Malignant Migrating Partial Seizures of Infancy (MMPSI): Expansion of Clinical Phenotypic and Genotypic Spectra

Abstract BackgroundMMPSI is a rare early infantile epileptic encephalopathy with unknown etiology and poor prognosis. With the development of genetic techniques, an increasing number of novel pathogenic genes have been shown to be related to MMSPI. This study included 36 patients who were diagnosed with MMPSI; the clinical features, etiology, treatment strategies and outcomes of these patients were determined to explore new genetic etiology and new precision medicine treatment strategies.Results36 patients were enrolled. The main seizure types were focal, tonic and spasms. The main EEG findings were seizure migration and hypsarrhythmia. 17/36 cases had causative variants across 11 genes, including 6 novel MMPSI genes: PCDH19, ALDH7A1, DOCK6, PRRT2, ALG1 and ATP7A. 13/36 patients had ineffective seizure control, 14/36 patients had severe retardation and 6/36 patients died. Of them, the genes for ineffective seizure control, severe retardation or death include KCNT1, SCN2A, SCN1A, ALG1, ATP7A and WWOX. Genes associated with seizure-free, mild-moderate retardation or normal development included PRRT2, SCN2A, ALDH7A1 and PNPO. Vitamin B6 allowed patients with ALDH7A1 and PNPO mutations to achieve seizure-free status, oxcarbazepine was effective for patients with SCN2A, ATP7A, WWOX, and PRRT2 mutations, and ACTH was partly effective for DOCK6 mutation patients with spasms and hypsarrhythmia. 17 patients had abnormal MRI, of which 8 had ineffective seizure control, 7 had severe retardation and 4 (4/17, 23.5%) died. 13 patients had hypsarrhythmia, of which 6 had ineffective seizure control, 6 had severe retardation and 2 died. Also, 7 patients had burst suppression, of which 1 had ineffective seizure control, 3 had severe retardation and 3 died.ConclusionThis study is the first to report that ALDH7A1, ATP7A, DOCK6, PRRT2, ALG1, and PCDH19 mutations cause the phenotypic spectrum of MMPSI to expand the genotypic spectrum. The genes KCNT1, SCN2A, SCN1A, ALG1, ATP7A and WWOX may be associated with poor prognosis. The patients presenting with MRI abnormalities, hypsarrhythmia and burst suppression in EEG may be associated with poor prognosis. Through early diagnosis with genetic tests and the administration of the corresponding precise treatment, the outcomes of MMPSI can be notably improved.