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Muscle Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Kourosh Rezania, Peter Pytel, Betty Soliven
Myotonia congenita, the most common muscle channelopathy, is caused by mutations in the skeletal muscle chloride channel gene CLCN-1, and is distinguished from myotonic dystrophy by the absence of progressive weakness and systemic features. The autosomal dominant form is called Thomsen's disease, while the recessive form is called Becker's disease.
Biogenic amines
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Infantile parkinsonism-dystonia is typically caused by inborn errors of metabolism affecting the dopamine biosynthetic pathway including pterin defects (see above and Chapter 16), and thus represents disorders of dopamine deficiency. In 2004, Assmann and colleagues described two girls and one boy with a novel combination of clinical and biochemical features [38]. In these patients, severe infantile parkinsonism-dystonia was associated with extremely elevated dopamine metabolites in CSF and a complex eye movement disorder of ocular flutter together with saccade initiation failure. Pyramidal tract signs emerged in the course of the disease. In 2009, Kurian and colleagues identified the underlying cause in autosomal recessively inherited loss-of-function mutations in SLC6A3, encoding the dopamine transporter, the principle regulator of the amplitude and duration of dopamine neurotransmission [39]. Combining these results, as well as additional patients, the term dopamine transporter deficiency syndrome was coined [40]. The disease added “transportopathy” to the well-established concept of “channelopathy” as a fundamental mechanism of neurologic disease. Later, a small number of milder, later onset cases were identified, presenting in childhood/adolescence with progressive (juvenile) parkinsonism [41, 42]. To date, approximately 25 patients with DTDS have been identified [40, 41, 42]. Treatment is very challenging and until now, no pharmacologic agents seem to stop disease progression.
Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
These are important causes of unexpected sudden death and may also cause symptoms including loss of consciousness (blackouts, syncope), which can be dangerous in its own right. They are often the result of mutation in one of the channelopathy genes, as are some of the epilepsy disorders that can be difficult to distinguish clinically.
Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade
Published in Expert Opinion on Drug Discovery, 2021
Alison Obergrussberger, Søren Friis, Andrea Brüggemann, Niels Fertig
The field of channelopathy and personalized medicine has increasingly adopted APC devices in recent years to investigate topics such as KCNB1 mutations in neurodevelopmental disorders, autism and epilepsy [22,23], KCNH2 variants in hERG trafficking and LQTS2 syndrome [24,25], KCNT1 variants in infantile encephalopathy [26], KCNQ1 in congenital arrhythmia syndromes [27], SCN5A variants in arrhythmia syndromes [28,29], and voltage-gated sodium and calcium channels in a number of diseases [30], among others. The ability to test a wide range of variants for loss- or gain-of-function mutations is changing the field of channelopathy for the better since many more variants associated with ion-channel diseases are identified every year through clinical genetic testing and genomic research studies. A large proportion of the identified variants get classified as variants of unknown significance, but the use of automated electrophysiology on platforms such as the SyncroPatch 384PE can provide much needed functional data to better classify variants. This work is mainly performed by university-based groups collaborating across the world, and efforts are now going into collecting and sharing the results in a publicly available database.
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
The patterns of congenital myopathy caused by SCN4A mutations appear to be axial and proximal predominant with eight of 13 patients having facial weakness. All newborns were hypotonic. This pattern is seen commonly in all causes of congenital myopathies [43]. Notably, episodic symptoms often considered to be classical of channelopathies were only seen in two patients and are not a sensitive clinical feature in this cohort to prompt activation of genetic testing for the channelopathy gene panel. Fetal hypokinesia was present in 10 patients and may provide pre-partum diagnostic clues or may prompt investigation for features of sodium channelopathies in the parents.
The challenges faced by clinicians diagnosing and treating infantile nystagmus Part II: treatment
Published in Expert Review of Ophthalmology, 2021
Eleni Papageorgiou, Katerina Lazari, Irene Gottlob
Interestingly, oral acetazolamide has been studied in an adult with INS and resulted in a broadened range of gaze angles and improved foveation waveforms. Hence, the authors suggested that hereditary INS is associated with an inherited channelopathy, and other agents with known effects on ion channels may represent potential therapeutic targets for INS [74].