Abstract
Channelopathies are a heterogeneous group of neurological disorders resulting from dysfunction of ion channels located in cell membranes and organelles. The clinical scenario is broad and symptoms such as generalized epilepsy (with or without fever), migraine (with or without aura), episodic ataxia and periodic muscle paralysis are some of the best known consequences of gain- or loss-of-function mutations in ion channels. We review the main clinical effects of ion channel mutations associated with a significant impact on migraine headache. Given the increasing and evolving use of genetic analysis in migraine research—greater emphasis is now placed on genetic markers of dysfunctional biological systems—we also show how novel information in rare monogenic forms of migraine might help to clarify the disease mechanisms in the general population of migraineurs. Next-generation sequencing (NGS) and more accurate and precise phenotyping strategies are expected to further increase understanding of migraine pathophysiology and genetics.
Highlights
The channelopathies are a heterogeneous group of neurological disorders that result from genetic dysfunction of ion channels located in cell membranes and organelles
Other mechanisms, such as gene-gene or gene-environment interactions and epigenetics, further complicate the already complex picture of the heritability of migraine syndromes (Rudkjobing et al, 2012), suggesting that genotyping data need to be integrated with the results of deep clinical stratification, gene expression data, and proteomics/metabolomics studies in order to fully understand the effects of genetic variability (Bras et al, 2012)
Focusing genetic analyses on groups with more homogeneous presentations will help in investigating the function and pathogenic relevance of gene variants emerging from Next-generation sequencing (NGS) studies, strongly increasing the power of genetic information and the strength of genotypephenotype correlations (Hennekam and Biesecker, 2012) and paving the way for more personalized/‘‘precision’’ medicine (Zhang et al, 2016)
Summary
The channelopathies are a heterogeneous group of neurological disorders that result from genetic dysfunction of ion channels located in cell membranes and organelles. The reason why defects in single channels can lead to seizures, episodic ataxia, movement disorders or migraine, or to a combination of these, is only partially understood and possibly dependent on diverse molecular mechanisms that affect channel function (i.e., gain- or lossof-function effects of mutations), and on the specific neuronal circuitry involved.
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