RESUMO
OBJECTIVE: To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. METHODS: We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. RESULTS: A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. SIGNIFICANCE: A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Assuntos
Síndrome de Landau-Kleffner/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Criança , Hibridização Genômica Comparativa , Proteínas da Matriz Extracelular/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Receptor EphB2/genética , Receptores de N-Metil-D-Aspartato/genética , Proteína Reelina , Serina Endopeptidases/genética , Gêmeos Monozigóticos/genética , Adulto JovemRESUMO
We report on seven children (five males, two females) who presented with marked, often asymmetrical, toe-walking from onset of independent walking, associated with abnormal foot postures and increased tone at the ankles with characteristics of dystonia. Most of the children had presented with unusual pre-walking locomotion and a mild delay in independent walking. They did not fit into the usual categories of 'habitual' toe-walking or congenital short tendo calcaneus but nor did they have the clinical signs of spastic diplegia or of a peripheral neuromuscular disease. Normalization occurred progressively in the second to fourth years of life. The children were re-examined several years later (1 to 11y) and were normal. We believe that their persistent toe-walking corresponded to a variant of 'transient focal dystonia of infancy'. Knowledge of its existence may justify a period of observation without special investigations, surgery, or casting.