Hipermetioninemia en el recién nacido pretérmino. Estudio de los factores predisponentes / Hypermethioninemia in the preterm newborn. Predisposing factors

Introducción: El exceso de metionina puede ser causa de alteraciones del sistema nervioso central, tales como edema cerebral difuso y trastornos de la mielinización. Pacientes y método: Estudio ambispectivo observacional durante un período de 15 meses de los recién nacidos prematuros ingresados en nuestro hospital que presentaron hipermetioninemia en las pruebas de cribado neonatal por espectrometría de masas en tándem. Seguimiento evolutivo de estos neonatos hasta el año de edad con valoración de sus niveles de metionina en relación con la alimentación, parámetros somatométricos y desarrollo neurológico. Resultados: De una población de estudio de 187 neonatos pretérmino, 16 de ellos presentaron hipermetioninemia aislada. El peso y la alimentación de estos recién nacidos con una fórmula de inicio especial enriquecida en metionina está relacionada con el aumento del número de casos de hipermetioninemia aislada transitoria (el 62,6% recibieron un aporte de metionina superior a 97mg/kg/día), además se halló una correlación estadísticamente significativa entre los días que los pacientes recibían esa fórmula y el tiempo que tardaron en normalizarse las cifras de metionina en plasma (r: 0,791; p: 0,000). No observamos correlación entre las cifras máximas de metionina alcanzadas en plasma y la puntuación obtenida en el test de Brunet Lézine a los 6 meses de edad corregida. Conclusiones: Este estudio pone de relevancia la importancia del suplemento de aminoácidos, concretamente de metionina, en las leches de fórmula de los recién nacidos prematuros por la trascendencia que pueden suponer para su desarrollo neurológico (AU)

Introduction: Excess methionine can cause central nervous system disorders such as diffuse cerebral edema and disorders of myelin. Patients and method: A retrospective and prospective (ambispective) observational study in preterm newborns admitted to our hospital over a period of 15 months and who had hypermethioninemia in neonatal screening tests by tandem mass spectrometry. The progress of these infants was monitored during the first year of life, assessing their methionine levels, diet, somatometric parameters and neurodevelopment. Results: From a study population of 187 preterm infants, 16 of them showed isolated hypermethioninemia. Weight and feeding the babies with a special formula enriched with methionine is related to an increased number of cases of transient isolated hypermethioninemia (62.6% received a higher contribution of methionine than 97mg/kg/day). We also found a statistically significant correlation between the days that patients received the formula and the time it takes to normalize the levels of methionine in plasma (R 0.791, p=0.000). There was no correlation between the methionine peak reached in plasma and the score on the Brunet Lézine test, at the corrected age of 6 months. Conclusions: This study highlights the importance amino acid supplements, particularly methionine, in premature infants’ formulas due to the impact they may have on neurological development (AU)

[Hypermethioninemia in the preterm newborn. Predisposing factors]. / Hipermetioninemia en el recién nacido pretérmino. Estudio de los factores predisponentes.

INTRODUCTION: Excess methionine can cause central nervous system disorders such as diffuse cerebral edema and disorders of myelin. PATIENTS AND METHOD: A retrospective and prospective (ambispective) observational study in preterm newborns admitted to our hospital over a period of 15 months and who had hypermethioninemia in neonatal screening tests by tandem mass spectrometry. The progress of these infants was monitored during the first year of life, assessing their methionine levels, diet, somatometric parameters and neurodevelopment. RESULTS: From a study population of 187 preterm infants, 16 of them showed isolated hypermethioninemia. Weight and feeding the babies with a special formula enriched with methionine is related to an increased number of cases of transient isolated hypermethioninemia (62.6% received a higher contribution of methionine than 97mg/kg/day). We also found a statistically significant correlation between the days that patients received the formula and the time it takes to normalize the levels of methionine in plasma (R 0.791, p=0.000). There was no correlation between the methionine peak reached in plasma and the score on the Brunet Lézine test, at the corrected age of 6 months. CONCLUSIONS: This study highlights the importance amino acid supplements, particularly methionine, in premature infants' formulas due to the impact they may have on neurological development.

[Importance of early diagnosis and treatment in the prognosis of type I Glutaric Acidaemia]. / Importancia del diagnóstico precoz y el tratamiento temprano en el pronóstico de la aciduria glutárica tipo I.

INTRODUCTION: Glutaric Acidaemia type I (GA-I) is an autosomal recessive progressive neurodegenerative inborn error of metabolism caused by deficient activity of the enzyme glutaryl-CoA dehydrogenase (GCDH). In most cases, the diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. Patients excreting small amounts of glutaric acid may be overlooked. OBJECTIVE: To investigate the value of expanded newborn screening by adding the measurement of urine glutarylcarnitine to conventional chromatography-mass spectrometry (GC-MS) in the diagnosis of GA-1. MATERIAL AND METHODS: We report clinical and biochemical data in 5 GA-I patients diagnosed in our Hospital. Details regarding biochemical diagnosis are emphasised and the absence or presence of symptoms was correlated with neuroimaging findings, age at diagnosis and treatment. RESULTS: Two patients showed high glutarylcarnitine levels in plasma and were identified by routine newborn GC-MS screening. Following early appropriate treatment they are asymptomatic 6 years later. Two patients with delayed diagnosis displayed neurological sequels in spite of treatment. The remaining patient, who presented with encephalopathic episode at age 8 months showed normal glutarylcarnitine levels in routine plasma GC-MS but high urine glutarylcarnitine levels in a retrospectively screened urine sample from the newborn period. CONCLUSIONS: Early treatment seems to positively influence the clinical evolution of GA-I patients. Thus, improving the identification of GA-I represents an important diagnostic challenge. The urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-I and allows the identification of patients without glutaric aciduria and with normal plasma acylcarnitine profiles.

Importancia del diagnóstico precoz y el tratamiento temprano en el pronóstico de la aciduria glutárica tipo I / Importance of early diagnosis and treatment in the prognosis of type I gluraric acidaemia

Introducción. La aciduria glutárica tipo I (AG-I) es un desorden metabólico de herencia autosómica recesiva y carácter progresivo debido al déficit de la enzima glutaril-CoA-deshidrogenasa (GCDH). El diagnóstico se realiza generalmente por una elevación del ácido glutárico y 3-hidroxiglutárico en la orina y de la glutarilcarnitina en el plasma. Existen casos falsos negativos en relación con la baja tasa excretora del ácido glutárico. Objetivo. Resaltar la importancia de la ampliación del cribado neonatal por espectrofotometría de masas en tándem (MS/MS) mediante la inclusión de la medición de glutarilcarnitina en la orina para su diagnóstico. Material y métodos. Se aportan los datos clínicos y el perfil bioquímico que llevaron al diagnóstico en 5 pacientes diagnosticados de AG-I en nuestro centro. Se analiza la evolución clínica y de neuroimagen en función de la edad, el diagnóstico y el inicio del tratamiento. Resultados. Dos casos de diagnóstico por cribado convencional mediante MS/MS siguieron un tratamiento precoz y están asintomáticos 6 años después. Dos pacientes de diagnóstico y tratamiento tardíos presentan secuelas neurológicas. El último paciente, diagnosticado a los 8 meses tras una presentación aguda encefalopática, mostraba valores de glutarilcarnitina en plasma en rango normal, mientras que el análisis retrospectivo de la orina del período neonatal reveló valores elevados de glutarilcarnitina. Conclusiones. El tratamiento temprano parece asociarse a una evolución neurológica favorable en pacientes con AG-I, por lo que su identificación precoz constituye un reto diagnóstico. La excreción urinaria de glutarilcarnitina es un marcador específico de AG-I y permite la identificación de pacientes sin aciduria glutárica y valores normales de glutarilcarnitina en sangre

Introduction. Glutaric Acidaemia type I (GA-I) is an autosomal recessive progressive neurodegenerative inborn error of metabolism caused by deficient activity of the enzyme glutaryl-CoA dehydrogenase (GCDH). In most cases, the diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. Patients excreting small amounts of glutaric acid may be overlooked. Objective. To investigate the value of expanded newborn screening by adding the measurement of urine glutarylcarnitine to conventional chromatography-mass spectrometry (GC-MS) in the diagnosis of GA-1. Material and methods. We report clinical and biochemical data in 5 GA-I patients diagnosed in our Hospital. Details regarding biochemical diagnosis are emphasised and the absence or presence of symptoms was correlated with neuroimaging findings, age at diagnosis and treatment. Results. Two patients showed high glutarylcarnitine levels in plasma and were identified by routine newborn GC-MS screening. Following early appropriate treatment they are asymptomatic 6 years later. Two patients with delayed diagnosis displayed neurological sequels in spite of treatment. The remaining patient, who presented with encephalopathic episode at age 8 months showed normal glutarylcarnitine levels in routine plasma GC-MS but high urine glutarylcarnitine levels in a retrospectively screened urine sample from the newborn period. Conclusions. Early treatment seems to positively influence the clinical evolution of GA-I patients. Thus, improving the identification of GA-I represents an important diagnostic challenge. The urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-I and allows the identification of patients without glutaric aciduria and with normal plasma acylcarnitine profiles

[Advances in the diagnosis and treatment of maple syrup urine disease: experience in Galicia (Spain)]. / Avances en el diagnóstico y tratamiento de la enfermedad de jarabe de arce, experiencia en Galicia.

INTRODUCTION: Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder caused by an inherited deficiency of branched chain alpha-ketoacid dehydrogenase activity. Accumulation of the amino acids leucine, isoleucine, valine and alloisoleucine and their metabolic products in cells and biological fluids results in severe brain dysfunction. PATIENTS AND METHODS: We present three cases of MSUD diagnosed in Galicia since 2000, the year in which the Extended Newborn Screening Program by tandem mass spectrometry was started in this region. One of the patients was diagnosed on the basis of early clinical presentation and the others by neonatal screening. Enzymatic and molecular studies confirmed two classic cases of MSUD and an intermediate variant. We describe the clinical and biochemical details at confirmation of diagnosis and the long-term outcome of the three patients. Throughout follow-up, all the patients maintained adequate leucine levels, which were near the normal range (mean levels: 220, 177 and 252 micromol/L, respectively). Several moderate metabolic decompensations were observed but leucine levels only occasionally exceeded 1000 micromol/L (one day in two patients). IQ tests were performed in all patients and scores were within the normal range. In view of our results, we believe the following measures are essential to improve the prognosis of MSUD: inclusion of this disease in Expanded Neonatal Screening Programs with early samples (at 2-3 days of life); aggressive treatment in the initial phase and during acute decompensations; strict metabolic control to prevent crises, monitoring of branched-chain amino acids (dried blood spot sample), and maintenance of long term plasma leucine levels below 300 micromol/L.