Encefalitis aguda necrotizante, diagnóstico retador en una niña con deterioro neurológico súbito

La encefalopatía aguda necrotizante (EAN) es una entidad muy poco frecuente, con compromiso neurológico importante, en la cual los hallazgos radiológicos de lesiones en sistema nervioso central necróticas, simétricas y multifocales son esenciales para diagnosticarla. Se asocia a una respuesta inmune exagerada. Se reporta el caso de una niña de 1 año y 3 meses, previamente sana y con un deterioro neurológico súbito posterior a un cuadro febril de un día y convulsiones, con necesidad de reanimación y ventilación. La neuroimagen demostró las lesiones características de EAN y se manejó con tratamiento inmunomodulador así como antibiótico y antiviral. Se aisló únicamente un adenovirus y rinovirus en muestra respiratoria. La paciente sobrevivió con morbilidad importante como secuelas neurológicas, traqueostomía y gastrostomía. Este es el primer de EAN caso publicado en Costa Rica.

Acute necroziting encephalopathy (ANE) is a rare and serious entity, with significant neurological involvement, in which the radiological findings of symmetric and multifocal necroziting lesions in central nervous system are characteristic. It is an immune-mediated disease with incompletely recognized pathogenesis. We present the case of a 1 year old child, previously healthy, that presented with acute neurological deterioration after a day of fever and seizures. She required reanimation and ventilation. Typical findings of ANE were found in neuroimaging and she was treated with inmunomodulating therapy, antibiotics and antivirals. Only rhinovirus and adenovirus were isolated in respiratory sample. The patient survived with significant neurological sequelae. This is the first case of ANE published in Costa Rica.

Epidemiology, Etiology and Clinical Aspects of Childhood Acute Encephalitis in a Tertiary Pediatric Hospital in Costa Rica.

BACKGROUND: Limited data are available on childhood encephalitis in Latin America. Our study aimed to increase insight on clinical presentation, etiology and outcome of children with acute encephalitis in Costa Rica. METHODS: We conducted a prospective, observational study during an 8-month period at the Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera" in Costa Rica. Case definition was according to "International Encephalitis Consortium" in children <13 years. We analyzed demographic characteristics, clinical symptoms, neurologic imaging, etiology, treatment and mortality. RESULTS: Forty patients were identified. Mean age was 5 years and 57.5% were male. Most frequently neurologic symptoms were altered mental status (100.0%), headache (57.5%) and seizures (52.5%). Etiology was determined in 52.5% of cases. Probable or confirmed viral etiology was identified in 6 cases (15.0%) and bacterial etiology in also 6 cases (15.0%). A possible etiology was identified in 7 cases (17.5%). Autoimmune encephalitis was diagnosed in 2 patients (5.0%). Enterovirus and Streptococcus pneumoniae were the most common confirmed agents. No cases of herpes simplex virus were found. Etiology of 19 cases (47.5%) remained unknown. Sequelae were reported in 45.0% of patients. Mortality rate was 15.0% (6 cases), 3 caused by virus (adenovirus, human herpesvirus 6, enterovirus), 2 by bacteria (S. pneumoniae, Haemophilus influenzae type b) and 1 of unknown etiology. Diffuse cerebral edema was the most important mortality predictor (P < 0.001). CONCLUSIONS: Acute encephalitis in our study was associated with significant morbidity and mortality. Early and aggressive antiviral, antibiotic and anticerebral edema treatment is necessary when acute encephalitis is suspected.

The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25.

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

First clinical and genetic description of a family diagnosed with late-onset Pompe disease from Costa Rica.

Glycogen storage disease type II, also known as Pompe disease, is an autosomal recessive disorder caused by deficiency of enzymatic activity of acid alpha-glucosidase. The wide phenotypical variation of this disease relates to the amount of residual enzymatic activity depending on the combination of mutations on each allele. We confirmed Pompe disease in a patient that presented with progressive weakness, recurrent episodes of respiratory failure associated with pneumonia, a predominantly demyelinating mixed sensorimotor polyneuropathy and paraspinal complex repetitive discharges. Genetic analysis of the GAA gene from this patient revealed two pathogenic compound heterozygous mutations: c.-32-13T>G (rs386834236, intronic), c.2560C>T (rs121907943, p.Arg854Ter); and one variant of unknown significance: c.1551+42G>A (rs115427918, intronic). We found expected mutations in two siblings and two nieces. Genetic variants reported in this family reflect on the European and African ancestry that we carry in our Costa Rican population.

A Homozygous Mutation in GPT2 Associated with Nonsyndromic Intellectual Disability in a Consanguineous Family from Costa Rica.

Intellectual disability is a highly heterogeneous disease that affects the central nervous system and impairs patients' ability to function independently. Despite multiples genes involved in the etiology of disease, most of the genetic background is yet to be discovered. We used runs of homozygosity and exome sequencing to study a large Costa Rican family with four individuals affected with severe intellectual disability and found a novel homozygous missense mutation, p. 96G>R, c. 286G>A, in all affected individuals. This gene encodes for a pyridoxal enzyme involved in the production of the neurotransmitter glutamate and is highly expressed in the white matter of brain and cerebellum. Protein modeling of GPT2 predicted that the mutation is located in a loop where the substrate binds to the active site of the enzyme, therefore, suggesting that the catalytic activity is impaired. With our report of a second mutation we fortify the importance of GPT2 as a novel cause of autosomal recessive nonsyndromic intellectual disability and support the premise that GPT2 is highly important for the neurodevelopment of the central nervous system. SYNOPSIS: The mutation p. 96G>R c. 286G>A in GPT2, located in a loop where the substrate binds to the active site of the enzyme, fortifies the importance of GPT2 in the pathogenesis of nonsyndromic intellectual disability.

Síndrome de Bickerstaff / Bickerstaff Syndrome

La encefalitis de Bickerstaff es una entidad infrecuente de origen post infeccioso de presentación grave, que pertenece al espectro de las patologías asociadas a los antigangliósidos, donde el paciente se presenta con compromiso subagudo de oftalmoplejia, ataxia, debilidad con signos piramidales y alteración del estado de conciencia con antecedentes recientes de infecciones respiratorias, gastrointestinales o ambas. Se reporta un caso de encefalitis de Bickerstaff presentado en el Hospital Nacional de Niños.

Bickerstaff encephalitis is a rare and severe inflammatory disease with a serious presentation, which belongs to the spectrum of diseases associated with antiganglioside. Patients present a subacute ophthalmoplegia, ataxia, weakness with pyramidal signs and altered mental status with a recent history of respiratory infections, gastrointestinal infections or both. We report a case of Bickerstaff encephalitis that was diagnosed and treated at the Hospital Nacional de Niños (National Children's Hospital).

Neuropatía autonómica sensorial hereditaria / Hereditary sensory and autonomic neuropathy

La insensibilidad congénita al dolor es una patología infantil poco frecuente. Existen cinco diferentes tipos de neuropatía sensorial y autonómica descritas hasta la fecha, cada una de ellas con hallazgos clínicos diversos. A continuación se reporta el caso de un niño de 10 años, con el diagnóstico de neuropatía autonómica sensorial hereditaria tipo IV, condición que presenta una herencia autosómica recesiva. Esta patología se caracteriza por la pérdida de la sensibilidad al dolor y temperatura, anhidrosis, automutilación y retardo mental. La anhidrosis lleva a trastornos de la termorregulación, que pueden causar episodios de fiebre y la pérdida de sensibilidad, se asocia con fracturas y traumas articulares recurrentes...

Aflatoxinas / Aflatoxins

Las aflatoxinas pertenecen a la familia de las micotoxinas, que son sustancias químicas producidas por cepas toxigénicas de hongos, principalmente Aspergillus flavus y Aspergillus parasiticus. Estas sustancias pueden causar enfermedad y muerte, tanto en animales como en seres humanos. Las aflatoxinas son frecuentemente aisladas de alimentos como maíz, arroz, maní y otros, que han tenido un mal manejo postcosecha. La ingestión de aflatoxinas puede producir una enfermedad conocida como aflatoxicosis. La aflatoxina B1 es el factor que más obstaculiza el desarrollo fetal, con mayor capacidad de provocar o acelerar el cáncer, y es además el tipo de aflatoxina que provoca mayores cambios repentinos y permanentes en los genes, entre estos, puede inducir una mutación específica en el codón 249 del gen supresor P53, relacionado con la génesis de tumores. Descriptores: Aflatoxinas, Aspergillus flavus, Aspergillus parasiticus, carcinoma hepatocelular, aflatoxicosis, teratógenos, virus de la hepatitis B.