Blood cell respiration rates and mtDNA copy number: A promising tool for the diagnosis of mitochondrial disease.

Human mitochondrial diseases are a group of heterogeneous diseases caused by defects in oxidative phosphorylation, due to mutations in mitochondrial (mtDNA) or nuclear DNA. The diagnosis of mitochondrial disease is challenging since mutations in multiple genes can affect mitochondrial function, there is considerable clinical variability and a poor correlation between genotype and phenotype. Herein we assessed mitochondrial function in peripheral blood mononuclear cells (PBMCs) and platelets from volunteers without known metabolic pathology and patients with mitochondrial disease. Oxygen consumption rates were evaluated and respiratory parameters indicative of mitochondrial function were obtained. A negative correlation between age and respiratory parameters of PBMCs from control individuals was observed. Surprisingly, respiratory parameters of PBMCs normalized by cell number were similar in patients and young controls. Considering possible compensatory mechanisms, mtDNA copy number in PBMCs was quantified and an increase was found in patients with respect to controls. Hence, respiratory parameters normalized by mtDNA copy number were determined, and in these conditions a decrease in maximum respiration rate and spare respiratory capacity was observed in patients relative to control individuals. In platelets no decay was seen in mitochondrial function with age, while a reduction in basal, ATP-independent and ATP-dependent respiration normalized by cell number was detected in patients compared to control subjects. In summary, our results offer promising perspectives regarding the assessment of mitochondrial function in blood cells for the diagnosis of mitochondrial disease, minimizing the need for invasive procedures such as muscle biopsies, and for following disease progression and response to treatments.

Current Practices and Challenges in the Diagnosis and Management of PKU in Latin America: A Multicenter Survey.

This study aimed to describe the current practices in the diagnosis and dietary management of phenylketonuria (PKU) in Latin America, as well as the main barriers to treatment. We developed a 44-item online survey aimed at health professionals. After a pilot test, the final version was sent to 25 practitioners working with inborn errors of metabolism (IEM) in 14 countries. Our results include 22 centers in 13 countries. Most countries (12/13) screened newborns for PKU. Phenylalanine (Phe) targets at different ages were very heterogeneous among centers, with greater consistency at the 0-1 year age group (14/22 sought 120-240 µmol/L) and the lowest at >12 years (10 targets reported). Most countries had only unflavored powdered amino acid substitutes (10/13) and did not have low-protein foods (8/13). Only 3/13 countries had regional databases of the Phe content of foods, and only 4/22 centers had nutrient analysis software. The perceived obstacles to treatment were: low purchasing power (62%), limited/insufficient availability of low-protein foods (60%), poor adherence, and lack of technical resources to manage the diet (50% each). We observed a heterogeneous scenario in the dietary management of PKU, and most countries experienced a lack of dietary resources for both patients and health professionals.

Caracterización bioquímica y genética de pacientes con defectos congénitos de la glicosilación: experiencia en Uruguay / Biochemical and genetic characterization of patients with congenital glycosylation defects: experience in Uruguay

Resumen Los desórdenes congénitos de la glicosilación son un grupo de desórdenes genéticos de herencia, generalmente autosómica y recesiva. Descriptos por primera vez por Jaeken en 1980, comprenden defectos en la N- y O-glicosilación de proteínas y de lípidos. Los pacientes con defectos de N-glicosilación muestran un amplio espectro de manifestaciones clínicas, con alto compromiso neurológico. Por esta razón, se hace necesaria la implementación de una metodología que ayude en el diagnóstico. El Laboratorio de Pesquisa Neonatal incorporó el isoelectroenfoque de transferrina como método de screening y, posteriormente, secuenciación del gen PMM2 como método confirmatorio para las muestras con screening alterado. Se presentan, en este trabajo, la experiencia y los resultados obtenidos entre noviembre de 2017 y diciembre de 2018, los que permitieron establecer un algoritmo de trabajo que impactó positivamente en el diagnóstico de estos pacientes.

Abstract Congenital disorders of glycosylation are a group of genetic, autosomal and recessive diseases, first reported by Jaeken in 1980. These include defects in N- and O-glycosilation of proteins and lipids. Most N-glycosylation defects are multi-organ diseases with neurological involvement. Therefore, the implementation of a screening methodology is necessary to contribute in the diagnosis. Newborn Screening Laboratory included the transferrin isoelectrofocusing as a screening method and, subsequently, PMM2 gene sequencing as a confirmatory method for samples with altered screening. The present study shows the experience and results obtained between November 2017 and December 2018, which made it possible to establish an algorithm that positively impacted in the diagnosis of these patients.

Resumo Os defeitos congênitos da glicosilação (CDG) são um grupo de doenças genéticas, autossômicas e recessivas.Descritos pela primeira vez por Jaeken em 1980, eles incluem na N- e O- glicosilação de proteínas e lipídios.Pacientes com defeitos da N-glicosilação mostram um amplo espectro de manifestações clínicas, com alto comprometimento neurológico. Por esse motivo, a implementação de uma metodologia necessária para contribuirno diagnóstico. O Laboratório de Pesquisa Neonatal incorporou isoeletro-enfoque da transferrina (IEF)como método de screening e posterior sequenciamento do gene PMM2 como método confirmatório para asamostras que apresentaram triagem alterada. Neste trabalho, são apresentadas as experiências e resultadosobtidos entre novembro de 2017 e dezembro de 2018, que permitiram estabelecer um algoritmo de trabalhoque teve um impacto positivo no diagnóstico desses pacientes.

Encefalopatía subaguda adquirida del lactante por deficiencia de vitamina B12 materna / Subacute acquired encephalopathy secondary to maternal vitamin B12 deficiency / Encefalopatia subaguda adquirida em lactente devida à deficiência materna de vitamina B12

Resumen: Introducción: la deficiencia de vitamina B12 es infrecuente en la edad pediátrica. Puede producir síntomas neurológicos y hematológicos de diferente severidad. Si no se diagnostica y trata oportunamente, puede determinar secuelas neurológicas permanentes. Objetivos: presentar una serie de casos clínicos de encefalopatía secundaria a déficit materno de vitamina B12, discutir su potencial severidad y resaltar la importancia de las medidas de prevención. Metodología: estudio observacional basado en la revisión de las historias clínicas de lactantes con criterios clínicos y de laboratorio compatibles con encefalopatía por deficiencia de vitamina B12 materna. Resultados: se incluyeron cuatro casos clínicos, con edades entre 7 y 15 meses, que presentaron una encefalopatía subaguda por deficiencia de vitamina B12 secundaria a déficit materno luego de un período libre de síntomas, con rechazo del alimento, detención del crecimiento, adelgazamiento, irritabilidad, apatía, regresión del desarrollo, movimientos extrapiramidales y desaceleración de la velocidad del crecimiento del perímetro craneano. Los exámenes complementarios revelaron anemia megaloblástica, niveles bajos de vitamina B12 en el suero, hiperhomocisteinemia y aciduria metilmalónica. Se realizó tratamiento con vitamina B12 con buena evolución posterior. Discusión: la deficiencia de vitamina B12 debe considerarse en el diagnóstico diferencial de lactantes con regresión del desarrollo, movimientos involuntarios de inicio agudo o subagudo, convulsiones y apatía, especialmente si se asocian a anemia megaloblástica. Dado que la sintomatología es relativamente inespecífica, se requiere un alto grado de sospecha para realizar el diagnóstico precoz. El tratamiento es sencillo y eficaz y, de ser precoz, puede prevenir el daño cerebral permanente o la muerte.

Summary: Introduction: cobalamin or vitamin B12 deficiency is unusual in childhood. It may cause neurologic and hematologic symptoms of diverse severity. If not diagnosed and treated on time, it can lead to a severe clinical case of permanent neurological sequelae. The purpose of this study is to report four clinical cases of infants with subacute encephalopathy due to vitamin B12 deficiency after a maternal deficit, discuss its potential severity and emphasize the importance of preventive measures. Methods: observational study based on a review of clinical records of infants that showed clinical and laboratory criteria compatible with encephalopathy secondary to maternal vitamin B12 deficiency. Results: four infants between 7 and 15 months of age were included. They were diagnosed with vitamin B12 deficiency secondary to a maternal deficit. Clinically, they had had a symptom-free period followed by rejection of food, growth arrest, failure to thrive, irritability, apathy, regression of development, extrapyramidal movements and deceleration of cranial perimeter growth. They showed megaloblastic anemia, low serum B12 vitamin levels, hyperhomocysteinemia, and methylmalonic aciduria. They were treated with parenteral B12 vitamin and showed a favorable evolution. Discussion: vitamin B12 deficiency should always be analyzed in the differential diagnosis of infants with developmental regression, involuntary acute onset movements, seizures and apathy, especially associated with megaloblastic anemia. Due to its fairly unspecific clinical features, it high levels of suspicion and an early diagnosis are required. Treatment is simple and effective and can prevent permanent brain damage if started early.

Resumo: Introdução: a deficiência de vitamina B12 é pouco frequente na idade pediátrica. Pode produzir sintomas neurológicos e hematológicos de diferentes níveis de gravidade. Se não for diagnosticada e tratada prontamente, pode determinar sequelas neurológicas permanentes. Objetivos: apresentar uma série de casos clínicos de encefalopatia devida à deficiência materna de vitamina B12, discutir sua potencial gravidade e destacar a importância de medidas preventivas. Metodologia: estudo observacional baseado na revisão de prontuários de lactentes com critérios clínicos e laboratoriais compatíveis com encefalopatia por deficiência materna de vitamina B12. Resultados: foram incluídos 4 casos clínicos, com idades entre 7 e 15 meses, que apresentaram encefalopatia subaguda por deficiência de vitamina B12 devida à deficiência materna após período livre de sintomas, com rejeição alimentar, parada de crescimento, perda de peso, irritabilidade, apatia, regressão do desenvolvimento, movimentos extrapiramidais e desaceleração da taxa de crescimento do perímetro cefálico. Os exames complementares revelaram anemia megaloblástica, baixos níveis séricos de vitamina B12, hiper-homocisteinemia e acidúria metilmalônica. O tratamento com vitamina B12 foi realizado com boa evolução subsequente. Discussão: a deficiência de vitamina B12 deve ser avaliada no diagnóstico diferencial de lactentes com regressão do desenvolvimento, movimentos involuntários de início agudo ou subagudo, convulsões e apatia, principalmente se estiverem associados à anemia megaloblástica. Como os sintomas são relativamente inespecíficos, é necessário um alto grau de suspeição para poder realizar o diagnóstico precoce. O tratamento é simples e eficaz e, se realizado precocemente, pode prevenir danos cerebrais permanentes ou morte.

Bi-allelic Mutations in EPRS, Encoding the Glutamyl-Prolyl-Aminoacyl-tRNA Synthetase, Cause a Hypomyelinating Leukodystrophy.

Hypomyelinating leukodystrophies are genetic disorders characterized by insufficient myelin deposition during development. They are diagnosed on the basis of both clinical and MRI features followed by genetic confirmation. Here, we report on four unrelated affected individuals with hypomyelination and bi-allelic pathogenic variants in EPRS, the gene encoding cytoplasmic glutamyl-prolyl-aminoacyl-tRNA synthetase. EPRS is a bifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species. It is a subunit of a large multisynthetase complex composed of eight aminoacyl-tRNA synthetases and its three interacting proteins. In total, five different EPRS mutations were identified. The p.Pro1115Arg variation did not affect the assembly of the multisynthetase complex (MSC) as monitored by affinity purification-mass spectrometry. However, immunoblot analyses on protein extracts from fibroblasts of the two affected individuals sharing the p.Pro1115Arg variant showed reduced EPRS amounts. EPRS activity was reduced in one affected individual's lymphoblasts and in a purified recombinant protein model. Interestingly, two other cytoplasmic aminoacyl-tRNA synthetases have previously been implicated in hypomyelinating leukodystrophies bearing clinical and radiological similarities to those in the individuals we studied. We therefore hypothesized that leukodystrophies caused by mutations in genes encoding cytoplasmic aminoacyl-tRNA synthetases share a common underlying mechanism, such as reduced protein availability, abnormal assembly of the multisynthetase complex, and/or abnormal aminoacylation, all resulting in reduced translation capacity and insufficient myelin deposition in the developing brain.

Asociación de melanocitosis dérmica con enfermedades lisosomales / Association of dermal melanocytosis with lysosomal storage diseases

Introducción: la melanocitosis dérmica incluye un espectro de lesiones de piel que abarca la mancha mongólica, entre otras lesiones. Las enfermedades lisosomales son afecciones de base genética que se caracterizan por la acumulación de metabolitos insolubles parciamente degradados en los compartimentos lisosomales, debido a una determinada deficiencia enzimática. Las deficiencias de b-galactosidasa y de a-L-iduronidasa provocan la gangliosidosis GM1 y la mucopolisacaridosis tipo I respectivamente, ambas presentando similitudes en su presentación clínica. La asociación de la melanocitosis dérmica con las enfermedades lisosomales es poco común y mal entendida. Objetivo: reportar dos pacientes con esta rara asociación. Casos clínicos: dos varones de 3 y 9 meses sin antecedentes prenatales ni perinatales a destacar y antecedentes de infecciones respiratorias reiteradas. Se presentaron con retraso del desarrollo, hipotonía central y trastorno deglutorio. Al examen se constató hepatomegalia, fascies tosca y melanosis dérmica extensa. Los estudios permitieron diagnosticar al paciente de 3 meses mucopolisacaridosis Tipo I y al de 9 meses gangliosidosis GM1. Discusión: no se conoce exactamente la causa de esta asociación. Se plantea que sería el resultado de la acumulación de gangliósidos y heparán sulfato que estimularían al receptor del factor de crecimiento neuronal de tipo tirosinquinasa, deteniendo la migración de los melanocitos en la dermis. Por lo tanto la melanosis dérmica aberrante, en el contexto clínico adecuado, puede ser un signo que facilite el diagnóstico de una enfermedad lisosomal subyacente.

Introduction: dermal melanocytosis includes a spectrum of skin lesions, mongolian spots being one of them. Lysosomal storage diseases are characterized by the accumulation of partially degraded insoluble metabolites in lysosomal compartments due to enzyme deficiency. Deficiency in b-galactosidosisis is the cause of GM1 gangliosidosis and deficiency in a-L-iduronidasa of mucopolysaccharidosis type I. Both have similar clinical presentations. Association of dermal melanocytosis and lysosomal storage diseases is uncommon and misunderstood. Objective: to report the case of two patients with this rare association. Clinical cases: the study presents two boys, 3 and 9 months old, with no remarkable family, pregnancy or delivery history. Both had repeated respiratory tract infections. They presented with developmental delay, central hypotonia and swallowing disorder. Upon clinical examination they showed hepatomegaly, coarse facies and extensive dermal melanocytosis. They were diagnosed with GM1 gangliosidosis and mucopolysaccharidosis type I. Discussion: the cause of this association is not well known. It is hypothesized that accumulation of gangliosides and heparan sulfates stimulates tyrosine-kinase neuronal growth factor receptor, stopping dermal melanocytosis migration. Therefore extensive dermal melanocytosis, in an appropriate clinical setting, may contribute to diagnosing lysosomal storage diseases.

3697G>A in MT-ND1 is a causative mutation in mitochondrial disease.

Mitochondrial diseases are a group of clinically heterogeneous disorders that can be difficult to diagnose. We report a two and a half year old girl with clinical symptoms compatible with Leigh disease but with no definitive diagnosis. Using next generation sequencing we found that mutation 3697G>A was responsible for the patient's clinical symptoms. Corroboration was performed via segregation analysis in mother and sister and by evolutionary analysis that showed that the mutation is located in a highly conserved region across a wide range of species. Functional analyses corroborated the mutation effect and indicated that the pathophysiological alterations were partially restored by Coenzyme Q10. In addition, we proposed that the presence of the mutation at high frequencies causes the phenotype in the patient, while other family members with intermediate levels of heteroplasmy are symptoms-free.

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America.

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase(®), Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients' responses.

Unusual Case of Phenylketonuria With Atypical Brain Magnetic Resonance Imaging Findings.

Phenylketonuria is a treatable inborn error of amino acid metabolism caused by deficiency of the enzyme phenylalanine hydroxylase, responsible for converting phenylalanine to tyrosine. We report a 10-month-old boy with psychomotor regression and infantile spasms. He was diagnosed with classic phenylketonuria and West syndrome. Treatment was initiated with phenylalanine-restricted diet and vigabatrin. After 5 months of treatment, he persists with developmental delay, severe hypotonia, swallowing disorder, and drug-resistant epilepsy. Brain magnetic resonance imaging showed the typical abnormalities in supratentorial white matter and exceptional infratentorial and basal ganglia compromise. Severity of white matter abnormalities and neurologic symptoms correlates with blood levels of phenylalanine. Infratentorial changes occur in severe cases. Other mechanisms could take part in cases like this with atypical neuroimaging abnormalities of the basal ganglia.

Déficit de succínico semialdehído deshidrogenasa: Primer caso de aciduria 4 OH butírica en Uruguay

Resumen El déficit de succínico semialdehído deshidrogenasa es una enfermedad rara cuya alteración en la vía catabólica del ácido aminobutírico (principal neurotransmisor del sistema nervioso central) impide el paso de ácido succínico semialdehído a ácido succínico, condicionando un aumento de ácido 4 hidroxibutírico en líquido cefalorraquídeo y plasma, lo que permite la detección de la enfermedad. La clínica es muy inespecífica, pudiendo presentar desde retraso psicomotor, hipotonía, convulsiones y ataxia no progresiva, hasta trastornos de conducta con crisis de ansiedad y rasgos autistas. Los hallazgos a nivel electroencefalográfico incluyen enlentecimiento del ritmo de base, con descargas epileptiformes focales o generalizadas. En la neuroimagen, en tanto, pueden hallarse frecuentemente hiperintensidades bilaterales y simétricas en T2, a nivel del núcleo pálido. Si bien el tratamiento con vigabatrina teóricamente inhibe la formación de succínico semialdehído con la consecuente reducción de los niveles de ácido 4 hidroxibutírico, no existe al momento actual un tratamiento efectivo para todos los casos. El principal objetivo de este artículo es presentar un paciente con deficiencia de succínico semialdehído deshidrogenasa, debido a su excepcionalidad, con solamente 350 casos identificados en el mundo, siendo el primer caso diagnosticado en Uruguay.

Summary Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the catabolic pathway of gamma-aminobutyric acid, the major central nervous system inhibitory neurotransmitter. Because of such deficiency, transamination of gamma-aminobutyric acid to succinic semialdehyde is shunted towards the production of 4-hydroxybutyric acid, a neurotoxic metabolite which becomes abundant in physiologic fluids which allows the detection of the disorder. Clinical features are not specific and consist of psychomotor retardation, seizures, hypotonia and non progressive ataxia. Electroencephalographic finding include background slowing and generalized or focal epileptiform discharges. Magnetic resonance imaging reveals in most of the cases, increased T2-weighted signal of the globus pallidi bilaterally and symmetrically. Eventhough vigabatrin should theoretically inhibit the formation of succinic semialdehyde and therefore 4-hydroxybutyric acid, to date there is no effective treatment for succinic semialdehyde dehydrogenase deficiency. Due to its uniqueness, the main objective of this article is to present a patient with succinic semialdehyde dehydrogenase deficiency, with only 350 cases identified worldwide.

Succinic semialdehyde dehydrogenase (SSADH) deficiency: Molecular analysis in a South American family.

We report the clinical, biochemical and molecular findings on the first documented patient with 4-hydroxybutyric aciduria (4-HBA, McKusick 271980) from Uruguay. The patient displayed a severe picture and turned out to be homozygous for a mutation (c.1226G < A) previously shown to be associated with null enzyme activity.

Tres casos de enfermedad de Gaucher tipo I / Three cases of type I Gaucher disease

La enfermedad de Gaucher tipo I es una afección de herencia autosómica recesiva determinada por deficiencia de actividad de la enzima b-glucosidasa ácida y acúmulo progresivo de glicosilceramida en los lisosomas de células macrofágicas. No tiene compromiso primario del sistema nervioso central, siendo sus síntomas habituales visceromegalias, sangrado, anemia y dolores óseos. Puede presentarse desde la edad pediátrica hasta el adulto mayor o permanecer asintomática. Han sido identificadas numerosas mutaciones, algunas muy frecuentes. Tiene tratamiento sintomático y específico Presentamos tres casos de inicio en edad adulta, no emparentados entre sí y sin padres consanguíneos, analizando aspectos clínicos, bioquímicos, moleculares y de tratamiento actual. Destacamos la importancia del diagnóstico de esta enfermedad genética que tiene pautas de seguimiento y tratamiento específico.

Aciduria glutárica tipo I: descripción del primer caso clínico nacional / Type I glutaric aciduria: first national case report

Presentamos el primer caso nacional de un niño portador de una aciduria glutárica tipo I. Esta afección es un error congénito del metabolismo de los aminoácidos esenciales lisina y triptofano determinado por la deficiencia de la enzima mitocondrial glutaril-coenzima A deshidrogenasa, y en nuestro paciente se presenta como la forma clásica ded la enfermedad con síntomas neurológicos de instalación aguda que involucran principalmente el sistema extrapiramidal. El diagnóstico se realiza al evidedniar la presencia del ácido 3-hidroxiglutárico, específico de esta afección. El tratamiento está dirigido a evitar el compromiso neurológico en los casos asintomáticos ya que una vez instalado el daño neurológico es irreversible.

Muerte inesperada del lactante: diagnóstico de situación en la ciudad de Montevideo / Sudden infant death in Montevideo: a diagnostic evaluation

Objetivo: 1) Aplicar un protocolo de estudio uniforme a todos los lactantes fallecidos en forma inesperada en la ciudad de Montevideo. 2) Obtener el diagnóstico de situación en relación a las verdaderas causas de mortalidad infantil inesperada en la ciudad de Montevideo. 3) Realizar el diagnóstico de situación y posicionamiento real del síndrome de muerte súbita del lactante dentro de las muertes inesperadasMaterial y método: a los lactantes fallecidos inesperadamente en Montevideo, en el período comprendido entre octubre de 1998 y marzo de 2000 se les aplicó sistemáticamente: 1) Autopsia completa protocolizada, con fotografía, radiología, toma de muestras para enfermedades metabólicas, microbiología, toxicología y estudio bioquímico (ionograma del humor vítreo). 2) Se realizó histología completa de todos los órganos. 3.) Se investigaron las circunstancias que rodearon a la muerte y se revisó la historia clínica. 4) Se discutió cada caso en grupo multidisciplinario. Resultados: Se estudiaron 115 casos de los cuales 109 (95 por ciento) correspondieron a menores de un año y 6 a menores entre los 12 y 18 meses. En 65 por ciento de los casos se confirmó una causa de muerte. Correspondieron al grupo de Muerte Explicable. Dentro de este grupo la infección respiratoria baja, las causas cardíacas, la diarrea con deshidratación y la sepsis constituyeron las causas más importantes. El síndrome de muerte súbita del lactante representó el 20 por ciento de la muestra y la zona gris el 15 por ciento. Conclusiones: La realización sistemática de la autopsia protocolizada por patólogo pediatra y forense ha permitido conocer la verdadera causa de muerte en los lactantes de Montevideo que han fallecido inesperadamente. El desarrollo del programa Muerte Inesperada del Lactante ha permitido tomar un tema que en el Uruguay estaba limitado a los archivos judiciales y ponerlo en la mesa de discusión pediátrica para su aplicación en la docencia, investigación y planificación de políticas de salud, siguiendo los criterios actualmente sugeridos por la literatura internacional