Clinical ObservationsIdentification of a Novel de Novo p.Phe932Ile KCNT1 Mutation in a Patient With Leukoencephalopathy and Severe Epilepsy
Introduction
Recent advances in magnetic resonance imaging (MRI) analysis have led to significant improvements in the diagnosis of pediatric leukoencephalopathy patients. At least 50% of these patients, however, remain without an ultimate diagnosis1—which, in part, may be due to the fact that the clinical and MRI presentation of leukoencephalopathies can be highly variable. The advent of whole genome and exome sequencing provides an agnostic platform by which to assess individual leukoencephalopathy cases (ideally within the context of their familial genetics) for known and novel disease-associated mutations.
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Patient History
The patient first came to medical attention at 1 month of age when, after an uneventful gestation and delivery, he was noted to have abnormal movements characterized as myoclonic seizures. Over the ensuing months, seizures evolved to consist of both generalized tonic clonic and myoclonic events, with frequent status epilepticus, which was exacerbated by febrile events, resulting in several dozen hospitalizations. Seizures are now better controlled, but on a regimen of oxcarbazepine, topiramate,
Discussion
Three recent reports have shown that mutations in KCNT1, a sodium-gated potassium channel, cause at least two forms of severe epilepsy.5, 6, 7 A set of missense KCNT1 mutations were recently described in four families with NFLE, including a de novo mutation associated with a sporadic case (Fig E).6 Additionally, a total of eight patients from two studies investigating malignant migrating partial seizures of infancy, one subtype of early infantile epileptic encephalopathy, were shown to have
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Cited by (0)
A.V. designed this study and performed clinical analyses; C.S. created the bioinformatics exome pipeline and performed data analyses; J.L.S. participated in study design, participant consent, and research genetic counseling; P.P. provided review of neurophysiology; M.B. participated in study design and provided the clinical description; D.M. performed the family exome sequencing; S.M.G. supervised the exome sequencing; and R.J.T. supervised the exome sequencing and data analysis, and designed this study.
Study Funding: A.V. is supported by a grant from the National Institutes of Health, National Institute of Neurological Disorders and Stroke (1K08NS060695) and the Myelin Disorders Bioregistry Project. R.J.T. is supported by an ARC Discovery Early Career Research Award, Institute for Molecular Bioscience core funds, and a University of Queensland Foundation Research Excellence Award. We acknowledge the Genomics Virtual Lab project and the use of computing resources from the NeCTAR Research Cloud.