Migrating partial seizures of infancy: delineation of the clinical and genetic features in a national patient cohort

Abstract

BACKGROUNDMigrating partial seizures of infancy (MPSI) is a severe, pharmacoresistant, early-onset epilepsy syndrome associated with high morbidity and mortality in which the underlying causal disease mechanisms are poorly understood. We aimed to describe the clinical, radiological, and pathological features of a national cohort of patients and to investigate the genetic basis of the syndrome.METHODSWe did a national surveillance study with data from the British Paediatric Neurology Surveillance Unit, with detailed endophenotyping on the referred cases. The genetic approaches that we took for molecular genetic investigation were: multiple gene panel testing of 29 genes associated with early-onset epilepsy, whole exome sequencing, and direct Sanger sequencing of KCNT1, a recently identified cause of MPSI. The multiple gene panel used Haloplex sequence capture (Agilent, Santa Clara, CA, USA) and Illumina sequencing with a MiSeq platform. For copy number variant analysis we used a custom Roche Nimblegen oligonucleotide 135K aCGH (Roche Diagnostic Ltd, Madison, WI, USA). We analysed sequence data using NextGENe software (Softgenetics, State College, PA USA) and array data using CGH Fusion (InfoQuant, London, UK). We did whole exome sequencing using Illumina paired-end library preparation and sequencing on a Hi-Seq platform. For Sanger sequencing, the genomic KCNT1 DNA sequence was taken from Ensembl and primer pairs for all exons, and flanking intronic regions were designed with primer3 software. Exons were amplified by PCR, sequenced by the BigDye terminator method, and analysed with Chromas/Sequencher software. The research genetic study was approved by the local research ethics committee and specific consent was given by individual parents for genetic studies to be undertaken on a research basis.FINDINGS14 patients met the electroclinical criteria for a diagnosis of MPSI. Several novel clinical findings (movement disorder and severe gut dysmotility) and electrographic features (hypsarrhythmia, burst suppression) were identified. Novel radiological features included delayed myelination in five patients with white matter hyperintensity on brain MRI in four, and decreased N-acetyl aspartate on magnetic resonance spectroscopy in three of four patients. Putaminal atrophy, evident in one patient, has not been previously reported. Neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Genetic investigation showed missense mutations of KCNT1 in three of the nine patients tested. One variant c.2800G>A (p.A934T) was found in several patients and likely to be a common mutation for KCNT1-MPSI. Another mutation, c.811G>T (p.V271F), is a novel, previously unreported variant, which is highly conserved, absent in control populations, and is predicted to be damaging (Polyphen score 0·733).INTERPRETATIONThis study is the first national cohort of patients with this rare condition and expands the electroclinical phenotype of MPSI. We have shown that KCNT1 is an important disease-causing gene in MPSI. However the absence of KCNT1 mutations in many patients suggests that this condition is genetically heterogeneous and further genetic causes are yet to be discovered.FUNDINGNeurology Charitable Fund (Alder Hey Children's Hospital), MPSI support group, Action Medical Research, UK Children's Neurological Research Campaign, Roald Dahl's Marvellous Children's Charity, Great Ormond Street Hospital Children's Charities.