Abstracts

Rationale: Advances in human molecular genetics are revealing the great genetic heterogeneity of infantile epileptic encephalopathies and the great variability of their pathological pathways. Much progress has been made in the past few years in the identification of genes responsible for genetic infantile epileptic encephalopathies Dravet syndrome (DS) is a genetically heterogeneous disorder commonly caused by mutation in SCN1A . For example, a single case of DS with a mutation in the c2 subunit gene of the GABAA receptor, GABRG2, and homozygous mutation inSCN1B has been reported. Recently, mutations in PCDH19, encoding protocadherin 19 on chromosome X, were identified in females with an EFMR or Dravet-like phenotype. The genetic data accumulated for Dravet syndrome and other related disorders have to be kept in mind when studying epileptic encephalopathies. Methods: Case series report of 3 sibling including history, sign and symptoms, neurophysiological findings and molecular genetics results Case series: Three siblings, aged 9, 6 and 5 years presented to us with history of severe epileptic encephalopathy and delayed psychomotor development. They are product of uneventful full term pregnancies and spontaneous vaginal deliveries. Phenotypically unaffected parents with consanguity (second degree cousin). Second affected child male who was died at 6yrs of age without a diagnosis. His presentation and course was similar to his brothers. There is a paternal family history of seizure disorder and brain atrophy. Other 4 siblings showed neither any evidence of epilepsy nor any major cognitive or motor deficits. The seizures in these two children started at 2 months of age, with brief shock- like movements. Patients had febrile seizures, which were soon followed by other seizure types including predominant generalized tonic-clonic seizures and absence seizures. Repeated episodes of status epilepticus triggered by illnesses or fever. Despite multiple medication trials, they continued to experience multiple seizures, many times per day up to ten times. In addition, both patients had myoclonic seizures. Seizures in all the three patients were reported to be fever-sensitive. In addition to early- onset epilepsy, they manifested intellectual disability, developmental delay, and hypotonia. They were able to walk independently just before they turned 3 years old and started to use 2 to 4 word phrases before the age of 4. With time they showed hyperactivity and inattention. Results: Serum ammonia , lactate, biotinidase, serum amino acids, congenital glycosylation defect, CSF neurotransmitter: Normal. Urine Sulphocysteine: unremarkable. Comprehensive Epilepsy Panel showed heterozygous susceptible mutations ( VUS) GH- Array ?" Excess Homozygosity. SCNA 1A Gene: Negative MRI/MRS brain: Unremarkable. EEGs : Both patients initially had normal EEGs. Follow up studies showed slowing of the background activity, diffuse delta and some theta activity. Low amplitude sharp discharges seen at frontocentral regions WES for both patients showed homozygous mutation IQSEC1: Chr3(GRCh37):g. 12977554C>T: NM_014869.4:c.1004G>A.(p.(Agr335Gin)) Segregation analysis for parents was sent. Result is expected in 6 weeks period Conclusions: The IQSEC1 gene is not yet described in a human disorder to be mutated in epilepsy. This gene encodes the IQ motif and Sec7 domain 1 protein that is involved in phospholipid binding and ARF guanyl-nucleotide exchange factor activity. We suggest to consider IQSEC1 gene mutation in SCN1A-negative Dravet like epileptic encephalopathy. Funding: NONE