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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.

Author information

1
Department of Biomedical, Metabolic and Neural Sciences, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
2
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
3
Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany.
4
Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
5
Department of Molecular Medicine, University of Pavia, Pavia, Italy.
6
Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome, Italy.

Abstract

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.

KEYWORDS:

epsilon-sarcoglycan; genetics; myoclonus-dystonia; pathophysiology

PMID:
31449710
DOI:
10.1002/mds.27822

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