Anatomical and physiological basis of continuous spike-wave of sleep syndrome after early thalamic lesions.

OBJECTIVE: Early neonatal thalamic lesions account for about 14% of continuous spike-wave of sleep (CSWS) syndrome, representing the most common etiology in this epileptic encephalopathy in children, and promise useful insights into the pathophysiology of the disease. METHODS: We describe nine patients with unilateral neonatal thalamic lesions which progressed to CSWS. Longitudinal whole-night and high-density electroencephalograms (EEGs) were performed, as well as detailed imaging and clinical evaluation. Visual evoked potentials were used to probe cortical excitability. RESULTS: Thalamic volume loss ranged from 19% to 94%, predominantly on medial and dorsal nuclei and sparing the ventral thalamus. Lesions produced white matter loss and ventricle enlargement on the same hemisphere, which in four patients was associated with selective loss of thalamic-cortical fibers. Cortical thickness quantification failed to reveal hemispheric asymmetries. Impact on EEG rhythms was mild, with a volume-loss-related decrease in alpha power and preservation of sleep spindles. The sleep continuous spiking was lateralized to the hemisphere with the lesion. Visual cortex stimulation in five patients with posterior cortex spiking revealed an abnormal frequency-dependent excitability at 10-20Hz on the side of the lesion. SIGNIFICANCE: Unilateral selective thalamic-cortical disconnection is a common feature in our patients and is associated with both a focal pattern of CSWS and a pathological type of frequency-dependent excitability (peak: 10-20Hz). We propose that this excitability represents an abnormal synaptic plasticity previously described as the augmenting response. This synaptic plasticity has been described as absent in the corticocortical interactions in healthy experimental animals, emerging after ablation of the thalamus and producing a frequency-dependent potentiation with a peak at 10-20Hz. Because this response is potentiated by sleep states of reduced brainstem activation and by appropriate stimulating rhythms, such as sleep spindles, the simultaneous occurrence of these two factors in nonrapid-eye-movement sleep is proposed as an explanation for CSWS in our patients.

LYRM7 mutations cause a multifocal cavitating leukoencephalopathy with distinct MRI appearance.

This study focused on the molecular characterization of patients with leukoencephalopathy associated with a specific biochemical defect of mitochondrial respiratory chain complex III, and explores the impact of a distinct magnetic resonance imaging pattern of leukoencephalopathy to detect biallelic mutations in LYRM7 in patients with biochemically unclassified leukoencephalopathy. 'Targeted resequencing' of a custom panel including genes coding for mitochondrial proteins was performed in patients with complex III deficiency without a molecular genetic diagnosis. Based on brain magnetic resonance imaging findings in these patients, we selected additional patients from a database of unclassified leukoencephalopathies who were scanned for mutations in LYRM7 by Sanger sequencing. Targeted sequencing revealed homozygous mutations in LYRM7, encoding mitochondrial LYR motif-containing protein 7, in four patients from three unrelated families who had a leukoencephalopathy and complex III deficiency. Two subjects harboured previously unreported variants predicted to be damaging, while two siblings carried an already reported pathogenic homozygous missense change. Sanger sequencing performed in the second cohort of patients revealed LYRM7 mutations in three additional patients, who were selected on the basis of the magnetic resonance imaging pattern. All patients had a consistent magnetic resonance imaging pattern of progressive signal abnormalities with multifocal small cavitations in the periventricular and deep cerebral white matter. Early motor development was delayed in half of the patients. All patients but one presented with subacute neurological deterioration in infancy or childhood, preceded by a febrile infection, and most patients had repeated episodes of subacute encephalopathy with motor regression, irritability and stupor or coma resulting in major handicap or death. LYRM7 protein was strongly reduced in available samples from patients; decreased complex III holocomplex was observed in fibroblasts from a patient carrying a splice site variant; functional studies in yeast confirmed the pathogenicity of two novel mutations. Mutations in LYRM7 were previously found in a single patient with a severe form of infantile onset encephalopathy. We provide new molecular, clinical, and neuroimaging data allowing us to characterize more accurately the molecular spectrum of LYRM7 mutations highlighting that a distinct and recognizable magnetic resonance imaging pattern is related to mutations in this gene. Inter- and intrafamilial variability exists and we observed one patient who was asymptomatic by the age of 6 years.

Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community.

Maple syrup urine disease (MSUD) is an autosomal recessive disorder, caused by the defective function of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD). BCKD is a mitochondrial complex, encoded by four nuclear genes (BCKDHA, BCKDHB, DBT and DLD), involved in the metabolism of branched-chain amino acids (BCAAs). Since the MSUD mutational spectrum has not been previously assessed in Portugal, in this study we present the molecular characterization of 30 MSUD Portuguese patients. Seventeen putative mutations have been identified (six in BCKDHA, five in BCKDHB and six in DBT); seven of them are here described for the first time. The most common mutation identified was a C deletion in BCKDHA gene (c.117delC; p.R40GfsX23), already reported in the Spanish population. Interestingly, it was found in all patients of a Gypsy community from South of the country, so a founder effect is probably responsible for the high incidence of the disease in this community. Structural models of MSUD missense mutations have been performed to understand their pathogenic effect, in order to elucidate and often to predict the severity of a mutation clinical consequence.

Variante faringo-cérvico-braquial da síndrome de Guillain-Barré:uma causa rara de disfunção bulbar aguda em crianças / Pharyngeal-cervical-brachial variant of Guillain-Barré syndrome:a rare cause of acute bulbar dysfunction in children

Aims: To report a case of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome, which is characterized by rapidly progressivebulbar palsy with upper limb, neck and oropharyngeal involvement. It is a rare disorder in childhood and most cases have been described inadolescents.Case Description: A seven year-old-boy presented with dysarthria, hoarseness, dysphagia, facial diplegia and bilateral progressive upperlimb weakness. These symptoms started two weeks after a gastrointestinal infection. Nerve conduction studies were compatible with an acutedemyelinating polyneuropathy in the upper extremities. Anti-ganglioside antibodies in the serum (anti-GT1a, GD1a, GQ1b) were positiveand Campylobacter jejuni was isolated from stools. The patient was treated with intravenous immunoglobulin and needed ventilatory supportduring the first 12 days of admission. He was discharged at day 15 showing improvement of his neurological deficits. He fully recovered aftereleven months of follow-up.Conclusions: Although pharyngeal-cervical-brachial variant of Guillain-Barré syndrome is uncommon in children, it should be consideredin a child with acute bulbar dysfunction because a timely diagnosis allows the early institution of therapeutic measures that can be lifesaving.

Objetivos: Relatar um caso da variante faringo-cervico-braquial da síndrome de Guillain-Barré, que se caracteriza por paralisia bulbarrapidamente progressiva com envolvimento dos membros superiores, pescoço e região orofaríngea. É um diagnóstico raro na criança, ocorrendoa maioria dos casos em adolescentes.Descrição do Caso: Um menino de sete anos de idade iniciou com queixas de disartria, disfonia, disfagia, diplegia facial e fraqueza muscularprogressiva dos membros superiores. Estes sintomas surgiram duas semanas após uma infeção gastrointestinal. Os estudos eletrofisiológicosforam compatíveis com polineuropatia aguda desmielinizante nos membros superiores. Os anticorpos anti-gangliosídeo no plasma(anti-GT1a, GD1a, GQ1b) foram positivos e Campylobacter jejuni foi isolado nas fezes. O paciente foi tratado com imunoglobulina endovenosae necessitou de suporte ventilatório durante os primeiros 12 dias. Teve alta no 15º dia com melhora dos sintomas neurológicos. Recuperou-setotalmente após 11 meses de seguimento.Conclusões: Apesar da variante faringo-cervico-braquial ser pouco frequente em idade pediátrica, é um diagnóstico que deve ser consideradoperante uma criança com disfunção bulbar aguda, pois a identificação precoce permite instituir rapidamente medidas terapêuticas que podemevitar a morte.

[Peutz-Jeghers syndrome: variability of gastrointestinal expression at pediatric age]. / Sindrome de Peutz-Jeghers. Diversidade de expressão gastrointestinal em idade pediátrica e considerações sobre a sua abordagem clínica.

Peutz-Jeghers syndrome is a rare autosomal dominant condition, characterized by gastrointestinal polyposis, mucocutaneous pigmentation and high risk of neoplasia in multiple organs. At pediatric age, major clinical impact is related to complications associated to intestinal polyps, but neoplasic risk isn't negligible. Though clinical surveillance is recommended since the age of 10 years, relevant lesions may occur before that age. Conventional radiology and endoscopy have recognized limitations at this age group, and new diagnostic and intervention tools, such as video-capsule and per-operative enteroscopy, are not yet widely used. We present 5 pediatric cases (age under 10 years) with diversity of gastrointestinal expression (including one case with histologic evidence of dysplasia in a large colonic polyp), emphasizing the need of specific guidelines concerning young children.