BACKGROUND Mutations in SCN1A can cause genetic epilepsy with febrile seizures plus (GEFS+, inherited missense mutations) or Dravet syndrome (DS, de novo mutations of all types). Although the mutational spectra are distinct, these disorders share major features and 10% of DS patients have an inherited SCN1A mutation. OBJECTIVES AND PATIENTS 19 selected families with at least one DS patient were studied to describe the mechanisms accounting for inherited SCN1A mutations in DS. The mutation identified in the DS probands was searched in available parents and relatives and quantified in the blood cells of the transmitting parent using quantitative allele specific assays. RESULTS Mosaicism in the blood cells of the transmitting parent was demonstrated in 12 cases and suspected in another case. The proportion of mutated allele in the blood varied from 0.04-85%. In the six remaining families, six novel missense mutations were associated with autosomal dominant variable GEFS+ phenotypes including DS as the more severe clinical picture. CONCLUSION The results indicate that mosaicism is found in at least 7% of families with DS. In the remaining cases (6/19, 32%), the patients were part of multiplex GEFS+ families and seemed to represent the extreme end of the GEFS+ clinical spectrum. In this latter case, additional genetic or environmental factors likely modulate the severity of the expression of the mutation.
We report five children who had recurrent central nervous system signs after conventional acyclovir therapy for herpes simplex encephalitis. Secondary exacerbation was characterized clinically by severe ballismic movement disorder in all five children, associated with fever, impairment of consciousness, and seizures. Biologic analysis in all children and magnetic resonance imaging and neuropathology studies of the brain in three cases were compatible with inflammatory reaction. In contrast, all viral cultures remained negative, herpes simplex virus antigen in one child and DNA tested by polymerase chain reaction in four children were undetectable in the first samples of cerebrospinal fluid during the relapse, suggesting a postinfectious, immune-mediated mechanism of relapse in these patients.
Summary
Lennox‐Gastaut syndrome (LGS) is a drug‐resistant epileptic encephalopathy of childhood with a heterogeneous etiology. Recently, genome‐wide association studies have led to the identification of new de novo mutations associated with this epileptic syndrome. Herein, we report an 8‐year‐old child with intellectual disability, severe postnatal microcephaly, Rett‐like features, and LGS, carrying a de novo missense mutation in the forkhead box G1 (FOXG1) gene. This gene is responsible for FOXG1 syndrome, characterized by severe postnatal microcephaly, moderate postnatal growth deficiency, mental retardation with poor social interaction, stereotyped behavior and dyskinesias, absent language, sleep disorders, and epilepsy. Nonspecific epilepsy syndromes have been associated with this genetic disorder. Thus, we hypothesize that FOXG1 might be a new candidate gene in the etiology of LGS and suggest screening for this gene in cases of LGS with concomitant microcephaly and clinical features overlapping with Rett syndrome.
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