RESUMO
We report the case of a Spanish pediatric patient with developmental delay, hypotonia, feeding difficulties, visual problems, and hyperkinetic movements. Whole-exome sequencing uncovered a new heterozygous de novo Synaptotagmin 1 (SYT1) missense variant, NM_005639.3:c.930T>A (p.Asp310Glu), in a female proband. This gene encodes the synaptotagmin-1 (SYT1) protein, which is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. Pathogenic SYT1 variants have been associated with Baker-Gordon syndrome (BAGOS), an autosomal dominant neurodevelopmental disorder. Although up to 30 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with mitochondrial respiratory chain deficiencies and rod-cone dysfunction. In conclusion, our data expand both the genetic and phenotypic spectrum associated with SYT1 variants.
Assuntos
Fenótipo , Sinaptotagmina I , Humanos , Feminino , Sinaptotagmina I/genética , Mutação de Sentido Incorreto , Sequenciamento do Exoma , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologiaRESUMO
We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3' of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.
Assuntos
Homozigoto , Síndromes Miastênicas Congênitas , Fenótipo , Proteína 1 Associada à Membrana da Vesícula , Feminino , Humanos , Masculino , Processamento Alternativo/genética , Sequenciamento do Exoma , Mutação , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/patologia , Isoformas de Proteínas/genética , Splicing de RNA/genética , Proteína 1 Associada à Membrana da Vesícula/genética , Lactente , Pré-EscolarRESUMO
Objetivos: Los objetivos son: identificar variables de eficacia empleadas en fármacos para enfermedades de depósito lisosomal (EDL), evaluar la calidad de esta evidencia, y conocer la efectividad y seguridad de estos tratamientos.Material y métodosEstudio observacional retrospectivo que incluyó pacientes con EDL tratados con terapia de sustitución enzimática (TSE) o de reducción de sustrato (TRS). Se revisaron los ensayos clínicos (EC) publicados y guías de tratamiento de EDL para seleccionar las variables de eficacia. Se obtuvieron los datos para medirlas (y efectos adversos) de la historia clínica.ResultadosNo se encontraron EC en los que se evalúe la eficacia con variables finales, todas fueron subrogadas. Se incluyeron 22 pacientes: 8 con enfermedad de Gaucher, 6 con enfermedad de Niemann-Pick tipo C, 2 con enfermedad de Hunter, uno con enfermedad de Morquio-A y 5 con enfermedad de Pompe. Ocho pacientes respondieron a TSE y uno a TRS. La TSE no se relacionó con efectos adversos. Miglustat produjo problemas de tolerancia que requirieron cambio de tratamiento en un paciente.ConclusionesLa efectividad fue variable según la enfermedad. Respecto a seguridad, se asociaron reacciones adversas a TRS manejables con ajustes posológicos. (AU)
Objectives: Identify the efficacy variables collected in the literature for therapies used in lysosomal storage diseases (LDS), evaluate the quality of this evidence, and know the effectiveness and safety of these treatments.Material and methodsRetrospective observational study that included patients with LDS treated with enzyme replacement therapy (ERT) or substrate reduction therapy (SRT). Published clinical trials (CT) and LDS treatment guidelines were reviewed to select efficacy variables. Data to measure them (and adverse effects) were obtained from the medical history.ResultsNo CTs have been found in which efficacy is evaluated with final variables, all have been surrogated. Twenty-two patients were included: eight with Gaucher disease, six with NiemannPickC disease, two with Hunter disease, one with Morquio-A disease, and five with Pompe disease. Eight patients have responded to ERT and one to SRT with eliglustat. ERT has not been associated with adverse effects. Miglustat has produced tolerance problems, requiring a change in a patient.ConclusionsThe effectiveness was variable according to the pathology. Regarding safety, manageable adverse reactions to SRT were associated with dosage adjustments. (AU)
Assuntos
Humanos , Terapia de Reposição de Enzimas , Doença de Gaucher/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II , Lisossomos , Estudos RetrospectivosRESUMO
OBJETIVO: La tecnología de espectrometría de masas en tándem (MS/MS) en los programas de cribado neonatal ha permitido la detección de gran número de errores congénitos del metabolismo (ECM). En la comunidad de Madrid se implementó en marzo de 2011 incluyendo 13 aminoacidopatías, defectos de la beta-oxidación de ácidos grasos y acidemias orgánicas. El objetivo de este estudio fue describir nuestra experiencia y analizar los casos positivos de cribado en un periodo de 9 años (2011-2019). MÉTODOS: Durante el periodo de estudio se realizó el cribado mediante MS/MS a 592822 recién nacidos en la Comunidad de Madrid. Se cuantificaron aminoácidos, acilcarnitinas y succinilacetona en todas las muestras que cumplieron los criterios de calidad. Se calcularon medias, medianas, percentiles y desviación típica de los analitos y ratios de interés. RESULTADOS: Se derivaron a las unidades clínicas de seguimiento por sospecha de una ECM un total de 901 (0,15 %) casos. Se confirmaron 230 casos de 30 ECM diferentes (prevalencia 1:2577), 11 de los cuales no eran inicialmente objetivo de detección del programa. El valor predictivo positivo global fue de 25,6 %. Durante este periodo se detectaron dos falsos negativos. Las enfermedades con mayor prevalencia fueron fenilcetonuria/hiperfenilalaninemia y deficiencia de acil-CoA deshidrogenasa de cadena media (1:6444 y 1: 13174 respectivamente). 93 % de los casos fueron detectados en fase presintomática. CONCLUSIONES: En estos 9 años de experiencia se han detectado numerosos casos de ECM con un valor predictivo positivo global aceptable. Estos resultados confirman la utilidad del cribado neonatal de ECM como programa de salud pública
OBJECTIVE: Tandem mass spectrometry (MS/MS) is being used for newborn screening since this laboratory testing technology increases the number of metabolic disorders that can be detected from dried blood-spot specimens. In the Community of Madrid, it was implemented in March 2011 and it includes 13 aminoacidopathies, fatty acid oxidation disorders and organic acidemias. The aim of this study was to describe our experience and evaluate the screening positive cases in a period of 9 years (2011-2019). METHODS: During the period of the study, a total of 592.822 neonates were screened with this expanded program by MS/MS in the Community of Madrid. Amino acids, acylcarnitines, and succinylacetone were quantified in all samples that met the quality criteria. Means, medians, percentiles and standard deviation of the analytes and ratios of interest were calculated. RESULTS: 901 patients (0,15 %) with a positive screening test were referred to clinical evaluation. 230 patients were diagnosed of 30 different inborn errors of metabolism (prevalence 1:2577), 11 of which were not included as a target in the Community of Madrid newborn screening program. The global positive predictive value was 25,6 %. During this period of time, two false negative cases were detected. The most prevalent disorders were phenylketonuria/hyperphenylalaninemia and medium chain acyl-CoA dehydrogenase deficiency (1:6444 and 1:13174 respectively). 93 % of the patients were detected in the presymptomatic stage. CONCLUSIONS: During the last 9 years a large number of cases of IEM have been detected with an acceptable global positive predictive value. These results confirm the utility of inborn errors of metabolism newborn screening as a public health program
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Carnitina/análogos & derivados , Carnitina/sangue , Cidades , Erros Inatos do Metabolismo Lipídico/epidemiologia , Valor Preditivo dos Testes , Prevalência , EspanhaRESUMO
No disponible
Assuntos
Humanos , Masculino , Lactente , Ataxia/genética , Mutação/genética , Doença CrônicaRESUMO
La acidosis D-láctica es una patología infrecuente, habitualmente descrita en pacientes con síndrome de intestino corto. Se caracteriza por episodios recurrentes de encefalopatía con D-lactato sérico elevado y, generalmente, acidosis metabólica. Para su desarrollo es necesario el sobrecrecimiento de bacterias productoras de D-lactato en el colon. Otros factores, como la ingesta abundante de carbohidratos o la disminución de la motilidad intestinal, pueden favorecer una acidosis D-láctica. Presentamos un caso clínico de acidosis D-láctica recurrente en una niña de cinco años con síndrome de intestino corto secundario a un vólvulo de intestino medio. Recibió tratamiento antibiótico para el sobrecrecimiento bacteriano y restricción de carbohidratos enterales, pese a lo cual presentó recurrencias. Posteriormente, se sustituyó un 25% de su fórmula de nutrición enteral por otra con aporte exclusivo de fructosa, y se restringieron los aportes de otros azúcares fermentables. La evolución a los 16 años ha sido satisfactoria, sin presentar nuevas recurrencias
D-lactic acidosis is an infrequent complication, mainly reported in patients with short bowel syndrome. It is characterized by recurrent episodes of encephalopathy with elevated serum D-lactic acid, usually associating metabolic acidosis. The presence of D-lactate-producing bacteria is necessary for the development of this complication. Other factors, such as the ingestion of large amounts of carbohydrates or reduced intestinal motility, contribute to D-lactic acidosis. We report a case of recurrent D-lactic acidosis in a 5-year-old girl with short bowel syndrome, due to a midgut volvulus. She initially received oral antibiotics in order to treat bacterial overgrowth, together with oral carbohydrates restriction. Nevertheless, recurrences did occur. Subsequently, 25% of the enteral nutrition was replaced for a formula containing fructose exclusively, while other fermentable sugars were restricted from the diet. After 16 years of follow up, further recurrences of D-lactic acidosis were not observed
Assuntos
Humanos , Feminino , Pré-Escolar , Frutose/uso terapêutico , Acidose Láctica/dietoterapia , Dieta da Carga de Carboidratos/efeitos adversos , Recidiva , Volvo Intestinal/complicações , Síndrome do Intestino Curto/complicações , Ácido Láctico/efeitos adversosRESUMO
Presentamos 2 casos clínicos de enfermedad de Gaucher tipo 1 en la infancia y su evolución tras 9 años de tratamiento de sustitución enzimática (TSE). El caso 1 es un niño de 6 años diagnosticado de enfermedad de Gaucher tras haber presentado, coincidiendo con la varicela, un exantema petequial, trombocitopenia, anemia y hepatoesplenomegalia. El caso 2 es una niña remitida a la consulta a los 9 años de edad. Presentaba hepatoesplenomegalia desde los 4 meses y, posteriormente, comenzó con trombocitopenia. Los 2 presentan la mutación N370S/L444P. Se inició TSE con imiglucerasa a 60U/kg cada 2 semanas a los 6 y 9 años, respectivamente. En ambos se alcanzaron los objetivos terapéuticos y se han mantenido a lo largo del tratamiento con una dosis de 30U/kg (AU)
We report two cases of type 1 Gaucher's disease in childhood and their outcomes after 9 years of enzyme replacement therapy. The first case concerns a 6-year-old boy who was diagnosed with Gaucher's disease after developing petechial exanthema, thrombocytopenia, anemia and hepatosplenomegaly, coinciding with chickenpox. The second case involves a 9-year-old girl who was referred to our unit. She had hepatosplenomegaly since 4-month-old and sub sequently developed thrombocytopenia. Both patients have the N370S/L444P mutation. Enzyme replacement therapy was started with 60U/kg imiglucerase every 2 weeks at the age of 6 and 9 years, respectively. In both patients, the therapeutic goals were achieved and maintained throughout treatment with a dose of 30U/kg (AU)