Abstracts

Rationale: Malignant migrating partial epilepsy in infancy (MMPEI) is a severe early onset epileptic encephalopathy with few known etiologies. We identify a novel genetic etiology for MMPEI in a boy whose parents were consanguineous. Methods: The proband was evaluated clinically at Children s Hospital Boston, including EEG, MRI, neurometabolic studies, SCN1A mutation analysis, and chromosome microarray analysis. We ascertained additional cases with features consistent with MMPEI. Blood samples were collected from consenting subjects; genomic DNA was extracted from peripheral blood lymphocytes; Sanger sequencing was used to evaluate additional MMPEI cases for mutations.Results: The proband, born at 42 weeks gestation after a normal pregnancy, is the first child of healthy parents who are first cousins of Palestinian descent. Seizures began at 6 months as episodes of perioral cyanosis, limpness, oral automatisms, eyelid fluttering, and oxygen desaturation. Prior to seizure onset, development was delayed but progressing; once seizures began, there was developmental regression. Examination was notable for marked truncal and appendicular hypotonia. EEG showed multifocal interictal spikes and abundant seizures arising from the right and left temporal lobes independently, at times with migration from one hemisphere to the other within a seizure. MRI revealed mildly prominent cerebrospinal fluid (CSF) spaces. MR spectroscopy was normal. Evaluation for an inborn error of metabolism was negative and included serum lactate, pyruvate, ammonia, amino acids, carnitine profile, biotinidase, and very long chain fatty acids; urine organic acids; and CSF glucose, protein, lactate, amino acids, and neurotransmitters. Point mutation and deletion analysis of SCN1A were also negative. Chromosomal microarray analysis revealed a homozygous ~476kb deletion of chromosome 20p12.3 (0 copies, chr20: 8047741-8523461). Both parents were heterozygous for the deletion. The deletion encompasses the first three exons of the gene phospholipase C beta 1 (PLCB1). We screened three families with more than one affected child with MMPEI and 14 single cases for additional PLCB1 mutations or exon deletions. No additional mutations were found.Conclusions: We report a novel association between MMPEI and PLCB1 in a child of consanguineous parents. The proband has an inherited homozygous deletion of chromosome 20p13, disrupting the PLCB1 gene. PLCB1 encodes an enzyme that generates the intracellular second messengers diacylglycerol and inositol 1,4,5-trisphosphate from phosphatidylinositol 4,5,-bisphosphonate. This gene has recently been associated with a phenotypically distinct epileptic encephalopathy. Animal models of PLCB1 defects have early onset seizures, further supporting the role of this gene in epilepsy. Our findings provide novel insight into the molecular mechanisms underlying MMPEI, highlight the potential importance of chromosome microarray analysis in epilepsy, and further implicate PLCB1 as a candidate gene for severe early onset epilepsy.