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Mov Disord. 2019 Nov;34(11):1588-1601. doi: 10.1002/mds.27822. Epub 2019 Aug 26.

Twenty years on: Myoclonus-dystonia and ε-sarcoglycan - neurodevelopment, channel, and signaling dysfunction.

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Department of Biomedical, Metabolic and Neural Sciences, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome, Italy.


Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related myoclonus-dystonia, these conditions can be collectively classified as "myoclonus-dystonia syndromes." In the present article, we present myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network.


epsilon-sarcoglycan; genetics; myoclonus-dystonia; pathophysiology


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