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Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.

ABSTRACT: Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C ?1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome diagnosis) and neurodevelopmental delay associated with compound heterozygous mutations in PLCB1. A case note review and molecular genetic investigations were performed for a child, approximately 10 months of age, admitted to Johns Hopkins University Hospital for developmental delay and new-onset seizures. The patient presented at 6 months of age with developmental delay, followed by the onset of intractable, focal, and generalized seizures associated with developmental regression from 10 months of age. Presently, at 2 years of age, the child has severe motor and cognitive delays. Diagnostic microarray revealed a heterozygous 476kb deletion of 20p12.3 (encompassing PLCB1), which was also detected in the mother. The genomic breakpoints for the heterozygous deletion were determined. In order to investigate the presence of a second PLCB1 mutation, direct Sanger sequencing of the coding region and flanking intronic regions was undertaken, revealing a novel heterozygous intron 1 splice site variant (c.99+1G>A) in both the index individual and the father. Advances in molecular genetic testing have greatly improved diagnostic rates in EIEE, and this report further confirms the important role of microarray investigation in this group of disorders. PLCB1-EIEE is now reported in a number of different EIEE phenotypes and our report provides further evidence for phenotypic pleiotropy encountered in early infantile epilepsy syndromes.

SUBMITTER: Ngoh A

PROVIDER: S-EPMC4230412 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.

Ngoh Adeline A McTague Amy A Wentzensen Ingrid M IM Meyer Esther E Applegate Carolyn C Kossoff Eric H EH Batista Denise A DA Wang Tao T Kurian Manju A MA

Developmental medicine and child neurology 20140329 11

Homozygous deletions of chromosome 20p12.3, disrupting the promoter region and first three coding exons of the phospholipase C β1 gene (PLCB1), have previously been described in two reports of early infantile epileptic encephalopathy (EIEE). Both children were born to consanguineous parents, one presented with infantile spasms, the other with migrating partial seizures of infancy. We describe an infant presenting with severe intractable epilepsy (without a specific EIEE electroclinical syndrome ...[more]

PMID: 24684524

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Project description:In this study, we have evaluated the underlying aetiologies, yield of genetic testing and long-term outcomes in patients with early-infantile developmental and epileptic encephalopathies. We have prospectively studied patients with seizure onset before 3 months of age. Based on the clinical details, neuroimaging, metabolic testing and comprehensive genetic evaluation, patients were classified into different aetiological groups. The phenotypic differences between genetic/unknown groups and remaining aetiologies were compared. Factors that could affect seizure control were also assessed. A total of 80 children (M:F ratio-1.5:1) were recruited. The median seizure onset age was 28 days (range, 1-90 days). The aetiologies were confirmed in 66 patients (83%). The patients were further classified into four aetiological groups: genetic (50%), structural (19%), metabolic (14%; all were vitamin responsive) and unknown (17%). On comparing for the phenotypic differences between the groups, children in the 'genetic/unknown' groups were more frequently observed to have severe developmental delay (Odds Ratio = 57; P < 0.0001), autistic behaviours (Odds Ratio = 37; P < 0.0001), tone abnormalities (Odds Ratio = 9; P = 0.0006) and movement disorder (Odds Ratio = 19; P < 0.0001). Clonic seizures were more common in the vitamin responsive/structural groups (Risk Ratio = 1.36; P = 0.05) as compared to patients with 'genetic/unknown' aetiologies. On the contrary, vitamin responsive/structural aetiology patients were less likely to have tonic seizures (Risk Ratio = 0.66; P = 0.04). Metabolic testing was diagnostic in three out of 41 patients tested (all three had biotinidase deficiency). MRI was abnormal in 35/80 patients (malformation observed in 16/35; 19/35 had non-specific changes that did not contribute to underlying aetiology). A molecular diagnosis was achieved in 53 out of 77 patients tested (69%). Next-generation sequencing had a yield of 51%, while microarray had a yield of 14%. STXBP1 was the most common (five patients) single-gene defect identified. There were 24 novel variants. The mean follow-up period was 30 months (range, 4-72 months). On multivariate logistic regression for the important factors that could affect seizure control (seizure onset age, time lag of first visit to paediatric neurologist and aetiologies), only vitamin responsive aetiology had a statistically significant positive effect on seizure control (P = 0.02). Genetic aetiologies are the most common cause of early-infantile developmental and epileptic encephalopathies. Patients in the genetic/unknown groups had a more severe phenotype. Patients with vitamin responsive epilepsies had the best probability of seizure control.

Dataset Information

Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.

Publications

Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum.

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