Combined exome analysis and exome depth assessment achieve a high diagnostic yield in an epilepsy case series, revealing significant genomic heterogeneity and novel mechanisms.

OBJECTIVES: Genetics of epilepsy are highly heterogeneous and complex. Lesions detected involve genes encoding various types of channels, transcription factors, and other proteins implicated in numerous cellular processes, such as synaptogenesis. Consequently, a wide spectrum of clinical presentations and overlapping phenotypes hinders differential diagnosis and highlights the need for molecular investigations toward delineation of underlying mechanisms and final diagnosis. Characterization of defects may also contribute valuable data on genetic landscapes and networks implicated in epileptogenesis. METHODS: This study reports on genetic findings from exome sequencing (ES) data of 107 patients with variable types of seizures, with or without additional symptoms, in the context of neurodevelopmental disorders. RESULTS: Multidisciplinary evaluation of ES, including ancillary detection of copy number variants (CNVs) with the ExomeDepth tool, supported a definite diagnosis in 59.8% of the patients, reflecting one of the highest diagnostic yields in epilepsy. CONCLUSION: Emerging advances of next-generation technologies and 'in silico' analysis tools offer the possibility to simultaneously detect several types of variations. Wide assessment of variable findings, specifically those found to be novel and least expected, reflects the ever-evolving genetic landscape of seizure development, potentially beneficial for increased opportunities for trial recruitment and enrollment, and optimized, even personalized, medical management.

Abnormal gait and hypoglycorrhachia in a toddler with seizures.

Introduction: Glucose transporter type 1 (Glut1) deficiency syndrome is a treatable neurometabolic disorder characterized by seizures, developmental delay, and hypoglycorrhachia. Due to the rareness and non-specific clinical manifestations, it is usually mis- or underdiagnosed. Case presentation: We report the case of a toddler who presented with afebrile epileptic seizures and abnormal gait. Brain imaging and electroencephalogram were normal. Further investigation of the cerebrospinal fluid revealed hypoglycorrhachia that was the clue to the diagnosis of Glut1 deficiency syndrome and the initiation of treatment with ketogenic diet. Conclusion: Our case highlights the importance of lumbar puncture while investigating a child with epileptic seizures and abnormal gait or developmental delay, in order not to miss treatable neurometabolic conditions, such as Glut1 deficiency syndrome.

Miller Fisher Syndrome Triggered by Infections: A Review of the Literature and a Case Report.

AIM: We reported a case of Miller Fisher syndrome following a breakthrough varicella zoster virus infection in an otherwise healthy 6-year-old male. The objective of this review was to summarize the infectious etiologic agents known to trigger Miller Fisher syndrome. METHODS: Review of the literature on infections associated with Miller Fisher syndrome. RESULTS: We identified 762 studies after duplicates were removed. Titles, abstracts, and full texts were screened. Finally, 37 studies were included in qualitative synthesis after citations and reference list were checked. The age range of cases reported was 0-78 years, and male sex was predominant in studies where these parameters were reported. The most common causative agent was Campylobacter jejuni followed by Haemophilus influenzae. CONCLUSIONS: Our review highlights the importance of recognizing the infections triggering Miller Fisher syndrome. We also present a unique case of Miller Fisher syndrome associated with breakthrough varicella zoster virus infection. Preventive policies may consider population immunization for certain causative agents.

Miller Fisher Syndrome Triggered by Infections: A Review of the Literature and a Case Report.

AIM: We reported a case of Miller Fisher syndrome following a breakthrough varicella zoster virus infection in an otherwise healthy 6-year-old male. The objective of this review was to summarize the infectious etiologic agents known to trigger Miller Fisher syndrome. METHODS: Review of the literature on infections associated with Miller Fisher syndrome. RESULTS: We identified 762 studies after duplicates were removed. Titles, abstracts, and full texts were screened. Finally, 37 studies were included in qualitative synthesis after citations and reference list were checked. The age range of cases reported was 0-78 years, and male sex was predominant in studies where these parameters were reported. The most common causative agent was Campylobacter jejuni followed by Haemophilus influenzae. CONCLUSIONS: Our review highlights the importance of recognizing the infections triggering Miller Fisher syndrome. We also present a unique case of Miller Fisher syndrome associated with breakthrough varicella zoster virus infection. Preventive policies may consider population immunization for certain causative agents.

Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.

CSF diversion in refractory idiopathic intracranial hypertension: single-centre experience and review of efficacy.

PURPOSE: The current surgical management strategies for refractory cases of idiopathic intracranial hypertension (IIH) remain unresolved. We evaluated the outcome of our paediatric patients who were offered a CSF diversion procedure in order to control their symptoms. METHODS: We retrospectively reviewed the medical notes of the patients under 16 years of age, who presented in our centre from 2005 to 2010, with a confirmed diagnosis of IIH, and ultimately had a lumboperitoneal shunt (LPS). We describe their immediate postoperative course, shunt-related complications and recent outcome. RESULTS: Seven patients presented at a mean age of 8.7 years. Two presented with significant visual loss and had a shunt acutely; the remaining five presented with headaches and were shunted within 2 years. In the immediate postoperative period two patients experienced low-pressure symptoms. All patients required shunt revisions; in total 15 revisions took place, mainly secondary to symptomatic overdrainage or obstruction. After a mean follow-up of 26 months, two patients have diminished visual acuity at least on one side; only one patient became headache-free, despite resolution of the CSF pressure post diversion in four out of the six remaining patients. CONCLUSIONS: All patients required shunt revisions and 6/7 (85.7%) had persisting headaches at their last follow-up. It is apparent that once functional, the LPS seems adequate to lower the CSF pressure but not effective in eliminating symptoms.