Novel frameshift mutation in LIS1 gene is a probable cause of lissencephaly: a case report.

BACKGROUND: Lissencephaly (LIS) is a cortical malformation, characterized by smooth or nearly smooth cerebral surface and a shortage of gyral and sulcal development, which is caused by deficient neuronal migration during embryogenesis. Neuronal migration involves many gene products, among which is the product of the PAFAH1B1 gene, associated with this disease. LIS is a rare disease, characterized by low population frequency, and with non-specific clinical symptoms such as early epilepsy, developmental delay or cerebral palsy-like motor problems. Given that high-throughput sequencing techniques have been improving diagnosis, we have chosen this technique for addressing this patient. CASE PRESENTATION: We present the case of a seven years old male patient with an undiagnosed rare disease, with non-specific clinical symptoms possibly compatible with lissencephaly. The patient was enrolled in a study that included the sequencing of his whole genome. Sequence data was analyzed following a bioinformatic pipeline. The variants obtained were annotated and then subjected to different filters for prioritization. Also mitochondrial genome was analyzed. A novel candidate frameshift insertion in known PAFAH1B1 gene was found, explaining the index case phenotype. The assessment through in silico tools reported that it causes nonsense mediated mechanisms and that it is damaging with high confidence scores. The insertion causes a change in the reading frame, and produces a premature stop codon, severely affecting the protein function and probably the silencing of one allele. The healthy mother did not carry the mutation, and the unaffected father was not available for analysis. CONCLUSIONS: Through this work we found a novel de novo mutation in LIS1/PAFAH1B1 gene, as a likely cause of a rare disease in a young boy with non-specific clinical symptoms. The mutation found correlates with the phenotype studied since the loss of function in the gene product has already been described in this condition. Since there are no other variants in the PAFAH1B1 gene with low population frequency and due to family history, a de novo disease mechanism is proposed.

[Bilateral paramedian thalamic infraction due artery of Percheron occlusion]. / Infarto talámico paramedial bilateral por oclusión de la arteria de Percherón.

INTRODUCTION: Artery of Percheron (AOP) is an anatomical variant responsible for the bilateral irrigation of both the medial thalami and rostral sector of the brainstem. Its obstruction causes infarcts in these areas. OBJECTIVE: To describe a clinical case of AOP infarction, highlighting the clinical and imaging fin dings to consider this pathology in the pediatric population with acute altered state of consciousness. CLINICAL CASE: A healthy 17-year-old adolescent presented with altered state of consciousness and diplopia, which was resolved in a few hours. Brain MRI showed a bilateral medial thalamic infarction, diagnosing an occlusion of the AOP. The only presumed etiological element was the presence of a patent foramen ovale. Surgical correction of the cardiac defect and anticoagulation were performed, with complete recovery. CONCLUSION: It is essential to know the clinical-radiological pattern of this condition, which is very characteristic, but infrequent in the pediatric age.

Mecanismos de lesión cerebral en niños prematuros / Mechanisms of brain injury of the premature baby

Los nacimientos prematuros son uno de los principales indicadores de salud de un país. Están asociados a una alta mortalidad e importante morbilidad en niños con parálisis cerebral y otros trastornos del neurodesarrollo, incluyendo problemas cognitivos y del aprendizaje. Los principales tipos de lesión encefálica en los recién nacidos prematuros son: a) las lesiones de la sustancia blanca, generalmente asociadas a alteraciones neuronales y axonales en la corteza cerebral y otras zonas de sustancia gris; b) hemorragias intracraneanas que incluyen las de la matriz germinal, intraventriculares e intraparenquimatosas y c) del cerebelo. Las lesiones de sustancia blanca incluyen la leucomalacia periventricular quística, no quística (con focos de necrosis microscópicos) y lesiones difusas de sustancia blanca, no necróticas. Estas lesiones tienen múltiples factores etiológicos. Las características anatómicas y fisiológicas de las estructuras vasculares periventriculares predisponen a la sustancia blanca a ser muy vulnerable a las situaciones de isquemia cerebral y, en interacción con factores infecciosos/inflamatorios, activan a las microglías generando estrés oxidativo (por liberación de radicales libres del oxígeno y del nitrógeno), liberación de citoquinas proinflamatorias, liberación de glutamato, fallo energético y alteración de la integridad vascular. Todo lo anteriormente mencionado genera una particular vulnerabilidad de los pre-oligodendrocitos que termina alterando la mielinización. La hipoxia-isquemia también puede producir necrosis neuronal selectiva en diferentes regiones encefálicas. La matriz germinal es un área altamente vascularizada en la región subependimaria periventricular con una estructura capilar muy frágil que la predispone a las hemorragias.

Preterm birth is one of the main country health indicators. It is associated with high mortality and significant morbidity in preterm newborns with cerebral palsy and potential long-term neurodevelopmental disabilities like cognitive and learning problems. The main lesions could be: a) white matter injuries, generally associated with cortical and other regions of grey matter neuronal-axonal disturbances; b) intracranial hemorrhage that includes germinal matrix, intraventricular and parenchymal, c) cerebellum injuries. The white matter lesions include cystic and non-cystic (with microscopic focal necrosis) periventricular leukomalacia and non-necrotic diffuse white matter injury. Multiple etiologic factors are associated with these injuries. Anatomical and physiological characteristics of periventricular vascular structures predispose white matter to cerebral ischemia and, interacting with infection/inflammation factors, activate microglia, generating oxidative stress (mediated by free oxygen and nitrogen radicals), pro-inflammatory cytokine and glutamate toxicity, energetic failure and vascular integrity disturbances. All these factors lead to a particular vulnerability of pre-oligodendrocytes that will affect myelination. Hypoxia-ischemia also may produce selective neuronal necrosis in different cerebral regions. Germinal matrix is a highly vascularized zone beneath ependymal or periventricular region that constitutes a capillary bed with a particular structural fragility that predispose it to hemorrhage.

Neuropatía oftalmoplejica dolorosa recurrente (migraña oftalmoplejica): Caso clínico / Ophthalmoplegic recurrent painful neuropathy (ophthalmoplegic migraine): Case report

La Neuropatía oftalmopléjica dolorosa recurrente o migraña oftalmopléjica es una variante infrecuente de cefalea primaria. Se define como al menos dos episodios de cefalea unilateral que se acompaña de paresia ipsilateral de uno, dos o los tres nervios oculomotores. Se debe excluir una lesión orbitaria, paraselar o de la fosa posterior, y no debe ser mejor explicada por otro diagnóstico. Se describe el caso de un pre-escolar de 3 años, sin antecedentes a destacar, que presenta 3 episodios de oftalmoparesia caracterizada por ptosis palpebral y estrabismo divergente con descenso ocular del ojo izquierdo, de hasta 10 días de duración, precedido por irritabilidad, cefalea, vómitos y somnolencia posterior. Se realizó estudios de laboratorio, los cuales fueron normales. La resonancia magnética craneal mostró captación de contraste a nivel de la emergencia del III par craneano izquierdodurante uno de los episodios. Destacamos la importancia de considerar este cuadro como causa recurrente de parálisis óculo-motora. Consideramos importante el valor de la resonancia, no solo para descartar diagnósticos diferenciales, sino como herramienta de confirmación diagnóstica. Se reporta la reducción de los días de compromiso oculomotor tras la administración de corticoides.

Recurrent painful ophtalmoplegic neuropathy or ophthalmoplegic migrane is a rare type of primary headache. It is characterized as at least two episodes of unilateral headaches accompanied by ipsilateral paresis of one, two or the three ocular motor nerves. Orbital, parasellar and posterior fossa lessions must be excluded, and it is not better accounted by other diagnosis. We report clinical, imaging and laboratory tests of a three years old boy who developed three episodes of left eye ptosis with divergent strabismus and downgaze deviation of left eye, preceded by headache, irritability, vomiting and sleepiness. Ophtalmoparesis episodes lasted up to 10 days. Laboratory tests were normal. Magnetic resonance showed gadolinium enhancement of the third cranial nerve during one attack. We highlight the need to consider ophtalmoplegicmigrane in all cases of recurrent oculomotor palsy, and the importance of themagnetic resonance imaging, not just to rule out other possible etiologies, but also as a confirmative test. This case showed improvement of clinical signs after steroid therapy.