RESUMEN
ABSTRACT: Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.
Asunto(s)
Encefalopatías , Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , Adolescente , Humanos , Niño , Hiperamonemia/complicaciones , Hiperamonemia/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Encefalopatías/complicaciones , Convulsiones , Servicio de Urgencia en HospitalRESUMEN
PURPOSE OF REVIEW: Urea cycle disorders (UCDs) cause elevations in ammonia which, when severe, cause irreversible neurologic injury. Most patients with UCDs are diagnosed as neonates, though mild UCDs can present later - even into adulthood - during windows of high physiologic stress, like critical illness. It is crucial for clinicians to understand when to screen for UCDs and appreciate how to manage these disorders in order to prevent devastating neurologic injury or death. RECENT FINDINGS: Hyperammonemia, particularly if severe, causes time- and concentration-dependent neurologic injury. Mild UCDs presenting in adulthood are increasingly recognized, so broader screening in adults is recommended. For patients with UCDs, a comprehensive, multitiered approach to management is needed to prevent progression and irreversible injury. Earlier exogenous clearance is increasingly recognized as an important complement to other therapies. SUMMARY: UCDs alter the core pathway for ammonia metabolism. Screening for mild UCDs in adults with unexplained neurologic symptoms can direct care and prevent deterioration. Management of UCDs emphasizes decreasing ongoing ammonia production, avoiding catabolism, and supporting endogenous and exogenous ammonia clearance. Core neuroprotective and supportive critical care supplements this focused therapy.
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Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , Adulto , Humanos , Amoníaco , Enfermedad Crítica , Hiperamonemia/etiología , Estudios Longitudinales , Trastornos Innatos del Ciclo de la Urea/complicaciones , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
Urea cycle defects (UCDs) are severe inherited metabolic diseases with high unmet needs which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life-long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of UCDs, improve quality of life and long-term outcomes: adenoviral vectors, adeno-associated viral vectors, gene editing, genome integration and non-viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.
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Trasplante de Hígado , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa , Trastornos Innatos del Ciclo de la Urea , Humanos , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/genética , Calidad de Vida , Urea/metabolismo , Donadores Vivos , Terapia Genética , Trastornos Innatos del Ciclo de la Urea/genética , Trastornos Innatos del Ciclo de la Urea/terapia , Trastornos Innatos del Ciclo de la Urea/complicacionesRESUMEN
Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.
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Citrulinemia , Trasplante de Hígado , Trastornos Innatos del Ciclo de la Urea , Humanos , Niño , Citrulinemia/tratamiento farmacológico , Trastornos Innatos del Ciclo de la Urea/terapia , Arginina , Benzoato de Sodio/uso terapéuticoRESUMEN
The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long-term follow-up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease-immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long-term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.
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Enfermedades Metabólicas , Trastornos Innatos del Ciclo de la Urea , Humanos , Trastornos Innatos del Ciclo de la Urea/terapia , Enfermedades Raras , Sistema de Registros , FenotipoRESUMEN
Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.
Asunto(s)
Humanos , Niño , Citrulinemia/tratamiento farmacológico , Trastornos Innatos del Ciclo de la Urea/terapia , Arginina , Benzoato de Sodio/uso terapéutico , Trasplante de HígadoRESUMEN
Urea cycle disorders (UCDs) are a group of rare inborn errors of metabolism caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. Current guidelines suggest that early diagnosis and treatment of mild UCDs may improve survival and prevent decompensation and neurocognitive impairment. Nevertheless, clinical studies are very difficult to carry out in this setting due to the rarity of the diseases, and high-level evidence is scant and insufficient to draw conclusions and provide clinical guidelines. With the early introduction of newborn screening, the Italian healthcare organization fostered an advancement in expertise in metabolic disease management and screening programs, by allocating resources, and favoring the expansion of newborn screening. A group of experts operating in Italian centers decided to share their experience and provide advice for the management of mild UCDs in clinical practice. A consensus was reached by the Estimate-Talk-Estimate (ETE) method. Five items were identified, and statements for each item were agreed. Briefly, the panel advised completing the diagnosis by expanded newborn screening (ENS) with biochemical and genetic confirmation and by following up with the patient during the first year of life, with a routine laboratory and metabolic profile as well as with clinical observation. Early initiation of therapy is advised and should be followed by therapy adjustment once the diagnostic profile is completed. The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment, clinical and neurocognitive evaluation, and laboratory and instrumental parameter monitoring.
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Testimonio de Experto , Trastornos Innatos del Ciclo de la Urea , Recién Nacido , Humanos , Tamizaje Neonatal , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapia , Cognición , ConsensoRESUMEN
Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 µmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 µmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients.
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Hiperamonemia/prevención & control , Trastornos del Neurodesarrollo/etiología , Trastornos Innatos del Ciclo de la Urea/fisiopatología , Trastornos Innatos del Ciclo de la Urea/terapia , Adolescente , Adulto , Amoníaco/sangre , Niño , Preescolar , Femenino , Humanos , Hiperamonemia/etiología , Japón/epidemiología , Trasplante de Hígado , Masculino , Diálisis Renal , Tasa de Supervivencia , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/epidemiología , Adulto JovenRESUMEN
The urea cycle protects the central nervous system from ammonia toxicity by converting ammonia to urea. N-acetylglutamate synthase (NAGS) catalyzes formation of N-acetylglutamate, an essential allosteric activator of carbamylphosphate synthetase 1. Enzymatic activity of mammalian NAGS doubles in the presence of L-arginine, but the physiological significance of NAGS activation by L-arginine has been unknown. The NAGS knockout (Nags-/-) mouse is an animal model of inducible hyperammonemia, which develops hyperammonemia without N-carbamylglutamate and L-citrulline supplementation (NCG + Cit). We used adeno associated virus (AAV) based gene transfer to correct NAGS deficiency in the Nags-/- mice, established the dose of the vector needed to rescue Nags-/- mice from hyperammonemia and measured expression levels of Nags mRNA and NAGS protein in the livers of rescued animals. This methodology was used to investigate the effect of L-arginine on ureagenesis in vivo by treating Nags-/- mice with AAV vectors encoding either wild-type or E354A mutant mouse NAGS (mNAGS), which is not activated by L-arginine. The Nags-/- mice expressing E354A mNAGS were viable but had elevated plasma ammonia concentration despite similar levels of the E354A and wild-type mNAGS proteins. The corresponding mutation in human NAGS (NP_694551.1:p.E360D) that abolishes binding and activation by L-arginine was identified in a patient with NAGS deficiency. Our results show that NAGS deficiency can be rescued by gene therapy, and suggest that L-arginine binding to the NAGS enzyme is essential for normal ureagenesis.
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N-Acetiltransferasa de Aminoácidos/genética , Técnicas de Transferencia de Gen , Hiperamonemia/genética , Trastornos Innatos del Ciclo de la Urea/genética , N-Acetiltransferasa de Aminoácidos/metabolismo , Animales , Arginina/metabolismo , Arginina/farmacología , Citrulina/metabolismo , Citrulina/farmacología , Dependovirus/genética , Modelos Animales de Enfermedad , Glutamatos/metabolismo , Glutamatos/farmacología , Humanos , Hiperamonemia/metabolismo , Hiperamonemia/patología , Hiperamonemia/terapia , Ratones , Ratones Noqueados , Proteínas Mutantes/genética , Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/patología , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
BACKGROUND: This study provides a general overview on liver and/or kidney transplantation in patients with an amino and organic acid-related disorder (AOA) with the aim to investigate patient characteristics and global outcome in Europe. This study was an initiative of the E-IMD and the AOA subnetwork of MetabERN. METHODS: A questionnaire was sent to all clinically active European Society for the Study of Inborn Errors of Metabolism (SSIEM) members. The questionnaire focused on transplanted individuals with methylmalonic acidemia (MMA), propionic acidemia (PA), maple syrup urine disease (MSUD), and urea-cycle disorders (UCDs). RESULTS: We identified 280 transplanted AOA patients (liver transplantation in 20 MMA, 37 PA, 47 MSUD, and 111 UCD patients, kidney or combined liver and kidney transplantation in 57 MMA patients and undefined transplantation type in 8 MMA patients), followed by 51 metabolic centers. At a median follow-up of 3.5 years, posttransplant survival ranged between 78% and 100%, being the lowest in PA patients. Overall, the risk of mortality was highest within 14 days posttransplantation. Neurological complications were mainly reported in Mut0 type MMA (n = 8). Nonneurological complications occurred in MMA (n = 28), PA (n = 7), and UCD (n = 14) patients, while it was virtually absent in MSUD patients. Only 116/280 patients were psychologically tested. In all, except MSUD patients, the intelligence quotient (IQ) remained unchanged in the majority (76/94, 81%). Forty-one percentage (9/22) of MSUD patient showed improved IQ. CONCLUSION: The survival in AOA individuals receiving liver and/or kidney transplantation seems satisfactory. Evidence-based guidelines, systematic data collection, and improved cooperation between transplantation centers and European Reference Networks are indispensable to improve patient care and outcomes.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/terapia , Trasplante de Riñón , Trasplante de Hígado , Enfermedad de la Orina de Jarabe de Arce/terapia , Acidemia Propiónica/terapia , Trastornos Innatos del Ciclo de la Urea/terapia , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Masculino , Enfermedad de la Orina de Jarabe de Arce/mortalidad , Acidemia Propiónica/mortalidad , Tasa de Supervivencia , Trastornos Innatos del Ciclo de la Urea/mortalidad , Adulto JovenRESUMEN
Primary hyperammonaemia is a term to describe an elevation of ammonia in blood or plasma due to a defect within the urea cycle, which is the pathway responsible for ammonia detoxification and arginine biosynthesis. Urea cycle disorders (UCDs) are rare diseases caused by genetic defects affecting any of the six enzymes or two transporters that are directly involved in the urea cycle function.The clinical situation is variable and largely depends on the time of onset. Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. Outside the neonatal period, symptoms are very unspecific but most often neurological (with wide variability), psychiatric and/or gastrointestinal. Early identification of patients is extremely important to start effective treatment modalities immediately. The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. Long-term management of patients with UCDs consists of a low-protein diet, which needs to be balanced and supplemented to avoid deficiencies of essential amino acids, trace elements or vitamins and the use of nitrogen scavengers.The reader will find here a brief overview describing the most relevant aspects of the clinical management of UCDs in an attempt to raise awareness for this important group of rare diseases.
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Amoníaco/sangre , Hiperamonemia/complicaciones , Hiperamonemia/diagnóstico , Hiperamonemia/fisiopatología , Hiperamonemia/terapia , Diálisis Renal/métodos , Trastornos Innatos del Ciclo de la Urea/sangre , Diagnóstico Precoz , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Resultado del Tratamiento , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
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.
Asunto(s)
Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , N-Acetiltransferasa de Aminoácidos/genética , Femenino , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/terapia , Lactante , Recién Nacido , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/genética , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
BACKGROUND: N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. METHODS: Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. RESULTS: In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. CONCLUSIONS: Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.
Asunto(s)
Hiperamonemia , Trastornos Innatos del Ciclo de la Urea , N-Acetiltransferasa de Aminoácidos/genética , Amoníaco , Humanos , Recién Nacido , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/genética , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.
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Peso Corporal , Desarrollo Humano , Trastornos Innatos del Ciclo de la Urea/epidemiología , Biomarcadores , Niño , Preescolar , Bases de Datos Factuales , Manejo de la Enfermedad , Femenino , Humanos , Lactante , Masculino , Vigilancia en Salud Pública , Evaluación de Síntomas , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Trastornos Innatos del Ciclo de la Urea/etiología , Trastornos Innatos del Ciclo de la Urea/terapia , Pesos y MedidasRESUMEN
Hyperammonaemia in children can lead to grave consequences in the form of cerebral oedema, severe neurological impairment and even death. In infants and children, common causes of hyperammonaemia include urea cycle disorders or organic acidaemias. Few studies have assessed the role of extracorporeal therapies in the management of hyperammonaemia in neonates and children. Moreover, consensus guidelines are lacking for the use of non-kidney replacement therapy (NKRT) and kidney replacement therapies (KRTs, including peritoneal dialysis, continuous KRT, haemodialysis and hybrid therapy) to manage hyperammonaemia in neonates and children. Prompt treatment with KRT and/or NKRT, the choice of which depends on the ammonia concentrations and presenting symptoms of the patient, is crucial. This expert Consensus Statement presents recommendations for the management of hyperammonaemia requiring KRT in paediatric populations. Additional studies are required to strengthen these recommendations.
Asunto(s)
Terapia de Reemplazo Renal Continuo/métodos , Hiperamonemia/terapia , Diálisis Peritoneal/métodos , Trastornos Innatos del Ciclo de la Urea/terapia , Arginina/uso terapéutico , Carnitina/uso terapéutico , Niño , Preescolar , Técnica Delphi , Dieta con Restricción de Proteínas , Humanos , Terapia de Reemplazo Renal Híbrido , Hiperamonemia/metabolismo , Lactante , Recién Nacido , Nutrición Parenteral/métodos , Fenilacetatos/uso terapéutico , Fenilbutiratos/uso terapéutico , Guías de Práctica Clínica como Asunto , Diálisis Renal/métodos , Benzoato de Sodio/uso terapéutico , Trastornos Innatos del Ciclo de la Urea/metabolismo , Complejo Vitamínico B/uso terapéuticoRESUMEN
Urea cycle disorders (UCD) are rare inherited metabolic disorders caused by deficiencies of enzymes and transporters required to convert neurotoxic ammonia into urea. These deficiencies cause elevated blood ammonia, which if untreated may result in death, but even with optimal medical management, often results in recurrent brain damage. There are two major treatments for UCD: medical management or liver transplantation. Both are associated with mortality and morbidity but the evidence comparing outcomes is sparse. Thus, families face a dilemma: should their child be managed medically, or should they undergo a liver transplant? To (a) describe the factors that contribute to treatment choice among parents of children diagnosed with UCD and to (b) organise these factors into a conceptual framework that reflects how these issues interrelate to shape the decision-making experience of this population. Utilising grounded theory, qualitative data were collected through semi-structured interviews with parents (N = 35) and providers (N = 26) of children diagnosed with UCD and parent focus groups (N = 19). Thematic content analysis and selective and axial coding were applied. The framework highlights the life-cycle catalysts that frame families' personal perceptions of risks and benefits and describes the clinical, personal, social, and system factors that drive treatment choice including disease severity, stability, and burden, independence, peer experiences, and cost, coverage and access to quality care. Findings equip providers with evidence upon which to prepare for productive patient interactions about treatment options. They also provide a foundation for the development of patient-centred outcome measures to better evaluate effectiveness of treatments in this population.
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Conducta de Elección , Toma de Decisiones , Padres/psicología , Trastornos Innatos del Ciclo de la Urea/terapia , Adolescente , Niño , Preescolar , Costo de Enfermedad , Manejo de la Enfermedad , Femenino , Grupos Focales , Humanos , Lactante , Recién Nacido , Entrevistas como Asunto , Trasplante de Hígado/métodos , Masculino , Investigación Cualitativa , Trastornos Innatos del Ciclo de la Urea/cirugíaAsunto(s)
Congresos como Asunto , Trastornos Innatos del Ciclo de la Urea , Animales , Congresos como Asunto/historia , Modelos Animales de Enfermedad , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Hiperamonemia/etiología , Hiperamonemia/patología , Hiperamonemia/terapia , Cooperación Internacional , Japón , Ratones , Ratones Transgénicos , Suiza , Trastornos Innatos del Ciclo de la Urea/etiología , Trastornos Innatos del Ciclo de la Urea/metabolismo , Trastornos Innatos del Ciclo de la Urea/patología , Trastornos Innatos del Ciclo de la Urea/terapiaRESUMEN
Urea cycle disorders (UCDs) are rare inherited metabolic conditions that impair the effectiveness of the urea cycle responsible for removing excess ammonia from the body. The estimated incidence of UCDs is 1:35 000 births, or approximately 113 new patients with UCD per year. This review summarizes neuropsychological outcomes among patients with the eight UCDs in reports published since 1980. Rates of intellectual disabilities published before (and including) 2000 and after 2000 were pooled and compared for each UCD. Since diagnoses for UCDs tended to occur earlier and better treatments became more readily available after the turn of the century, this assessment will characterize the extent that current management strategies have improved neuropsychological outcomes. The pooled sample included data on cognitive abilities of 1649 individuals reported in 58 citations. A total of 556 patients (34%) functioned in the range of intellectual disabilities. The decline in the proportion of intellectual disabilities in six disorders, ranged from 7% to 41%. Results from various studies differed and the cohorts varied with respect to age at symptom onset, age at diagnosis and treatment initiation, current age, severity of the metabolic deficiency, management strategies, and ethnic origins. The proportion of cases with intellectual disabilities ranged from 9% to 65% after 2000 in the seven UCDs associated with cognitive deficits. Positive outcomes from some studies suggest that it is possible to prevent or reverse the adverse impact of UCDs on neuropsychological functioning. It is time to "raise the bar" in terms of expectations for treatment effectiveness.
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Cognición/fisiología , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/etiología , Trastornos Innatos del Ciclo de la Urea/complicaciones , Trastornos Innatos del Ciclo de la Urea/epidemiología , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/terapia , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Resultado del Tratamiento , Estados Unidos/epidemiología , Trastornos Innatos del Ciclo de la Urea/psicología , Trastornos Innatos del Ciclo de la Urea/terapia , Adulto JovenRESUMEN
Metabolic liver diseases are attractive gene therapy targets that necessitate reconstitution of enzymatic activity in functionally complex biochemical pathways. The levels of enzyme activity required in individual hepatocytes and the proportion of the hepatic cell mass that must be gene corrected for therapeutic benefit vary in a disease-dependent manner that is difficult to predict. While empirical evaluation is inevitably required, useful insights can nevertheless be gained from knowledge of disease pathophysiology and theoretical approaches such as mathematical modeling. Urea cycle defects provide an excellent example. Building on a previously described one-compartment model of the urea cycle, we have constructed a two-compartment model that can simulate liver-targeted gene therapy interventions using the computational program Mathematica. The model predicts that therapeutically effective reconstitution of ureagenesis will correlate most strongly with the proportion of the hepatic cell mass transduced rather than the level of enzyme-encoding transgene expression achieved in individual hepatocytes. Importantly, these predictions are supported by experimental data in mice and human genotype/phenotype correlations. The most notable example of the latter is ornithine transcarbamylase deficiency (X-linked) where impairment of ureagenesis in male and female patients is closely simulated by the one- and two-compartment models, respectively. Collectively, these observations support the practical value of mathematical modeling in evaluation of the disease-specific gene transfer challenges posed by complex metabolic phenotypes.