Asuri N. Prasad

Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses

Background Heparan sulfate proteoglycans are vital components of the extracellular matrix and are essential for cellular homeostasis. Many genes are involved in modulating heparan sulfate synthesis, and when these genes are mutated, they can give rise to early-onset developmental disorders affecting multiple body systems. Herein, we describe a consanguineous family of four sibs with a novel disorder, which we designate as seizures-scoliosis-macrocephaly syndrome, characterised by seizures, intellectual disability, hypotonia, scoliosis, macrocephaly, hypertelorism and renal dysfunction. Methods Our application of autozygosity mapping and whole-exome sequencing allowed us to identify mutations in the patients. To confirm the autosomal-recessive mode of inheritance, all available family members were genotyped. We also studied the effect of these mutations on protein expression and function in patient cells and using an in vitro system. Results We identified two homozygous mutations p.Met87Arg and p.Arg95 Cys in exostosin 2, EXT2, a ubiquitously expressed gene that encodes a glycosyltransferase required for heparan sulfate synthesis. In patient cells, we observed diminished EXT2 expression and function. We also performed an in vitro assay to determine which mutation has a larger effect on protein expression and observed reduced EXT2 expression in constructs expressing either one of the mutations but a greater reduction when both residues were mutated. Conclusions In short, we have unravelled the genetic basis of a new recessive disorder, seizures-scoliosis-macrocephaly syndrome. Our results have implicated a well-characterised gene in a new developmental disorder and have further illustrated the spectrum of phenotypes that can arise due to errors in glycosylation.

Primary Disorders of Metabolism and Disturbed Fetal Brain Development

There exists a link between the in utero metabolic environment and the development of the fetal nervous system. Prenatal neurosonography offers a unique, noninvasive tool in the detection of developmental brain malformations and the ability to monitor changes over time. This article explores the association of malformations of cerebral development reported in association with inborn errors of metabolism, and speculates on potential mechanisms by which such malformations arise. The detection of cerebral malformations prenatally should lead to a search for both genetic etiologies and inborn errors of metabolism in the fetus. Improving the changes of an early diagnosis provides for timely therapeutic interventions and it is hoped a brighter future for affected children and their families.

Linkage analysis and exome sequencing identify a novel mutation in KCTD7 in patients with progressive myoclonus epilepsy with ataxia

Epilepsy affects approximately 1% of the worlds population. Genetic factors and acquired etiologies, as well as a range of environmental triggers, together contribute to epileptogenesis. We have identified a family with three daughters affected with progressive myoclonus epilepsy with ataxia. Clinical details of the onset and progression of the neurologic presentation, epileptic seizures, and the natural history of progression over a 10‐year period are described. Using autozygosity genetic mapping, we identified a high likelihood homozygous region on chromosome 7p12.1‐7q11.22. We subsequently applied whole‐exome sequencing and employed a rare variant prioritization analysis within the homozygous region. We identified p.Tyr276Cys in the potassium channel tetramerization domain–containing seven gene, KCTD7, which is expressed predominantly in the brain. Mutations in this gene have been implicated previously in epileptic phenotypes due to disturbances in potassium channel conductance. Pathogenicity of the mutation was supported by bioinformatic predictive analyses and variant cosegregation within the family. Further biologic validation is necessary to fully characterize the pathogenic mechanisms that explain the phenotypic causes of epilepsy with ataxia in these patients.

The expanding phenotype of MELAS caused by the m.3291T > C mutation in the MT-TL1 gene.

m.3291T > C mutation in the MT-TL1 gene has been infrequently encountered in association with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), however remains poorly characterized from a clinical perspective. In the following report we describe in detail the phenotypic features, long term follow up (> 7 years) and management in a Caucasian family with MELAS due to the m.3291T > C mutation and review the literature on m.3291T > C mutation. The clinical phenotype in the proposita included overlapping features of MELAS, MERRF (Myoclonic epilepsy and ragged-red fiber syndrome), MNGIE (Mitochondrial neurogastrointestinal encephalopathy), KSS (Kearns-Sayre Syndrome) and CPEO (Chronic progressive external ophthalmoplegia).

Epilepsy, comorbid conditions in Canadian children: Analysis of cross-sectional data from Cycle 3 of the National Longitudinal Study of Children and Youth

PURPOSEnThe purpose of this study was to analyze national survey data to provide estimates of prevalence of epilepsy and associated developmental disabilities and comorbid conditions.nnnMETHODSnWe analyzed data from Cycle 3 of Canadas National Longitudinal Survey of Children and Youth. The NLSCY captured, socio-demographic information, as well as age, sex, education, ethnicity, household income, chronic health related conditions from birth to 15 years old. The main survey question intended to identify epilepsy, cerebral palsy, intellectual disability, learning disability, and emotional and nervous difficulties in the population of children surveyed. Prevalence was based on the national cross-sectional sample and used 1000 bootstrap weights to account for survey design factors.nnnRESULTSnCycle 3 of the NLSCY had the largest number of patients with diagnosed epilepsy. Prevalence figures (n/1000) for epilepsy and cerebral palsy (EPI_CP), epilepsy and intellectual disability (EPI_ID), epilepsy and learning disability (EPI_LD), and epilepsy and emotional nervous difficulties (EPI_EMO_NERV) were 1.1, 1.17, 2.58 and 1.34 respectively. Amongst children with epilepsy, 43.17% reported the presence of one or more of the above comorbid conditions.nnnCONCLUSIONnThese results provide an initial prevalence estimate of comorbid conditions with epilepsy in Canadian children. In a high proportion of children with epilepsy, the PMK had reported at least one comorbid disorder. These findings carry implications for health care utilization and long-term outcomes. We discuss methodological aspects related to the ascertainment of epilepsy in both surveys, and to the validity and implications of our findings.

Genetic Aspects of Human Epilepsy

Advances in genetics and molecular genetics are shaping new insights in our understanding of inheritance patterns and phenotypic variability in human epilepsy. It is now generally accepted that traditional monogenic Mendelian inheritance patterns leading to human epilepsy syndromes are relatively rare in comparison to more common (idiopathic) epilepsies with complex genetics. Inheritance patterns in the latter can be explained by a polygenic heterogeneity model, involving a dosage effect resulting from the combined effect of both common and rare variants of susceptibility genes. The evidence thus far suggests that ion channel dysfunction constitutes a key mechanistic pathway among many in determining seizure susceptibility. Several monogenic epilepsy syndromes are now proven to be channelopathies with mutations in genes coding of voltage-gated and ligand-gated channel subunits resulting in altered excitability patterns in neuronal networks and epileptogenesis. There are other genetic mechanisms that lead to seizure susceptibility involving gene deletions/duplications, copy number variations, chromosomal aberrations and biochemical perturbations from inborn errors of metabolism. In this chapter, we will discuss selected genetic epilepsy syndromes, inheritance patterns, the clinical aspects, molecular basis, and current understanding of pathology and mechanisms leading to epileptogenesis in genetic epilepsy. We further discuss a bedside approach to identify the genetic basis of epilepsy syndromes, the role of molecular genetic testing relevance, and clinical utility in the diagnosis and management of epilepsy.