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Contact sport and blast-related neuropathology
Published in Helen Whitwell, Christopher Milroy, Daniel du Plessis, Forensic Neuropathology, 2021
Daniel du Plessis, Christopher Milroy
Some studies appear to suggest that the development of brain swelling after a mild head impact may be related to genetic risk rather than serial impacts. Multiple case reports have described disproportionate brain swelling to a single mild head injury in patients with a personal or family history of hemiplegic migraine related to a familial or de novo mutation in one of the CACNA1A calcium channel subunit genes. Based on current understanding of concussion pathophysiology, other types of ion channel dysfunction are thought plausible contributing mechanisms (Kamins and Giza 2016).
Balance Disorders in Children
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Louisa Murdin, Gavin A.J. Morrison
Migraine is a common multifactorial neurovascular disorder. Several mutations have been discovered for rare forms of migraine; one within CACNA1A on chromosome 19p13, a gene encoding for part of a neuronal calcium channel codes mutations for familial hemiplegic migraine type 1 and also in episodic ataxia type 2. Genome-wide association studies have been carried out for more common forms of migraine; however, these are genetically complex with many different contributory genetic variations.
Migraine: diagnosis and treatment
Published in Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby, Headache in Clinical Practice, 2018
Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby
In 20% of unselected FHM families, patients can have fixed cerebellar symptoms and signs such as nystagmus and progressive ataxia. Cerebellar ataxia may occur before the first hemiplegic migraine attack and progress independently of the frequency or severity of hemiplegic migraine attacks. All these families have been shown to be linked to chromosome 19.31 Episodic ataxia type 2 (EA2) Is also an autosomal dominant disorder that is characterized by paroxysmal attacks of ataxia that last from 15 minutes to hours or days. It is provoked by emotional or physical stress, alcohol, or coffee, but not by startle, and is associated with interictal nystagmus and acetazolamide responsiveness. The gene for 60% of affected families has been localized to the short arm of chromosome 19pl3, and has been cloned.32 Mutations within CACNA1A, a gene encoding for the αlA subunit of a neuronal P/Q type calcium channel, cause both FHM and EA2. Another gene has been mapped to chromosome 1, CACNA1A.33 All EA2 families have been linked to chromosome 19.34–35
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
Mutations in genes that are not ion channels or that are not expressed in skeletal muscle can present with symptoms associated with skeletal muscle channelopathies. SLC2A1 is implicated in Glucose Transporter Deficiency Syndrome [24]. While this is not a skeletal muscle channelopathy, the episodic symptoms predominantly affect the lower limbs and are often triggered by movement or exercise, which can cause diagnostic confusion with periodic paralysis. Glucose Transport Deficiency syndromes are highly treatable and should not be missed. CACNA1A encodes calcium channel Cav2.1 with neuronal expression. It is implicated in Familial Hemiplegic Migraine and Episodic Ataxia type 2 [25]. These conditions can also have overlapping symptoms or cause diagnostic confusion with presentations of skeletal muscle channelopathies including paresis, and share common triggers. Expansion from a four gene to a seven-gene panel has improved diagnostic rates of previously undiagnosed rare causes of channelopathies and allows parallel diagnosis of channelopathy mimics.
Migraine pathways and the identification of novel therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Innocenzo Rainero, Fausto Roveta, Alessandro Vacca, Cecilia Noviello, Elisa Rubino
In the last two decades, molecular genetic studies have provided considerable insights into the molecular mechanisms of migraine, suggesting new therapeutic targets. First of all, Familial Hemiplegic Migraine (FHM), a rare MA subtype characterized by an autosomal dominant transmission of the phenotype and presence of transient motor deficits, has been associated with mutations in three different genes, CACNA1A, ATP1A2, and SCN1A, coding for protein linked to ion channels functions [44–46]. In addition, investigating families with rare, monogenic forms of migraine, pathogenic variants in other genes, as KCNK18, PRRT2, PNKD, SLC2A1, SLC1A3, and SLC4A4 have been demonstrated [47,48]. In the more common form of migraine, candidate gene association studies showed that more than 200 genetic variants in approximately 100 different genes may be associated or influence the clinical characteristics of the disease [49]. However, these studies often report conflicting results and have been rarely replicated. Finally, several genome-wide association studies (GWAS) provided evidence that numerous single-nucleotide polymorphisms (SNPs), and related genes, are significantly associated with migraine and its clinical variants. The most recent meta-analysis combined the data from 22 GWAS, comprising 59,674 migraine cases from clinic- and population-based collections as well as 316,078 controls [50]. This study demonstrated that 44 independent SNPs at 38 distinct genomic loci are significantly associated with migraine, providing new molecular insight into the molecular pathways of migraine.
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
The success of NGS in a research setting is outlined by its role in the discovery of several new ataxia associated genes, including TGM6 (SCA36) [29], CACNA1G (SCA42) [109], ATP2B3 (X-linked congenital cerebellar ataxia) [110], PNKP (ataxia with oculomotor apraxia type 4) [111], ABCB7 (X-linked congenital cerebellar ataxia) [112], KCND3 (SCA19/22) [113], and TPP1 (SCAR7). Some of these genes have previously been described in the context of other neurological and non-neurological diseases, such as ceroid lipofuscinosis (TPP1) and Brugada syndrome type 9 (KCND3). Mechanism of genetic pleiotropy includes different downstream effects of mutations within the same gene, modifier genes, and oligogenic inheritance [114]. The best known example of genetic pleiotropy within the group of ataxias is CACNA1A mutations that can present as SCA6, episodic ataxia type II and familial hemiplegic migraine due to different functional downstream mechanisms [115].