Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum

Abstract

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

SCN2A encephalopathy

“…25,26 Phenotypic features that distinguish SCN2A-associated EIMFS from KCNT1-associated EIMFS 25 include severe movement disorders and response to phenytoin in some patients. Two patients showed a considerably better outcome than is usual for EIMFS.…”

“…While Dravet syndrome is differentiated by age at onset and seizure types, rare cases of EIMFS due to SCN1A mutations are described. 26,36,38 SCN8A encephalopathy can present with early-onset EE and responds to sodium channel blockers 27,30,39 in contradistinction to SCN1A diseases. 38,40 However, the median age at onset of 5 months for SCN8A is later, [4][5][6][7][8][9][10][11][12][13][14][15][16][17]19,27 which may reflect the respective patterns of expression of the subunits.…”

KCNT1 gain-of-function mutations linked to human epilepsy are modulated by quinidine

“…In the last decade research has also shown that these channels have additional modulatory functions, which are regulated by a number of signaling pathways [5][6] . The majority of the recently identified mutations [7][8][9][10] are situated in the c-terminus of the alpha subunit of KCNT1, where modulatory regions, such as the NAD + binding domain [5] and several putative consensus sites for protein kinase C (PKC) [6] are located. Emerging evidence indicates that subtle changes in the function of this channel have a deleterious impact on the fragile developing brain [7][8][9][10] .…”

“…The majority of the recently identified mutations [7][8][9][10] are situated in the c-terminus of the alpha subunit of KCNT1, where modulatory regions, such as the NAD + binding domain [5] and several putative consensus sites for protein kinase C (PKC) [6] are located. Emerging evidence indicates that subtle changes in the function of this channel have a deleterious impact on the fragile developing brain [7][8][9][10] . Our latest study sought to examine the functional phenotype of KCNT1 mutations associated with these early-onset epileptic syndromes.…”

“…Importantly, the magnitude of this gain-of-function correlates with the severity of the clinical presentation, albeit confirmation with more samples will strengthen this finding. KCNT1 linked early-onset epileptic syndromes are refractory with devastating clinical severity [7][8][9][10] , generating a serious need for effective therapies. This prompted us to investigate the effects of quinidine; an FDA approved antiarrhythmic compound and an earlier proven blocker of rodent KCNT1 channels [12][13] .…”