Diálisis peritoneal en un neonato con enfermedad de la orina con olor a jarabe de arce. A propósito de un caso / Peritoneal dialysis in a neonate with maple syrup urine disease. A case report

La enfermedad de jarabe de arce es una entidad autosómica recesiva producida por un error congénito en el metabolismo de tres aminoácidos esenciales de cadena ramificada: valina, leucina e isoleucina. La forma neonatal de esta enfermedad se manifiesta por un cuadro de compromiso neurológico grave y progresivo, asociado a un olor peculiar de la orina, consecuencia de la eliminación del exceso de estos aminoácidos. Este olor a azúcar quemada remeda a la melaza obtenida de los arces, lo que da nombre a esta enfermedad. El mejor método para eliminar estos tóxicos es la hemodiafiltración, pero, en los centros en los que esta práctica no es posible, la diálisis peritoneal constituye una alternativa.Se presenta a un recién nacido con leucinosis, con compromiso grave del sistema nervioso central, en quien la diálisis peritoneal fue de utilidad para superar la descompensación metabólica.

Maple syrup disease is an autosomal recessive entity caused by a congenital error in the metabolism of three essential branched-chain amino acids: valine, leucine and isoleucine. The neonatal form of this disease is expressed by a severe and progressive neurological compromise, associated with a peculiar smell of urine, a consequence of the elimination of the excess of these amino acids. This smell of burnt sugar mimics the molasses obtained from maples, which gives its name to this disease. The best method to eliminate these toxins is hemodiafiltration, but in centers where this practice is not possible, peritoneal dialysis is an alternative.We present a newborn with leukinosis with severe central nervous system involvement in whom peritoneal dialysis was useful to overcome metabolic decompensation.

Enfermedad de la orina de jarabe de arce: trastornos metabólicos y limitaciones en Honduras / Maple Syrup Urine Disease: Metabolic Disorders and Limitations in Honduras

Antecedentes: La Enfermedad de la Orina con olor a Jarabe de Arce es un error innato del metabolismo causada por deficiencia de actividad de la deshidrogenasa de los cetoácidos, que lleva acumular aminoácidos de cadena ramificada que produce una encefalopatía neonatal y al no ser tratada tempranamente, deja secuelas neurológicas permanentes hasta la muerte. Caso Clínico: Recién nacida producto de parto eutocico, a término, respiración espontanea, llanto vigoroso y buen tono muscular, alimentación exclusiva con lactancia materna. Antecedentes maternos de 2 hijos muertos en período neonatal. Paciente se presenta a los 7 días con pobre succión, vómitos, hipoactividad y fiebre. Examen físico: hipoactivo, reflejo de moro incompleto, llanto débil y constante. Posteriormente movimientos en extremidades superiores que simulan "boxeo" e hipertonicos, y pedaleo en extremidades inferiores, fontanela tensa y abombada, respiración irregular y bradipnea, se realiza intubación endotraqueal, ventilación mecánica y manejo en UCIN, EEG actividad eléctrica convulsiva, TAC cerebral normal. Se investiga enfermedad metabólica y se solicita tamizaje neonatal . Se inicia tiamina/levocarnitina ante sospecha de un error innato del metabolismo. A los 23 días de vida los resultados revelan niveles elevados de los aminoácidos específicos de la MSUD. Discusión: MSUD es una entidad rara en el mundo, que cursa con secuelas neurológicas permanentes y muerte de no ser tratada. Honduras no realiza métodos de Tamizaje Neonatal, es importante que el médico sospeche de manera temprana estas enfermedades, realizar un diagnóstico oportuno, se conduzca un tratamiento multidisciplinario y exista una mayor accesibilidad a las fórmulas especializadas..(AU)

Enfermedad de orina con olor a jarabe de arce: reporte de dos casos / Maple urine disease: two case reports

Introducción: La enfermedad de orina con olor a jarabe de arce (EOJA) es un trastorno del metabolismo de los aminoácidos de cadena ramificada (ACR). Tiene una incidencia de 1 en 85.000­185.000 recién nacidos (RN) vivos, siendo mayor en poblaciones con alta tasa de consanguineidad. Se debe al déficit del complejo enzimático BCKDC (Branched-chain alpha-keto acid dehydrogenase complex). Objetivo: Sensibilizar respecto al diagnóstico precoz, describiendo la presentación y evolución clínica de 2 casos presentados en menos de un año. Presentación del caso: Caso 1: Recién nacido de término (RNT), sin antecedentes mórbidos personales ni familiares, consulta al 11er día de vida (DDV) por cuadro de irritabilidad, rechazo alimentario, mirada fija e hipertonía. Hospitalizado por 55 días con progresiva mejoría neurológica. Al alta solo leve retraso del desarrollo psicomotor (RDSM). Caso 2: RNT, sin antecedentes mórbidos personales ni familiares, consultó al 12° DDV por cuadro de hipoactividad y rechazo alimentario. Hospitalizado por 70 días con evolución clínica y neurológica dificultosa. Al alta con trastorno deglutorio que requirió gastrostomía. En ambos casos se planteó sospecha de EOJA por aminoacidemia y aminoaciduria característica, confirmándose por medición cuantitativa de aminoácidos. Discusión: Existen cinco fenotipos diferentes, clasificados principalmente por presentación clínica y edad de debut, siendo el más frecuente la forma clásica (ambos casos). Resulta muy importante el diagnóstico precoz y manejo por su relación con el pronóstico neurológico, sin embargo, en Chile no se cuenta actualmente con un screening neonatal universal. El tratamiento se basa en un manejo nutricional estricto y la corrección de desequilibrios metabólicos e hidroelectrolíticos, ambos frecuentes en esta condición.

Introduction: The maple syrup urine disease (MSUD) is a metabolic disorder of branchedchain amino acids. It has an incidence of 1/85000 ­ 185000 live newborns being higher in in populations with a high rate of consanguinity. It is due to deficit BKDC enzyme complex (Branched-chain alpha-keto acid dehydrogenase complex). Objective: To raise awareness to early diagnosis, describing the presentation and clinical course of 2 cases presented in less than one year. Case report: Case 1: Full-term newborn with no personal or family history of morbidity presented the 11th day of life with irritability, food rejection, fixed stare and hypertonia. He was hospitalized for 55 days with progressive neurological improvement. At discharge only slightly delayed psychomotor development. Case 2: Full-term newborn with no personal or family history of morbidity presented the 12th day of life with hipoactivity and food rejection. He was hospitalized for 70 days with difficult clinical and neurological outcome. The patient was discharged with swallowing disorder that required gastrostomy. In both cases MSUP suspicion arises by aminoacidemia and aminoaciduria and confirmed by quantitative measurement of amino acids. Discussion: There are 5 different phenotypes classified chiefly by clinical presentation and age, being most frequent the classical form. It is very important to do an early diagnosis and management for its impact on neurological outcome; however, Chile does not currently has an universal neonatal screening. The treatment is based on a strict nutritional management and correction of metabolic and electrolyte imbalances, both common in this condition.

Enfermedad de orina a jarabe de arce: presentación de caso clínico / Maple Syrup Urine Disease: A case report

Antecedentes: La enfermedad de orina olor a jarabe de arce (EOJA) es un error congénito del metabolismo de herencia autosómica recesiva, causado por la actividad defectuosa del com- plejo enzimático deshidrogenasa de α -cetoáci- dos, ocasionando que los aminoácidos de cadena ramificada; valina, leucina e isoleucina no puedan catabolizarse completamente. Se trata de lactante menor, tres meses de edad, con antecedente de vómitos frecuentes y rechazo a la alimentación desde la primera semana de vida, tratado por alergia a la proteí- na de la leche de vaca y reflujo gastroesofágico grado IV, con varios cambios de formula en su alimentación. Trasladado al Instituto Hondure- ño del Seguro Social, Hospital Regional del Norte (IHSS-HRN) con historia de cinco días de tos, fiebre y aproximadamente nueve horas de dificultad respiratoria. Tres horas más tarde presenta convulsiones tónicas y choque, por lo que se trasladado a sala de cuidados intensivos pediátricos, acoplándose a ventilador mecáni- co. Laboratorialmente: acidosis metabólica persistente que se logró controlar a las 48 horas, Anión Gap: 17, cetonuria, IRM con impor- tante atrofia cortical. Se encontró elevación de los metabolitos de aminoácidos de cadena ramificada; 2-OH isovalerico, 2- OH isocaproico, 2-ceto-3 methylvalerico, 2 cetoisocaproico consistentes con EOJA y elevación del ácido láctico y alfa cetoglutarato; que podrían indicar defectos en la subunidad E3 de la enzima deshidrogenasa. Conclusiones: Los errores innatos del metabolismo son más frecuente- mente diagnosticados cada día, y deben sospe- charse en los niños con vómitos frecuentes...(AU)

Maple syrup urine disease in Brazil: a panorama of the last two decades / Doença da urina de xarope de bordo no Brasil: um panorama das últimas duas décadas

OBJECTIVE: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p = 0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n = 12) and without (n = 71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. .

OBJETIVO: Caracterizar uma amostra de pacientes brasileiros com a doença da urina de xarope de bordo (DXB) diagnosticados entre 1992 e 2011. MÉTODOS: Os pacientes foram identificados por meio de um laboratório de referência nacional para o diagnóstico de DXB e por meio do contato com outros serviços de genética médica no Brasil. Os dados foram coletados por meio de uma revisão de prontuários. RESULTADOS: Foram incluídos no estudo 83 pacientes de 75 famílias (idade média: três anos; intervalo interquartil (IQR): 0,57-7). A idade média no surgimento dos sintomas era de 10 dias (IQR: 5-30), ao passo que a idade média no diagnóstico era de 60 dias (IQR: 29-240; p = 0,001). Somente três (3,6%) pacientes foram diagnosticados antes do surgimento de manifestações clínicas. Uma comparação entre pacientes com (n = 12) e sem (n = 71) um diagnóstico precoce mostra que o diagnóstico precoce está associado à presença de histórico familiar positivo e à redução na prevalência de manifestações clínicas no momento do diagnóstico, porém sem melhor resultado. Em geral, 98,8% dos pacientes têm algum atraso no desenvolvimento psicomotor ou neurológico. CONCLUSÃO: No Brasil, os pacientes com DXB normalmente recebem um diagnóstico tardio e exibem um envolvimento neurológico e baixa sobrevivência, mesmo com um diagnóstico precoce. Sugerimos que políticas públicas específicas para o diagnóstico e tratamento da DXB sejam desenvolvidas e implementadas no país. .

Maple syrup urine disease in Thai infants.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism, caused by a deficiency in activity of the branched chain alpha-keto acid dehydrogenase impairing the degradation of the branched-chain amino acids (leucine, isoleucine and valine). Classic MSUD usually manifests in the neonatal period with poor feeding, vomiting, lethargy, muscular hypertonicity, seizure, coma and death. Thirteen cases of classic MSUD were diagnosed from 1997-2007 at the Queen Sirikit National Institute of Child Health. All cases presented in the neonatal period. The onset of symptoms ranged from 3 to 20 days (median 8 days). The time taken to make the diagnosis ranged from 18 to 356 days (median 55 days). The diagnosis was accomplished by clinical diagnosis and confirmed by detecting abnormal levels of amino acids in the blood and organic acids in the urine. Clinical manifestations were non-specific such as poor suck, weak cry, drowsiness and seizures. Majority of cases were initially diagnosed as sepsis and/or meningitis. All patients had neurological sequelae and psychomotor retardation. This results show the need for increase awareness of metabolic disorder such as MSUD and the requirement for early detection and treatment to ensure a better outcome.

Enfermedad de orina a jarabe de arce / Maple syrup urine disease

Las enfermedades metabólicas pueden presentarse con síntomas, signos y laboratorios inespecíficos, que si no se consideran entre los diagnósticos diferenciales pueden retrasar el diagnóstico de estos pacientes, lo que lleva a un alto grado de secuelas neurológicas o muerte en etapas tempranas. La enfermedad de Orina a Jarabe de Arce es una enfermedad metabólica de baja incidencia caracterizada por la acumulación de niveles tóxicos de valina, isoleucina y principalmente leucina. Se presenta un paciente sin antecedentes que a los 11 días de vida comienza con mala actitud alimentaria, letargia y fontanela tensa. Descartadas las causas infectológicas se realizó un screening para enfermedades metabólicas. Se diagnosticó Leucinosis (Enfermedad de orina con olor a Jarabe de Arce) y se inició el tratamiento con restricción de leucina, valina e isoleucina en la dieta. A los pocos días del tratamiento el paciente mostró evidencias de mejoría clínica y en los parámetros de laboratorio.

Clinical signs, symptoms and lab tests of neonatal metabolic diseases may be unspecific and a high grade of suspicion is necessary to include them among the differential diagnosis avoiding a significant delay in recognizing this condition and consequent risk of neurologic handicap or early dead. Maple syrup urine disease is a congenital metabolic disorder with a low rate of prevalence and characterized by a toxic accumulation of the amino acids valine, isoleucine and mainly leucine. In this report we describe the history of a patient apparently healthy that on the 11th day after birth initiates symptoms like poor feeding, lethargy and tense fontanel. Excluded sepsis a work up for metabolic disease was performed, being diagnosed a leucinosis (Maple syrup urine disease). A dietary treatment with leucine, valine and isoleucine restriction was immediately initiated and a few days after the patient showed significant clinical and lab improvement. A short description and discussion of this disease is presented.

Inborn errors of metabolism (IEM) -- an Indian perspective.

The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinical manifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seen in the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult disorders in the context of a developing country.

Selective screening of phenylketonuria, tyrosinemia and maple syrup urine diease in southern Iran

Inborn errors of amino-acids metabolism and other inherited Mendelian disorders are common in the Middle East. The number of diagnosed inborn errors of amino acid metabolism is growing constantly on account of and availability and improved of analytical techniques. The aim of this work was to determine a rough estimate of the incidence rates of phenylketonuria [PKU], tyrosinemia, and maple syrup urine disease [MSUD] in Fars Province, South of Iran. Using a high performance liquid chromatography, 1044 patients with signs and symptoms suggestive of PKU, tyrosinemia and MSUD were investigated between 1996 and 2001, for the presence of the disorders. Of 1044 patients, 43 cases [4.1%] with PKU, 15 [1.4%] with tyrosinemia and 6 [0.6%] with MSUD were diagnosed. The incidence rates of PKU, tyrosinemia and MSUD were found to be 27.2, 9.4, and 4.7 per 100,000 births, respectively. The incidence rates of PKU, tyrosinemia and MSUD in our region is higher than the rates reported from Europe presumably because of the relatively higher rates of consanguinity

Cutaneous lesions during dietetic therapy in patients with maple syrup urine disease

Maple syrup urine disease is a rare, autosomal, recessive, manifestations. We report two affected Arab children organic aciduria previously described with different with skin manifestation

Detection of inherited metabolic disorders via tandem mass spectrometry in Thai infants.

From a retrospective study in Medical Genetics Unit, Department of Pediatrics, Siriraj Hospital Faculty of Medicine, Mahidol University in Bangkok (1983-1988), the estimated pediatric patients with clinically suspected IEM are approximately 2-4% of total annual pediatrics admission of 5,000 or more. This is, a low estimation since survey from all teaching hospitals in the country including the largest Children's Hospital in Bangkok indicated the presence of numerous IEM. However, most IEM were clinically diagnosed with limited laboratory facilities. We started a collaboration with Magee Womens Hospital of Pittsburgh and NeoGen Screening, USA; using tandem mass spectrometry to diagnose high risk infants and children for IEM from July 1993 to March 1998. Of total 146 samples sent, we detected numerous metabolic disorders (11.2%) eg phenylketonuria, organic acidemia, maple syrup urine disease, isovaleric acidemia, methylmalonic acidemia, albinism, translocase/carnitine palmitoyltransferase type II, G6PD deficiency and lysinuric protein intolerance.

Enzymatic method for branched chain alpha-ketoacid determination: application to rapid analysis of urine and plasma samples from maple syrup urine disease patients

A new method for the determination of branched-chain alpha-ketoacid concentration using lactate dehydrogenase (E C 1.1.1.27) isozyme C4 (LDH) C4) from mouse testes is proposed. The assay is performed on urine and plasma without previous treatment. Alpha-ketoglutarate and pyruvate are determined on the same sample using glutamate dehydrogenase (GDH,EC 1.4.1.2) and lactate dehydrogenase isozyme A4 (LDH5) respectively and subtracted from the total alpha-ketoacid concentration obtained with LDH C4. This value corresponds to the branched chain alpha-ketoacid. Results were linear within the concentration range 8 to 170 mumoles/L. Detection limit was 8 mumoles/L. Analytical recovery was higher than 91 per cent. For microplate assays, recoveries were higher than 84 per cent and the detection limit was 20 mumoles/L. Determinations performed with GDH, LDH A4 and LDH C4 allow differentiation of E3 deficiency from other clinical phenotypes of maple syrup urine disease. The method is simple and fast, and adaptation to microplates would allow screening of newborns.

Inborn errors of metabolic diseases in Malaysia: a preliminary report of maple syrup urine diseases for 1993.

The Malaysian level of health care has greatly improved so that many of the infectious diseases are now under control. However, perinatal death or death due to unknown childhood diseases remains high (10.3%) being second on the list of causes of death amongst Malaysians. Could inborn metabolic diseases be the main cause of death among these children? Recently, with our success in the development of confirmatory techniques for amino acid disorders using high performance liquid chromatography (HPLC), we have examined 404 samples received from all over the country in 1993. Each specimen with abnormal findings from screening tests by one-dimensional thin layer chromatography was confirmed using HPLC. 41% had generalized aminoacidurias and 4.2% had maple syrup urine disease (MSUD). Patients were aged between 11 days to 6 years. Most of them were Malay males and presented with a history suggestive of MSUD. With this preliminary finding, further studies will be carried out in order to have an investigation and management protocol for the diseases and more importantly to formulate a strategy of screening for the country.

Manifestaciones cutáneas en la enfermedad de orina con olor a jarabe de arce / Cutaneous alterations in maple syrup urine disease

Introducción. La enfermedad de orina con olor a jarabe de arce (EOJA), fue descrita por primera vez en 1954 por Menkes; se caracteriza por cuadro neurológico progresivo, orina con olor a caramelo y muerte inexplicable. La herencia es autosómica recesiva y la mayor incidencia se observa en población Menonita. El defecto metabólico consiste en deficiencia de descarboxilación oxidativa de los Ó-cetoácidos de cadena ramificada, derivados de los aminoácidos esenciales leucina, isoleucina y valina, que tiene como consecuencia incremento de Ó-cetoácidos en líquidos y células corporales. Casos clínicos. Reportamos tres pacientes con EOJA, de las variedades clásica e intermedia, quienes presentaron manifestaciones cutáneas llamativas en algún momento de su evolución. Conclusiones. La EOJA no produce manifestaciones cutáneas "per se", y se considera que estas son secundarias a déficit carenciales por el tratamiento

Metodología de atención de niños con fenilcetonuria (FC) y enfermedad de la orina con olor a miel de arce (EOMA) / Methodology of care for children with phenylketonuria and maple-syrup urine disease

Maple Syrup Urine Disease (MUSD) and Phenylketonuria (PKU), are two metabolic disease in which the nutritional management are essential. Nevertheless, in Costa Rica and the rest of Central America, the dietetical attention of the children with this illness aren't normalized. These work was developed to fill this necessity. The nutritional management was separate in three steps: 1-Initial diet: is the feeding that the children must receive while the blood amino acid level falls, 2-Stabilization diet: is the one where the requirement of limits amino acid are defined, 3-Follow up diet: this is the diet that is prescribed for the rest of his life. This attention methodology, was very important to an adequate physical and neurological development of the children with PKU and MSUD.

The diagnosis and management of MSUD in Saudi Arabia by using two different methods.

Plasma amino acid concentrations were measured in Maple Syrup Urine Disease (MSUD) infants using reversed phase high performance liquid chromatography (HPLC). The technique involved an automated data acquisition system and phenylisothiocyanate (PITC) pre-column derivatization. During a period of three years more than 14 cases of MSUD have been confirmed in our hospital suggesting an alarmingly high rate of incidence of this disease in the Kingdom as compared to the West. We present here a simple and reliable method of quantitating the branched chain and other amino acid concentrations in plasma samples of children with metabolic disorders. In addition, we also present a fluorimetric COBAS based enzymatic method for the rapid semiquantitative measurement of branched chain amino acids for a disease in which a prompt initial diagnosis is essential.