REVIEW Twenty Years on: Myoclonus-Dystonia and ε-Sarcoglycan — Neurodevelopment, Channel, and Signaling Dysfunction Elisa Menozzi, MD,1,2 Bettina Balint, MD,2,3 Anna Latorre, MD,2,4 Enza Maria Valente, MD, PhD,5,6 John C. Rothwell, PhD,2 and Kailash P. Bhatia, MD, FRCP2* 1Department of Biomedical, Metabolic and Neural Sciences, University-Hospital of Modena and Reggio Emilia, Modena, Italy 2Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK 3Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany 4Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy 5Department of Molecular Medicine, University of Pavia, Pavia, Italy 6Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome, Italy ABSTRACT: Myoclonus-dystonia is a clinical syndrome epsilon-sarcoglycan gene–related myoclonus-dystonia, characterized by a typical childhood onset of myoclonic jerks these conditions can be collectively classified as “myoclonus- and dystonia involving the neck, trunk, and upper limbs. Psy- dystonia syndromes.” In the present article, we present chiatric symptomatology, namely, alcohol dependence and myoclonus-dystonia caused by epsilon-sarcoglycan gene phobic and obsessive-compulsive disorder, is also part of mutations, with a focus on genetics and underlying the clinical picture. Zonisamide has demonstrated effective- disease mechanisms. Second, we review those conditions ness at reducing both myoclonus and dystonia, and deep falling within the spectrum of myoclonus-dystonia syn- brain stimulation seems to be an effective and long-lasting dromes, highlighting their genetic background and therapeutic option for medication-refractory cases. In a sub- involved pathways. Finally, we critically discuss the normal set of patients, myoclonus-dystonia is associated with path- and pathological function of the epsilon-sarcoglycan gene ogenic variants in the epsilon-sarcoglycan gene, located on and its product, suggesting a role in the stabilization of the chromosome 7q21, and up to now, more than 100 different dopaminergic membrane via regulation of calcium homeo- pathogenic variants of the epsilon-sarcoglycan gene have stasis and in the neurodevelopmental process involving been described. In a few families with a clinical phenotype the cerebello-thalamo-pallido-cortical network. © 2019 resembling myoclonus-dystonia associated with distinct clini- International Parkinson and Movement Disorder Society cal features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and Key Words: epsilon-sarcoglycan; genetics; myoclonus- neurodevelopment. Because of phenotypic similarities with dystonia; pathophysiology In 1983 the first description of a clinical syndrome “inherited myoclonus-dystonia.”1-3 Myoclonus-dystonia is characterized by myoclonus as the most prominent sign a rare condition, with an estimated prevalence of about and dystonia was provided, subsequently identified as 2 per 1.000.000 in Europe.4 Usually presenting in early --------------------------------------------------------- childhood and following a benign course, it was described *Correspondence to: Professor Kailash P. Bhatia, Department of to follow an autosomal-dominant pattern with variable Clinical and Movement Neurosciences, UCL Queen Square Institute of penetrance and expression.2 Twenty years ago, the first Neurology, Box 13, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK; E-mail: [email protected] locus for myoclonus-dystonia was mapped to chromo- somal region 7q21-q31.5-8 Two years later, heterozygous Relevant conflicts of interest/financial disclosures: The authors declare no financial disclosures/conflict of interest related to the present study. pathogenic variants in the epsilon-sarcoglycan (SGCE)gene 9 Funding agencies: The authors declare no funding sources for the pre- were reported to be causative for myoclonus-dystonia, sent study. implicating a member of the sarcoglycan family generally Received: 1 February 2019; Revised: 19 June 2019; Accepted: 14 associated with muscular dystrophies was involved in the July 2019 pathogenesis of a central nervous system (CNS) disorder.9 SGCE Published online 00 Month 2019 in Wiley Online Library From then, mutational screenings for in cohorts of (wileyonlinelibrary.com). DOI: 10.1002/mds.27822 patients presenting with myoclonus-dystonia have revealed Movement Disorders, 2019 1 MENOZZI ET AL that SGCE is the main causative gene for this syn- in pediatric cases, in whom it may be the sole presenting drome.10,11 As a consequence, the designation DYT-SGCE feature.35,36 Although isolated writer’s cramp presenting (OMIM 604149) now replaces the classic locus symbol as the first manifestation of SGCE-MD in early adult- 36 DYT11.12,13 hood has been reported, a screening of 43 patients with Over the years, patients presenting with a combination simple or complex writer’s cramp failed to identify any 49 of features typical of SGCE-related-myoclonus-dystonia association with SGCE mutations. Other studies also and additional distinct aspects have been reported to failed to identify SGCE mutations in patients with differ- carry pathogenic or likely pathogenic variants in genes ent subtypes of focal, segmental, or generalized dysto- 50,51 52 involved in neurodevelopment, channel, and signaling nia ; hence, except for pediatric writer’s cramp, pathways. As these genetic conditions share a number of SGCE mutation analysis is not recommended in sporadic clinical features with SGCE-related-myoclonus-dystonia, isolated dystonia in the absence of myoclonic jerks, or they can collectively be included in the phenotypic spec- additional nonmotor features (see below).51 trum of myoclonus-dystonia syndromes. Amelioration of motor signs with alcohol is a classic fea- 53,54 The aim of the present article is to provide an overview of ture of SGCE-MD, likely because of the GABAergic the clinical syndrome of myoclonus-dystonia because of deficit caused by Purkinje cell dysfunction secondary to SGCE mutations, hereafter referred to as SGCE-myoclo- SGCE mutations (see below), which alcohol might improve 55 nus-dystonia (SGCE-MD), discussing the clinical and elec- by increasing GABAergic transmission. The disease trophysiological features and the current therapeutic course of SGCE-MD is generally benign, with variable pro- 20,56 options, and highlighting the genetic background and gression. Spontaneous remission has been found at a underlying disease mechanisms. We then describe the con- rate of 5% of patients for myoclonus and in 22% for dysto- ditions within the spectrum of myoclonus-dystonia syn- nia, especially during childhood and adolescence,31 but also 57 dromes, focusing on their genetic basis and involved in early adulthood. Therefore, this variability should be pathways. Finally, as identifying different genetic causes taken into account when invasive therapeutic options are associated with similar phenotypes may provide new clues considered.31 to pathophysiology,14 we discuss and compare the patho- Psychiatric symptomatology is part of the clinical 54,58-63 physiological mechanisms of SGCE-MD in light of the spectrum of SGCE-MD. A recent multicenter study pathways unraveled by genetic determinants of myoclonus- investigated psychiatric symptomatology in a large cohort dystonia syndromes. of SGCE-MD patients, showing that 65% of manifesting carriers had at least 1 psychiatric diagnosis, one and a half times more than population estimates.64 Among them, SGCE-MD: A Clinical Overview specific phobias and social phobia were the most common diagnoses, followed by alcohol dependence and obsessive- Clinical Spectrum: compulsive disorder.64 Anxiety and depression have also Motor and Neuropsychiatric Features been frequently reported.62,63,65 As few studies failed to SGCE-MD usually manifests in childhood, with a mean detect any psychiatric symptoms assessing patients by age of onset of 6 years,15 and earlier onset is associated clinical scales rather than comprehensive diagnostic with female sex.16 Although rare, very early onset interviews,58,62 we would discourage the use of these tools (before 1 year)17-20 and onset in early adulthood (21 to in the clinical practice. Whether psychiatric symptomatol- 41 years)18,21-24 or after 40 years25,26 have also been ogy represents the expression of a pleiotropic function of reported. The predominant motor sign in SGCE-MD is the SGCE gene in the CNS or is secondary to motor signs myoclonus, presenting with very brief, “lightning-like” or is still debated.59,60,64 Some studies have shown an excess “tic-tac” jerks, typically involving the upper part of the of psychiatric symptoms in manifesting SGCE carriers ver- body (neck, trunk, limb), more in the proximal than distal sus asymptomatic subjects, including nonmanifesting car- muscles.27,28 Less frequently, other body parts, such as the riers and normal controls,59,64 and others did not report face,7,29-31 larynx,30-33 and lower limbs,16,20,22,23,31,34-38 any difference between SGCE carriers and noncarriers.66 can be affected. The myoclonic jerks may be present at rest but are typically aggravated or elicited by action, posture, SGCE and psychological stress.15,20,31 It is important to note that Positive and Negative Predictors for -MD a subset of patients can present with postural tremor of the Although SGCE is the main causative gene for upper limbs,39,40 which is often clinically indistinguishable myoclonus-dystonia,11