situación, de una revisión bibliográfica internacional sobre el tema y de la experiencia de los autores, se elaboraron una serie de recomendaciones para el manejo pediátrico inicial de esta emergencia, que tienen como objetivo poder reducir las deficiencias, permitir una sospecha clínica adecuada que lleve a un diagnóstico y tratamiento de emergencia oportunos, con utilización racional de recursos farmacológicos (algunos de ellos de alto costo), para reducir la morbimortalidad que asocia la patología.

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Urea cycle disorders (UCD) are a group of genetic diseases caused by deficiencies in the enzymes and transporters involved in the urea cycle. The impairment of the cycle results in ammonia accumulation, leading to neurological dysfunctions and poor outcomes to affected patients. The aim of this study is to investigate and describe UCD patients' principal clinical and biochemical presentations to support professionals on urgent diagnosis and quick management, aiming better outcomes for patients. We explored medical records of 30 patients diagnosed in a referral center from Brazil to delineate UCD clinical and biochemical profile. Patients demonstrated a range of signs and symptoms, such as altered levels of consciousness, acute encephalopathy, seizures, progressive loss of appetite, vomiting, coma, and respiratory distress, in most cases combined with high levels of ammonia, which is an immediate biomarker, leading to a UCD suspicion. The most prevalent UCD detected were ornithine transcarbamylase deficiency, followed by citrullinemia type 1, hyperargininemia, carbamoyl phosphate synthase 1 deficiency, and argininosuccinic aciduria. Clinical symptoms were highly severe, being the majority developmental and neurological disabilities, with 20% of death rate. Laboratory analysis revealed high levels of ammonia (mean ± SD: 860 ± 470 µmol/L; reference value: ≤80 µmol/L), hypoglycemia, metabolic acidosis, and high excretion of orotic acid in the urine (except in carbamoyl phosphate synthetase 1 [CPS1] deficiency). We emphasize the need of urgent identification of UCD clinical and biochemical conditions, and immediate measurement of ammonia, to enable the correct diagnosis and increase the chances of patients' survival, minimizing neurological and psychomotor damage caused by hepatic encephalopathy.

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Inborn errors of intermediary metabolism (IEiM) are a group of monogenic disorders that affect a metabolic pathway of proteins, carbohidrates, or lipids; when not treated timely, IEiM are associated with high morbidity and mortality. To date, nutritional therapy is the cornerstone of treatment for patients with IEiM, which aims to prevent the accumulation of toxic metabolites by restricting the substrates involved in the affected pathway. Nutritional management in infants includes a metabolic formula free of the nutrients involved in IEiM and breastmilk or infant formula. Because of its amino acid profile, the content of essential fatty acids, and protection against disease, breast milk is an excellent food for patients with IEiM. This literature review on breastfeeding in some IEiM aims to serve as a guide for health care personnel involved in the medical care of these patients. Breastfeeding can be successfully carried out in patients with IEiM as long as there is a close and continuous follow-up, preferably in specialized centers. The nutrition professional and the pediatrician should individualize the recommendations to provide on-demand breastfeeding in conjunction with metabolic formula or quantified breastfeeding to achieve a good clinical evolution in this group of patients.

Los errores innatos del metabolismo intermediario (EIMi) son un grupo de enfermedades monogénicas que afectan alguna vía del metabolismo de las proteínas, los hidratos de carbono o los lípidos; cuando no son tratados a tiempo, se asocian con una elevada morbimortalidad. A la fecha, la piedra angular del tratamiento de los EIMi ha sido la terapia nutricional, cuyo propósito es evitar la acumulación de metabolitos tóxicos al restringir los sustratos que están involucrados en la vía afectada. El manejo nutricional en lactantes incluye una fórmula metabólica sin los nutrimentos involucrados en el EIMi más el aporte de alimentación al seno materno o fórmula infantil. Por el perfil de aminoácidos, la proporción de ácidos grasos esenciales y la protección contra enfermedades, la leche materna resulta un alimento ideal para los pacientes con EIMi. El objetivo de esta revisión de la literatura sobre la lactancia materna en algunos EIMi es servir de guía para el personal de salud involucrado en la atención médica de estos pacientes. La lactancia materna puede ser llevada a cabo de forma exitosa en pacientes con EIMi siempre que exista un seguimiento estrecho y continuo, de preferencia en centros especializados. El profesional de la nutrición y el pediatra deben individualizar las recomendaciones para proporcionar una lactancia a libre demanda en conjunto con una fórmula metabólica o una lactancia materna cuantificada, y con ello lograr una adecuada evolución en estos pacientes.

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Resumen Los errores innatos del metabolismo intermediario (EIMi) son un grupo de enfermedades monogénicas que afectan alguna vía del metabolismo de las proteínas, los hidratos de carbono o los lípidos; cuando no son tratados a tiempo, se asocian con una elevada morbimortalidad. A la fecha, la piedra angular del tratamiento de los EIMi ha sido la terapia nutricional, cuyo propósito es evitar la acumulación de metabolitos tóxicos al restringir los sustratos que están involucrados en la vía afectada. El manejo nutricional en lactantes incluye una fórmula metabólica sin los nutrimentos involucrados en el EIMi más el aporte de alimentación al seno materno o fórmula infantil. Por el perfil de aminoácidos, la proporción de ácidos grasos esenciales y la protección contra enfermedades, la leche materna resulta un alimento ideal para los pacientes con EIMi. El objetivo de esta revisión de la literatura sobre la lactancia materna en algunos EIMi es servir de guía para el personal de salud involucrado en la atención médica de estos pacientes. La lactancia materna puede ser llevada a cabo de forma exitosa en pacientes con EIMi siempre que exista un seguimiento estrecho y continuo, de preferencia en centros especializados. El profesional de la nutrición y el pediatra deben individualizar las recomendaciones para proporcionar una lactancia a libre demanda en conjunto con una fórmula metabólica o una lactancia materna cuantificada, y con ello lograr una adecuada evolución en estos pacientes.

Abstract Inborn errors of intermediary metabolism (IEiM) are a group of monogenic disorders that affect a metabolic pathway of proteins, carbohidrates, or lipids; when not treated timely, IEiM are associated with high morbidity and mortality. To date, nutritional therapy is the cornerstone of treatment for patients with IEiM, which aims to prevent the accumulation of toxic metabolites by restricting the substrates involved in the affected pathway. Nutritional management in infants includes a metabolic formula free of the nutrients involved in IEiM and breastmilk or infant formula. Because of its amino acid profile, the content of essential fatty acids, and protection against disease, breast milk is an excellent food for patients with IEiM. This literature review on breastfeeding in some IEiM aims to serve as a guide for health care personnel involved in the medical care of these patients. Breastfeeding can be successfully carried out in patients with IEiM as long as there is a close and continuous follow-up, preferably in specialized centers. The nutrition professional and the pediatrician should individualize the recommendations to provide on-demand breastfeeding in conjunction with metabolic formula or quantified breastfeeding to achieve a good clinical evolution in this group of patients.

RESUMEN

Ammonia is a neurotoxic compound which is detoxified through liver enzymes from urea cycle. Several inherited or acquired conditions can elevate ammonia concentrations in blood, causing severe damage to the central nervous system due to the toxic effects exerted by ammonia on the astrocytes. Therefore, hyperammonemic patients present potentially life-threatening neuropsychiatric symptoms, whose severity is related with the hyperammonemia magnitude and duration, as well as the brain maturation stage. Inherited metabolic diseases caused by enzymatic defects that compromise directly or indirectly the urea cycle activity are the main cause of hyperammonemia in the neonatal period. These diseases are mainly represented by the congenital defects of urea cycle, classical organic acidurias, and the defects of mitochondrial fatty acids oxidation, with hyperammonemia being more severe and frequent in the first two groups mentioned. An effective and rapid treatment of hyperammonemia is crucial to prevent irreversible neurological damage and it depends on the understanding of the pathophysiology of the diseases, as well as of the available therapeutic approaches. In this review, the mechanisms underlying the hyperammonemia and neurological dysfunction in urea cycle disorders, organic acidurias, and fatty acids oxidation defects, as well as the therapeutic strategies for the ammonia control will be discussed.

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Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle. Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

Los defectos del ciclo de la urea son enfermedades metabólicas hereditarias que se producen por defecto en una de las enzimas encargadas de la desintoxicación del amonio, lo que genera su acumulación en el organismo. Las manifestaciones clínicas pueden presentarse en la etapa neonatal, con morbimortalidad elevada, o de forma tardía. La heterogeneidad de los síntomas y la falta de sospecha clínica en neonatos conducen a un diagnóstico erróneo y se puede confundir con sepsis neonatal o hemorragias cerebrales. El aumento de amonio plasmático en el examen bioquímico orienta su diagnóstico hacia un defecto del ciclo de la urea. La aciduria argininosuccínica es el tercer defecto más frecuente del ciclo de la urea y es causada por deficiencia de la enzima argininosuccínico liasa. Se presenta el informe de un caso de inicio neonatal. Los objetivos son enfatizar en su sospecha diagnóstica y proponer herramientas diagnósticas tempranas, como su incorporación a la pesquisa metabólica neonatal.

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Los defectos del ciclo de la urea son enfermedades metabólicas hereditarias que se producen por defecto en una de las enzimas encargadas de la desintoxicación del amonio, lo que genera su acumulación en el organismo. Las manifestaciones clínicas pueden presentarse en la etapa neonatal, con morbimortalidad elevada, o de forma tardía. La heterogeneidad de los síntomas y la falta de sospecha clínica en neonatos conducen a un diagnóstico erróneo y se puede confundir con sepsis neonatal o hemorragias cerebrales. El aumento de amonio plasmático en el examen bioquímico orienta su diagnóstico hacia un defecto del ciclo de la urea.La aciduria argininosuccínica es el tercer defecto más frecuente del ciclo de la urea y es causada por deficiencia de la enzima argininosuccínico liasa. Se presenta el informe de un caso de inicio neonatal. Los objetivos son enfatizar en su sospecha diagnóstica y proponer herramientas diagnósticas tempranas, como su incorporación a la pesquisa metabólica neonatal.

Urea cycle defects are inborn errors of metabolism produced by a defect in one of the enzymes responsible for the detoxification of ammonia, which generates its accumulation in the body. The clinical manifestations can present early, with high morbidity and mortality, or late onset. The heterogeneity of the symptoms and the lack of clinical suspicion in neonates leads to a wrong diagnosis, which can be confused with neonatal sepsis or cerebral hemorrhages. The increase in plasma ammonia in the biochemical examination orients his diagnosis towards a defect of the urea cycle.Argininosuccinic aciduria is the third most frequent defect of the urea cycle, and is caused by a argininosuccinate lyase deficiency. A neonatal onset case report is presented. The objective is to emphasize its diagnostic suspicion, and to propose early diagnostic tools such as its incorporation into the neonatal metabolic screening.

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Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency.The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG).NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia

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RESUMEN

Urea cycle disorders (UCD), are genetically inherited diseases that may have a poor outcome due to to profound hyperammonemia. We report the case of a baby girl diagnosed as N-acetylglutamate synthase (NAGS) deficiency. The patient was evaluated due to diminished sucking and hypotonicity. Physical examination showed hepatomegaly. Complete blood count, biochemical values and blood gas analyses were normal, acute phase reactants were negative. Further laboratory analyses showed no ketones in blood and highly elevated ammonia. Metabolic tests were inconclusive. Emergency treatment was initiated immediately and she was discharged on the 15th day of admission. NAGS deficiency was confirmed by DNA-analysis. She is now without any dietary restriction or other medication, except N-carbamylglutamate (NCG). NAGS deficiency is the only UCD which can be specifically and effectively treated by NCG. Early recognition of disease will lead to early treatment that may prohibit devastating effects of hyperammonemia.

Los trastornos del ciclo de la urea (TCU) son enfermedades hereditarias con un posible desenlace desfavorable por hiperamoniemia grave. Se informa de una bebé con deficiencia de N-acetilglutamato sintasa (NAGS), quien tenía succión débil e hipotonicidad. Al examinarla, se observó hepatomegalia. El hemograma, los análisis y la gasometría eran normales, y las proteínas de la fase aguda, negativas. En los análisis, no se observaron cetonas en sangre, pero sí concentraciones elevadas de amoníaco. Las pruebas metabólicas no fueron concluyentes. Se inició el tratamiento de emergencia inmediatamente y recibió el alta el día 15 después del ingreso. Se confirmó deficiencia de NAGS mediante análisis de ADN. La paciente no tiene restricciones alimentarias ni toma medicamentos, excepto N-carbamil glutamato (NCG). La deficiencia de NAGS es el único TCU que puede tratarse específica y eficazmente con NCG. La detección temprana permite iniciar un tratamiento temprano y evitar los efectos devastadores de la hiperamoniemia.

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Abstract X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. Hemizygous males with complete deficiency manifest neonatal acute hyperammonemia, while those with partial deficiency have a late presentation. The symptomatology of heterozygotes depends on the inactivation pattern of X chromosome. Hyperammonemic episodes can cause neurological damage and are potentially fatal. Here, we match clinical, biochemical, and molecular findings with bioinformatics analyses to report genotype-phenotype correlations in 14 Argentine patients with OTCD from 11 unrelated families: 4 hemizygotes with neonatal onset (complete OTC gene deletion, 533C > T, c.540+1G > A, c.697delG); 4 hemizygotes with late onset (c.216+1G > A, c.386G > A, c.622G > A, c.829C > T); and 6 symptomatic heterozygotes (complete OTC gene deletion, c.533C > T, c.452T > G, c.540+1G > A, dupE1-9/delE10). Three of these mutations were previously unreported: c.540+1G > A, c.697delG, and dup1-9/del10. Our data highlight the relevance of combining molecular and bioinformatics analyses for accurate diagnosis and outcome prediction in suspected patients with OTCD and the importance of carrier testing for effective genetic counseling.

RESUMEN

La citrulinemia tipo I es un desorden autosómico recesivo causado por la mutación del gen ASS1, que expresa argininosuccinato sintetasa, enzima limitante del ciclo de la urea. Las variantes clásicas están asociadas con la forma neonatal/infantil, que llevan a hiperamoniemia y a la muerte si el tratamiento no es instaurado. Los síntomas iniciales de los trastornos del ciclo de la urea incluyen deterioro neurológico con leve o moderado daño hepático. Reportamos un caso de falla hepática recurrente en un lactante con diagnóstico de citrulinemia tipo I sin compromiso neurológico grave, que fue derivado a nuestro centro para trasplante hepático. La falla hepática aguda puede ser causada por una gran variedad de desórdenes, dentro de los que se incluyen errores congénitos del metabolismo. El tratamiento adecuado de los trastornos del ciclo de la urea y, en particular, la citrulinemia I puede evitar la necesidad de un trasplante.

Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors ofmetabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant.

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Citrullinemia type I is an autosomal recessive disorder caused by mutation of the gene expressing ASS1 argininosuccinate synthetase, limiting enzyme of the urea cycle. The classic variants are associated with neonatal/infantile forms that cause hyperammonemia leading to death if treatment is not established. Initial symptoms of disorders of the urea cycle include neurological impairment with mild or moderate liver damage. We report a case of recurrent liver failure in an infant diagnosed with type I citrullinemia without severe neurological involvement that was referred to our center for liver transplantation. Acute liver failure can be caused by a wide range of disorders in which inborn errors of metabolism are included. Appropriate treatment of disorders of the urea cycle and in particular citrullinemia I can avoid the need for a transplant.

La citrulinemia tipo I es un desorden autosómico recesivo causado por la mutación del gen ASS1, que expresa argininosuccinato sintetasa, enzima limitante del ciclo de la urea. Las variantes clásicas están asociadas con la forma neonatal/ infantil, que llevan a hiperamoniemia y a la muerte si el tratamiento no es instaurado. Los síntomas iniciales de los trastornos del ciclo de la urea incluyen deterioro neurológico con leve o moderado daño hepático. Reportamos un caso de falla hepática recurrente en un lactante con diagnóstico de citrulinemia tipo I sin compromiso neurológico grave, que fue derivado a nuestro centro para trasplante hepático. La falla hepática aguda puede ser causada por una gran variedad de desórdenes, dentro de los que se incluyen errores congénitos del metabolismo. El tratamiento adecuado de los trastornos del ciclo de la urea y, en particular, la citrulinemia I puede evitar la necesidad de un trasplante.

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OBJECTIVES: Biallelic mutations in the ARG1 gene result in an uncommon autosomal recessive inborn defect of the urea cycle known as hyperargininemia (OMIM #207800). ARG1 splicing mutations are not reported often, and they are probably related to a more severe phenotype than missense mutations. In this article, we describe the results of molecular studies in a young hyperargininemia patient carrying a novel splicing mutation in ARG1. DESIGN AND METHODS: Molecular analyses included PCR amplification and direct nucleotide sequencing of the ARG1 gene. RT-PCR analysis was performed to investigate the effect of the mutation in mRNA splicing and in the expression of ARG1 isoforms. RESULTS: Mutational analysis identified a novel homozygous ARG1 IVS4-1G>C point mutation in the patient's DNA. Blood leukocyte mRNA was analyzed to demonstrate the splicing defect caused by this mutation. Sequencing of ARG1 RT-PCR products allowed the characterization of a mutated transcript retaining 51-bp from intron 4. In addition, two new, alternatively spliced ARG1 transcripts lacking either exon 4 or exons 4 and 5 were identified in mRNA from the patient and from controls. CONCLUSIONS: Our results expand the mutational spectrum in hyperargininemia patients and indicate that the novel splicing mutation results in an aberrant transcript retaining intronic sequences. Two novel alternatively spliced ARG1 transcripts were also recognized.

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Los trastornos del ciclo de la urea suponen hasta el 60% de las hiperamoniernias graves neonatales. La base de los trastornos de este ciclo deriva en el déficit de una de sus enzimas. El déficit de la enzima ornitina transcarbamilasa es el más frecuente. Su pronóstico dependerá del grado de deficiencia enzimOtica, la edad, la precocidad del diagnóstico e inicio del tratamiento. Presentamos el caso de un adolescente que, a partir de un cuadro de parálisis facial periférica tratado con prednisona, presentó agravamiento de su estado general y falleció a los pocos días. Las cifras elevadas de amoniaco en sangre hicieron sospechar tardíamente de una alteración congénita del ciclo de la urea, que fue confirmada por su estudio genético post mortem. Se estudiaron los familiares y se asesoró a los afectos y portadores. Reflexionamos sobre la importancia de los programas de cribado neonatal y la posibilidad de aplicarlos en la detección de los errores congénitos del metabolismo.(AU)

Disorders of urea cycle account for up to 60% of severe neonatal hyperamoniemias. The base of this cycle disorders results in a deficit of its enzymes. Deficiency of the enzyme ornithine transcarbamylase is the most frequently detected. The prognosis depends on the degree of enzyme deficiency, age, early diagnosis and initiation of treatment. We report the case of a teenager who was treated with prednisone because of a peripheral facial palsy. He showed a progressive worsening and died a few days later. The high levels of ammonia made suspect a congenital disorder of urea cycle. The postmortem genetic study confirmed it. We studied the family and advised carriers. We reflect about the importance of the neonatal screening programs and their applicability for detection of inborn errors of metabolism.(AU)

RESUMEN

Los trastornos del ciclo de la urea suponen hasta el 60% de las hiperamoniernias graves neonatales. La base de los trastornos de este ciclo deriva en el déficit de una de sus enzimas. El déficit de la enzima ornitina transcarbamilasa es el más frecuente. Su pronóstico dependerá del grado de deficiencia enzimàtica, la edad, la precocidad del diagnóstico e inicio del tratamiento. Presentamos el caso de un adolescente que, a partir de un cuadro de parálisis facial periférica tratado con prednisona, presentó agravamiento de su estado general y falleció a los pocos días. Las cifras elevadas de amoniaco en sangre hicieron sospechar tardíamente de una alteración congénita del ciclo de la urea, que fue confirmada por su estudio genético post mortem. Se estudiaron los familiares y se asesoró a los afectos y portadores. Reflexionamos sobre la importancia de los programas de cribado neonatal y la posibilidad de aplicarlos en la detección de los errores congénitos del metabolismo.

Disorders of urea cycle account for up to 60% of severe neonatal hyperamoniemias. The base of this cycle disorders results in a deficit of its enzymes. Deficiency of the enzyme ornithine transcarbamylase is the most frequently detected. The prognosis depends on the degree of enzyme deficiency, age, early diagnosis and initiation of treatment. We report the case of a teenager who was treated with prednisone because of a peripheral facial palsy. He showed a progressive worsening and died a few days later. The high levels of ammonia made suspect a congenital disorder of urea cycle. The postmortem genetic study confirmed it. We studied the family and advised carriers. We reflect about the importance of the neonatal screening programs and their applicability for detection of inborn errors of metabolism.

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OBJECTIVE: To prospectively characterize acute hyperammonemic episodes in patients with urea cycle disorders (UCDs) in terms of precipitating factors, treatments, and use of medical resources. STUDY DESIGN: This was a prospective, longitudinal observational study of hyperammonemic episodes in patients with UCD enrolled in the National Institutes of Health-sponsored Urea Cycle Disorders Consortium Longitudinal Study. An acute hyperammonemic event was defined as plasma ammonia level >100 µmol/L. Physician-reported data regarding the precipitating event and laboratory and clinical variables were recorded in a central database. RESULTS: In our study population, 128 patients with UCD experienced a total of 413 hyperammonemia events. Most patients experienced between 1 and 3 (65%) or between 4 and 6 (23%) hyperammonemia events since study inception, averaging fewer than 1 event/year. The most common identifiable precipitant was infection (33%), 24% of which were upper/lower respiratory tract infections. Indicators of increased morbidity were seen with infection, including increased hospitalization rates (P = .02), longer hospital stays (+2.0 days; P = .003), and increased use of intravenous ammonia scavengers (+45%-52%; P = .003-.03). CONCLUSION: Infection is the most common precipitant of acute hyperammonemia in patients with UCD and is associated with indicators of increased morbidity (ie, hospitalization rate, length of stay, and use of intravenous ammonia scavengers). These findings suggest that the catabolic and immune effects of infection may be a target for clinical intervention in inborn errors of metabolism.

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