The Application of Clinical Genetics (Mar 2023)
Genetic Links to Episodic Movement Disorders: Current Insights
Abstract
Divyani Garg,1 Shekeeb Mohammad,2,3 Anju Shukla,4 Suvasini Sharma5 1Department of Neurology, All India Institute of Medical Sciences, New Delhi, India; 2Kids Neuroscience Centre, The Children’s Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia; 3TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, The University of Sydney, Westmead, New South Wales, Australia; 4Department of Medical Genetics, Kasturba Medical College and Hospital, Manipal, India; 5Department of Pediatrics (Neurology Division), Lady Hardinge Medical College and Kalawati Saran Hospital, New Delhi, IndiaCorrespondence: Suvasini Sharma, Department of Pediatrics (Neurology Division), Kalawati Saran Children’s Hospital, New Delhi, 110001, India, Tel +91 9910234344, Email [email protected]: Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1– 9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5-related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.Keywords: paroxysmal movement disorders, episodic ataxia, PRRT2, PNKD, KCNA1
