|Year : 2022 | Volume
| Issue : 2 | Page : 81-92
A clinical approach to the patients with combination of dystonia and myoclonus
Anjali Chouksey1, Sanjay Pandey2
1 Department of Neurology, Sri Narayani Hospital and Research Centre, Vellore, Tamil Nadu, India
2 Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India
|Date of Submission||19-Nov-2021|
|Date of Decision||21-Feb-2022|
|Date of Acceptance||17-Mar-2022|
|Date of Web Publication||17-Jun-2022|
Dr. Anjali Chouksey
Consultant, Sri Narayani Hospital and Research Centre Vellore, Tamil Nadu - 632055
Source of Support: None, Conflict of Interest: None
Myoclonus–dystonia syndrome is one of the well-defined “combined dystonia” syndromes, now observed in many conditions, including genetic and acquired. With widespread access to next-generation sequencing techniques, the list of genetic diseases manifesting as combined dystonia with myoclonus continues to expand. In this article, we aim to review different etiologies of combined dystonia with myoclonus. We searched databases such as PubMed, OMIM, and Gene Review using the keywords “dystonia and myoclonus” and “myoclonus–dystonia” to identify such disorders. We identified different acquired and genetic disorders manifesting with the combination of dystonia and myoclonus, with or without other movement disorders, irrespective of the predominant movement disorder. In addition, we propose the diagnostic algorithms for children and adults with myoclonus and dystonia, based on clinical manifestations to guide diagnostic procedures and further management.
Keywords: ADCY5, DYT-11, epsilon-sarcoglycan, KCTD17, myoclonus–dystonia
|How to cite this article:|
Chouksey A, Pandey S. A clinical approach to the patients with combination of dystonia and myoclonus. Ann Mov Disord 2022;5:81-92
|How to cite this URL:|
Chouksey A, Pandey S. A clinical approach to the patients with combination of dystonia and myoclonus. Ann Mov Disord [serial online] 2022 [cited 2022 Dec 7];5:81-92. Available from: https://www.aomd.in/text.asp?2022/5/2/0/347773
| Key Message:|| |
The myoclonus–dystonia phenotype can be observed in different genetic and acquired conditions. Some of these conditions have remarkable overlap; however, subtle clinical clues can help differentiate among them.
| Introduction|| |
Dystonia is a movement disorder mainly characterized by “sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.” The new classification system classifies different dystonic conditions into two groups: isolated dystonia and combined dystonia, i.e., dystonia with myoclonus, parkinsonism, or other movement disorders. In our review, the terms “isolated” or “combined” are solely based on phenomenology but not on underlying etiology. In combined forms, dystonia does not necessarily have to be the predominant motor phenomenology. The well-described combined dystonia syndromes include dystonia–parkinsonism, dystonia–ataxia, and myoclonus–dystonia (M–D)., The combination of dystonia and myoclonus can be observed in several conditions. In the last few decades, marked advancement in the field of genetics has led to the identification of several monogenic disorders related to M–D. Neurologists need to be familiar with the spectrum of the underlying diseases manifesting as M–D syndrome. In this review, we discuss in detail all the reported genetic causes of M–D and briefly summarize the other acquired causes that manifest as dystonia and myoclonus.
| Methods|| |
A systematic literature search of databases such as PubMed, OMIM, and Gene Review was performed on June 3, 2021, using the keywords “Myoclonus-dystonia” and “Myoclonus and dystonia.” The inclusion criteria were as follows: human subjects, original studies, case reports, case series, studies investigating M-D, and literature published in English. AC first identified and retrieved all relevant original studies, based on titles and abstracts. SP and AC independently analyzed the retrieved articles and selected studies that fulfilled the inclusion criteria. In addition, we manually searched the reference lists of selected articles.
| Result|| |
Initially, 1646 articles were selected, based on the review topic. After excluding non-English articles and those with incomplete details or contentious or analogous descriptions, 87 articles were included in the final reference list [Figure 1] and [Table 1].
|Figure 1: Flowchart depicting the search strategy for the review of combined myoclonus–dystonia syndrome|
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|Table 1: The list of non-SGCE Myoclonus-Dystonia genetic syndromes with their clinical characteristics|
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| Combined Dystonia and Myoclonus|| |
The terminology used to describe different conditions coexisting with dystonia and myoclonus as a single group has always been debatable. The term “myoclonus–dystonia (M–D) syndrome” is generally used for genetically heterogeneous conditions characterized by the association of nonepileptic myoclonus and dystonia as the sole or prominent feature. Different genes and loci are now known to be associated with this syndrome, and in a proportion of patients, no genetic alteration was found. Although the epsilon-sarcoglycan (SGCE) gene-associated myoclonus–dystonia is considered to be a prototype of M–D, other conditions presenting with this combination of symptoms need to be alternatively considered. In addition to genetic causes, other acquired degenerative and nondegenerative conditions may lead to the development of dystonia and myoclonus together. Such presentations often hold major diagnostic challenges for neurologists due to the notable overlap of the manifestations of underlying disorders. In this review, we have classified different conditions with dystonia and myoclonus into SGCE M–D and non-SGCE M–D. Non SGCE M–D can be further classified based on 1) etiology: genetic [Table 1] or acquired and 2) age of presentation: childhood onset [Figure 2] or adult onset [Figure 3]. First, we discuss the conditions where dystonia and myoclonus are predominant, followed by a brief review of the conditions, where the combination of dystonia and myoclonus can occur as a part of syndromic disorders.
|Figure 2: An approach to the etiological diagnosis for the combination of myoclonus and dystonia in children|
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|Figure 3: The list of different conditions causing dystonia+myoclonus in adults|
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| I Genetic Causes|| |
DYT–SGCE, previously known as DYT-11, represents the most extensively studied genetic cause of M–D. It results from the mutations in the gene located on chromosome 7q21–q31. Although the exact function of the ε-sarcoglycan and protein remains unknown, it is expressed in the midbrain monoaminergic neurons, cerebellar Purkinje cells, and in other brain regions, including the hippocampus and cortex. The age of onset of M–D is usually in the first decade. The most common presentation is “lightning-like myoclonic jerks,” predominantly involving the proximal upper limbs, but it can also occur in any other body part. Myoclonus is present at rest but is worsened with activity. It is subcortical in origin and is not sensitive to stimulus. In the SGCE mutation, myoclonus can be observed either as isolated presentations or in association with mild-to-moderate dystonia. The most common form of dystonia observed in this condition is cervical dystonia or writer’s cramp, while lower limb dystonia is rarely observed in patients with early age of onset. It usually does not occur in the face, larynx, and trunk. Alcohol responsiveness of the motor symptoms is an important feature of M–D due to the SGCE mutation. The motor manifestations in the SGCE mutation are often accompanied by psychiatric manifestations, including anxiety-related disorders and obsessive-compulsive disorder. The SGCE mutation was previously considered to be inherited in an autosomal-dominant manner with reduced penetrance, but it was later found to be maternally imprinted. When the mutated gene is inherited from the father, the mutation carriers manifest symptoms with complete penetrance. The features not typically observed with the SGCE mutation include truncal dystonia, myoclonus, and dystonia in the same body part and abnormal brain magnetic resonance imaging., The myoclonus in the SGCE mutation is subcortical in origin, as suggested by features such as lack of stimulus sensitivity, a negative C-reflex finding, absence of pre-myoclonic cortical potential, and absence of giant somatosensory evoked potential. Myoclonus–dystonia differs from other primary dystonia. Studies have revealed lower membrane excitability of the corticocortical axons and normal intracortical γ-aminobutyric acid inhibition in M–D patients compared to other forms of primary dystonia. The treatment of this condition is usually symptomatic and response to oral medication is often incomplete. Pallidal deep-brain stimulation (DBS) is an effective and well-tolerated therapeutic option for patients with drug-resistant M–D due to the SGCE mutation.
Cases that fulfil the clinical criteria for the M–D phenotype, including inheritance pattern, alcohol responsiveness, and associated psychiatric symptoms but are negative for the SGCE mutation have been described. Grimes et al. and Schüle et al. separately reported the M–D phenotype in families where linkage analysis identified a novel locus on chromosome 18p11, named DYT15.
B Non SGCE M–D syndromes
The pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause a myoclonus–dystonia-like phenotype.,,,,,,,ANO3 is a calcium-gated chloride channel encoded by a gene located on chromosome 11 and is expressed in the striatum. Mutations in this gene result in abnormalities in the endoplasmic reticulum-dependent calcium ion signaling. The age at onset ranges from the first to the fourth decade. Although M–D has been described in the literature, dystonia and tremor predominate over myoclonus. Myoclonus in the ANO3 mutation usually affects the neck and upper limbs. Cervical dystonia is the most common site of onset, followed by laryngeal dystonia, the oromandibular region, and blepharospasm. The dystonia caused by the ANO3 mutation slowly progresses to become segmental, but the legs usually remain unaffected and generalized dystonia is rarely observed. These features help differentiate DYT–ANO3 from other primary dystonia like DYT–THAP or DYT–GNAL., Another characteristic feature of the ANO3 mutation is the presence of tremor. Therefore, the patients with M–D who also have prominent cervical dystonia or tremor with mild dystonia should be tested for ANO3 mutations.
The KCTD17 gene mutation represents a rare genetic cause of the M–D syndrome inherited in an autosomal dominant manner. The KCTD17 protein belongs to the recently identified family of 26 closely related and highly conserved proteins, the potassium channel tetramerization domain (KCTD)-containing proteins. The KCTD17 gene is highly expressed in the putamen. Patients with the KCTD17 mutation usually manifest as early-onset progressive M–D.,,, The laryngeal involvement appears to be a more frequent and prominent finding in the KCTD17-related phenotype. In contrast, with the SGCE mutation, dystonia progressively spreads from the larynx to the eyelids and upper limbs and predominates over milder myoclonus. There are case reports on late-onset presentation with early and marked laryngeal involvement. In the KCTD17 mutation, myoclonus occurs in the dystonic muscles, but it is brief, and occurs outside of the dystonic spasm as a distinct electrophysiological phenomenon. It differs from the SGCE mutation, where myoclonic discharges are of a longer duration and superimposed on the dystonic activity. Alcohol responsiveness and psychiatric symptoms are not observed in the KCTD17 mutation. It has been reported to have an excellent response to pallidal stimulation.
The TUBB2B gene encodes for the β-isoform of tubulin protein that are the building blocks of microtubules. TUBB2B mutations have been known to affect the nervous system, typically presenting as severe symptoms, including psychomotor developmental delay, cognitive impairment, and epilepsy.TUBB2B mutations are commonly associated with structural brain abnormalities, the most common being polymicrogyria, while others include lissencephaly, micro-lissencephaly, pachygyria or agyria, and dysmorphic basal ganglia. Geiger et al. reported that case of an adult woman with a mild form of the TUBB2B gene tubulopathy characterized by dystonia, myoclonus, and seizures.
The CACNA1B gene encodes for neuronal voltage-gated calcium channels CaV2.2. CACNA1B mutations are reported to be associated with the M–D phenotype and progressive epilepsy–dyskinesia. Gorman et al. reported six affected individuals with bi-allelic loss-of-function variants of the CACNA1B gene and a neurodevelopmental disorder characterized by developmental and epileptic encephalopathy; postnatal microcephaly; and complex hyperkinetic movement disorders, including M–D, choreoathetosis, dyskinesia and stereotypy. Groen et al. reported five affected members of a family; the features described included M–D, cervical and axial dystonia at rest, writer’s cramp and action-induced foot dystonia with walking, myoclonic jerks in legs and arms, alcohol-responsiveness, and behavioral issues. The additional features reported with the CACNA1B mutation are gait unsteadiness due to high-frequency continuous myoclonus in the leg, cardiac arrhythmias, and attacks of painful cramps in upper and lower limbs. The association of the M–D phenotype with the CACNA1B gene was not replicated in a large European cohort. However, the previously reported R1389H variant was focused on, and the CACNA1B gene was not extensively screened in this study.
The KCNN2 gene, a member of the KCNN family of potassium channel genes, is highly expressed in the human brain, particularly the cerebellum. Balint et al. recently reported a novel missense variant of the KCNN2 gene as a cause of autosomal dominant tremulous M–D in the UK kindred with affected individuals in three generations. The phenotype described in their report includes tremulous dystonia, predominantly affecting the hands and neck, with superimposed myoclonus and subtle cerebellar eye signs. Onset was typically in infancy, with writer’s cramp and tremor. The myoclonus is distal, sometimes occurring in a “shivering-like fashion,” differentiating it from the classic M–D due to SGCE mutations, consisting of “lightening” jerks mainly affecting the neck and arms. Another differentiating feature is the cerebellar eye signs to variable degrees, ranging from mildly broken pursuit to end-gaze nystagmus.
6 Russell–Silver Syndrome
The myoclonus–dystonia phenotype has been described in the Russell–Silver syndrome (RSS) in different case reports.,,, It is caused by hypomethylation on chromosome 11p15, identified in 30%–60% patients. The maternal uniparental disomy for chromosome 7 (mUPD7) has been reported in approximately 10% cases. In mUPD7, the patients have two copies of the maternal allele for chromosome 7 rather than one from each parent. Maternal imprinting causing functional absence of the SGCE gene expression is likely to be responsible for the M–D phenotype. The Russell–Silver syndrome is typically characterized by intrauterine and postnatal growth retardation and dysmorphic features like relative macrocephaly, prominent forehead, body asymmetry, triangular face, fifth finger clinodactyly, and café au lait spot. Other features include feeding difficulty, low muscle mass, excessive sweating, hypoglycemia, global developmental delay, and mild learning difficulties.
7 NKX2-1 mutation
The NKX2-1 mutation is an autosomal dominant genetic disorder known as benign hereditary chorea (BHC), which is mainly characterized by nonprogressive chorea but heterogeneous phenotype including dystonia, tremor, and myoclonus has been described.,,,, There is considerable phenotypic overlap between BHC and the SGCE mutation, such as family history, associated psychiatric disturbance, and occasionally, alcohol responsiveness., Peall et al. found two cases with NKX2-1 mutations among 70 suspected M–D patients negative for SGCE mutations. Asmus et al. described certain clinical features that can help differentiate between BHC and SGCE mutations, including early-onset hypotonia, chorea, and association with thyroid or lung disease. Armstrong et al. reported a case with genetically proven BHC with typical childhood chorea that progressed to a myoclonic syndrome more suggestive of M–D in adulthood. It is important to differentiate between these two conditions because of the therapeutic and prognostic implications. In a French cohort, chorea improved in adolescence or early adulthood, remaining stable thereafter; however, myoclonus became the predominant disabling feature in some patients. In a recent review by Farrenburg et al., the NKX2-1 mutation contributed to 50% of the levodopa-responsive chorea cases reported in the literature.
8 ADCY5-related dyskinesia
ADCY5-related dyskinesia is an autosomal dominant disorder caused by gain-of-function mutations in the ADCY5 gene. It encodes for adenylyl cyclases that are involved in the conversion of adenosine triphosphate to cyclic adenosine-3′, 5′-monophosphate, a second messenger in a broad range of cellular activities. ADCY5-related dyskinesia is characterized by heterogenous hyperkinetic disorders such as myoclonus, paroxysmal dyskinesia, chorea, dystonia, and tremor. One of the hallmark features of this condition is the paroxysmal exacerbations of dyskinesias on awakening and while falling asleep. In addition, there are several case reports of M–D associated with the ADCY5 mutation.,,,,, Some of the features of the ADCY5 mutation are similar to those of the SGCE mutation, including young-onset presentation, myoclonus, and/or dystonia predominantly involving the cranio-cervical region and autosomal dominant inheritance. However, additional features observed in the ADCY5 mutation include facial myoclonus, oculomotor apraxia, sleep exacerbations, axial hypotonia, developmental delay and paroxysmal episodes, chorea, leg involvement, orolingual dystonia causing speech impairment, and sometimes, ataxia.
9 Dopa-responsive dystonia (DYT–GCH1 and DYT–TH)
Among different dopa-responsive dystonia, the M–D phenotype has been described in autosomal dominant mutations in the GCH1 (GTP cyclohydrolase1) gene and autosomal recessive mutations in the TH (tyrosine hydroxylase) gene.,, The myoclonus described in these conditions is usually generalized and tends to increase with posture and activity and is not stimulus sensitive. The typical features of dopa-responsive dystonia such as female preponderance and diurnal fluctuation of symptoms were absent in the reported cases., In such cases, an increase in prolactin and alteration in cerebrospinal fluid biogenic amine and pterin concentrations can reveal the etiology. Unlike DYT–SGCE, most of these reported cases revealed a dramatic, sustained, although incomplete, improvement with L-dopa treatment.
10 Other rare conditions
There are isolated case reports of the M–D phenotype in the mutation of different genes such as GNAL, GNB1, RELN, and 22q11.2 Deletion.,,,,,,, Although the GNAL mutation most commonly manifests as adult-onset cervical dystonia with or without superimposed tremor, there are rare case reports of associated myoclonus with this mutation.,, Furthermore, a mutation in another related GNB1 gene, encoding for guanine nucleotide-binding beta-1 protein, has been reported to be associated with the M–D phenotype, resembling the ADCY5 mutation because of associated features such as hypotonia and upward-gaze palsy. In addition, Jones et al. reported the response to bilateral globus pallidus interna DBS in one patient with M–D with GNB1 mutation. Groen et al. screened 25 SGCE-negative M–D patients, of which five carried the RELN rare missense variants. The RELN mutation carriers showed a homogeneous M–D phenotype, with myoclonus and mild dystonia of the neck and upper limbs that aggravated during stress. Furthermore, psychiatric abnormalities were common among these carriers.
The 22q11.2 deletion syndrome, which is the most common chromosomal microdeletion disorder, has been reported to manifest as M–D syndrome., It is unknown whether the M–D phenotype is primarily related to mutation or secondary to associated comorbidities observed with the 22q11 deletion syndrome (22q11.2DS), such as hypocalcemia, thyroid dysfunction, or drug-induced manifestations. Other common manifestations of 22q11.2DS include congenital cardiac and/or palatal malformations, neuropsychiatric disorders, and epilepsy. Therefore, patients with the M–D syndrome with dysmorphic facial features and multiorgan involvement should be considered for microarray analysis to investigate for possible 22q11.2DS.
C Myoclonus and dystonia as a part of the syndrome
Other conditions where dystonia and myoclonus occur as a part of the syndrome are considered as “myoclonus–dystonia plus syndrome.” The important conditions that can be placed under this category are listed below.
1 Ataxia syndromes
There are case reports of autosomal recessive cerebellar ataxias manifesting as a combination of myoclonus and dystonia, including ataxia–telangiectasia, Vitamin-E deficiency syndrome, and cerebrotendinous xanthomatosis.,, These conditions usually involve additional findings such as peripheral neuropathy, eye movement abnormalities, and biochemical findings. Ataxia usually precedes or follows a few months or years after the onset of dystonia and myoclonus.
Different spinocerebellar ataxias (SCAs) are known to have myoclonus and/or dystonia, including SCA2, SCA14, SCA17, and SCA19; however, the M–D phenotype has been described mainly in SCA14, predominantly involving the trunk., SCA14 is caused by mutations in the protein kinase C gamma (PRKCG) gene located on chromosome 19q. It is characterized by slowly progressive cerebellar features such as ataxia, dysarthria, and nystagmus, with onset at approximately 20 years of age. In addition, other neurological symptoms such as cognitive impairment, tremor, and parkinsonism may be observed.
2 Inherited defects of metabolism
Myoclonus and dystonia can be observed in different inherited neurometabolic disorders such as lysosomal storage diseases, mitochondrial cytopathies, metal storage disorders, organic acidurias, disorders of carbohydrate metabolism, and vitamin and cofactor deficiency., These disorders usually have addition clinical and radiological features that help differentiate them from typical M–D syndromes. The two noteworthy metal storage disorders in this context include Wilson’s disease and neurodegeneration with brain iron accumulation, which usually present with prominent dystonia, especially involving the oromandibular region. However, there are several case reports of myoclonus as the presenting symptoms of Wilson’s disease., Similarly, myoclonus can be observed in different neurodegeneration with brain iron accumulation, e.g., facial-faucial-finger myoclonus in Kufor–Rakeb syndrome.
| II Acquired Causes|| |
The acquired conditions may sometimes present with a combination of dystonia and myoclonus and other neurological features. Subacute onset of myoclonus and dystonia with encephalopathy can have a varied differential diagnosis, including metabolic (e.g., renal and liver failure), infectious, and autoimmune encephalitis. In children, subacute sclerosing panencephalitis and Japanese encephalitis are common infectious causes. Slow myoclonus is the early and characteristic feature of subacute sclerosing panencephalitis; however, dystonia is usually observed in advanced stages.,, The most common movement disorder in Whipple disease is oculomasticatory myorhythmia, i.e., a slow (1–4 Hz), rhythmic, or semirhythmic form of segmental myoclonus, while dystonia is relatively rare. In a systemic review of 324 cases with prion disease, myoclonus was the most frequent movement disorder observed with genetic diseases such as Creutzfeldt–Jakob disease and fatal familial insomnia, followed by gait ataxia. Dystonia was found to be uncommon in prion diseases, but when present, it was more often associated with sporadic Creutzfeldt–Jakob disease (75% cases). Among autoimmune encephalitis, antibodies against NMDAR, CV2/CRMP5, LGI1, CASPR2, DPPX, IgLON5, thyroid peroxidase and Ma 2 are known to have dystonia and myoclonus as their manifestations, along with seizures, behavioral changes, and rapidly progressive dementia.
Late-onset neurodegenerative diseases that are sometimes accompanied by dystonia and myoclonus include Parkinson’s disease (PD), multiple system atrophy, corticobasal syndrome (CBS), Alzheimer’s disease (AD), and Huntington’s disease (HD). While myoclonus (especially stimulus-sensitive myoclonus) and dystonia are common in CBS, it is less common in abovementioned neurodegenerative diseases. The occurrence of both dystonia and myoclonus has been described as a motor complication in PD patients after chronic levodopa treatment. Dystonia usually occurs as an off-period phenomenon or as a part of peak/biphasic dyskinesia, mainly the foot of the more affected side causing painful toe extension. Myoclonus can be rarely observed in peak-dose dyskinesia and may lead to confusion of PD with CBS. In addition to levodopa, other medications such as amantadine and bromocriptine have been shown to induce myoclonus in PD. Caviness et al. have reported the occurrence of myoclonus in PD patients unrelated to medication with an incidence of approximately 5%. Dystonia, particularly affecting the orofacial and truncal regions, and minipolymyoclonus are considered important supportive features for the diagnosis of multiple system atrophy. In addition, both dystonia and myoclonus are known to occur in AD. Dystonia in AD is commonly caused by drugs such as rivastigmine, mirtazapine, and neuroleptics. Cortical reflex myoclonus is common in advanced AD (approximately 50%) and early-onset familial AD. Similarly, dystonia and myoclonus are more common in juvenile HD compared to adult HD.
| Conclusion|| |
The M–D syndrome comprises an etiologically heterogeneous group of disorders. Most of the causes of childhood-onset disorders are genetic disorders, while acquired conditions usually occur in adulthood. There is a notable overlap in the manifestations of different causes of M–D. However, subtle clues listed in our review can help differentiate among them. Genetic testing is often required to confirm the diagnosis. Our review provides the list of both genetic and acquired causes, as well as a clinical approach to guide further diagnostic procedures. We believe that the list of diseases manifesting as combined myoclonus and dystonia will continue to expand in the future, with the increasing availability of next-generation sequencing techniques. Furthermore, our review highlights the relevance of the genotype in predicting a response to DBS and other pharmacological options in patients with inherited dystonia and myoclonus.
- Research Project: A. Conception, B. Organization, C. Execution;
- Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
- Manuscript Preparation: A. Writing of the first draft, B. Review and Critique;
Ac: 1A, 1B, 1C, 2A, 2B, 3A.
SP: 1A, 2B, 3A, 3B.
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| References|| |
Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al
. Phenomenology and classification of dystonia: A consensus update. Mov Disord 2013;28:863-73.
Rossi M, Balint B, Millar Vernetti P, Bhatia KP, Merello M. Genetic dystonia-ataxia syndromes: Clinical spectrum, diagnostic approach, and treatment options. Mov Disord Clin Pract 2018;5:373-82.
Weissbach A, Saranza G, Domingo A. Combined dystonias: Clinical and genetic updates. J Neural Transm (Vienna) 2021;128:417-29.
Roze E, Lang AE, Vidailhet M. Myoclonus-dystonia: Classification, phenomenology, pathogenesis, and treatment. Curr Opin Neurol 2018;31:484-90.
Nardocci N, Zorzi G, Barzaghi C, Zibordi F, Ciano C, Ghezzi D, et al
. Myoclonus-dystonia syndrome: Clinical presentation, disease course, and genetic features in 11 families. Mov Disord 2008;23:28-34.
Esapa CT, Waite A, Locke M, Benson MA, Kraus M, McIlhinney RA, et al
. SGCE missense mutations that cause myoclonus-dystonia syndrome impair epsilon- sarcoglycan trafficking to the plasma membrane: Modulation by ubiquitination and torsinA. Hum Mol Genet 2007;16:327-42.
Weissbach A, Kasten M, Grünewald A, Brüggemann N, Trillenberg P, Klein C, et al
. Prominent psychiatric comorbidity in the dominantly inherited movement disorder myoclonus-dystonia. Parkinsonism Relat Disord 2013;19:422-5.
Grünewald A, Djarmati A, Lohmann-Hedrich K, Farrell K, Zeller JA, Allert N, et al
. Myoclonus-dystonia: Significance of large SGCE deletions. Hum Mutat 2008;29:331-2.
Menozzi E, Balint B, Latorre A, Valente EM, Rothwell JC, Bhatia KP. Twenty years on: Myoclonus-dystonia and β-sarcoglycan - neurodevelopment, channel, and signaling dysfunction. Mov Disord 2019;34:1588-601.
Popa T, Milani P, Richard A, Hubsch C, Brochard V, Tranchant C, et al
. The neurophysiological features of myoclonus-dystonia and differentiation from other dystonias. JAMA Neurol 2014;71:612-9.
Wang X, Yu X. Deep brain stimulation for myoclonus dystonia syndrome: A meta-analysis with individual patient data. Neurosurg Rev 2021;44:451-62.
Grimes DA, Han F, Lang AE, St George-Hyssop P, Racacho L, Bulman DE. A novel locus for inherited myoclonus-dystonia on 18p11. Neurology 2002;59:1183-6.
Schüle B, Kock N, Svetel M, Dragasevic N, Hedrich K, De Carvalho Aguiar P, et al
. Genetic heterogeneity in ten families with myoclonus-dystonia. J Neurol Neurosurg Psychiatry 2004;75:1181-5.
Laurencin C, Broussolle E, Danaila T, Anheim M, Chelly J, Thobois S. A novel heterozygous ANO3 mutation responsible for myoclonic dystonia. J Neurol Sci 2019;403:65-6.
Stamelou M, Charlesworth G, Cordivari C, Schneider SA, Kägi G, Sheerin UM, et al
. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov Disord 2014;29:928-34.
Charlesworth G, Plagnol V, Holmstrom KM, Bras J, Sheerin UM, Preza E, et al
. Mutations in ANO3 cause cranio-cervical dystonia: A novel molecular mechanism. Am J Hum Genet 2012;91:1040-50.
Carvalho V, Martins J, Correia F, Costa M, Massano J, Temudo T. Another twist in the tale: Intrafamilial phenotypic heterogeneity in ANO3-related dystonia. Mov Disord Clin Pract 2021;8:758-62.
Zech M, Boesch S, Jochim A, Weber S, Meindl T, Schormair B, et al
. Clinical exome sequencing in early-onset generalized dystonia and large-scale resequencing follow-up. Mov Disord 2017;32:549-59.
Tunc S, Denecke J, Olschewski L, Bäumer T, Münchau A, Lessel D, et al
. A recurrent de-novo ANO3 mutation causes early-onset generalized dystonia. J Neurol Sci 2019;396:199-201.
Yoo D, Kim HJ, Lee JS, Lee S, Kim SY, Choi M, et al
. Early- onset generalized dystonia starting in the lower extremities in a patient with a novel ANO3 variant. Parkinsonism Relat Disord 2018;50:124-5.
Delamarre A, Chelly J, Guehl D, Drouot N, Tranchant C, Anheim M, et al
. Novel anoctamin-3 missense mutation responsible for early-onset myoclonic dystonia. Parkinsonism Relat Disord 2019;64:346-8.
Xiromerisiou G, Houlden H, Scarmeas N, Stamelou M, Kara E, Hardy J, et al
. THAP1 mutations and dystonia phenotypes: Genotype phenotype correlations. Mov Disord 2012;27:1290-4.
Fuchs T, Saunders-Pullman R, Masuho I, Luciano MS, Raymond D, Factor S, et al
. Mutations in GNAL cause primary torsion dystonia. Nat Genet 2013;45:88-92.
Mencacci NE, Rubio-Agusti I, Zdebik A, Asmus F, Ludtmann MH, Ryten M, et al
. A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia. Am J Hum Genet 2015;96:938-47.
Marcé-Grau A, Correa M, Vanegas MI, Muñoz-Ruiz T, Ferrer-Aparicio S, Baide H, et al
. Childhood onset progressive myoclonic dystonia due to a de novo KCTD17 splicing mutation. Parkinsonism Relat Disord 2019;61:7-9.
Todisco M, Gana S, Cosentino G, Errichiello E, Arceri S, Avenali M, et al
. KCTD17-related myoclonus-dystonia syndrome: Clinical and electrophysiological findings of a patient with atypical late onset. Parkinsonism Relat Disord 2020;78:129-33.
Graziola F, Stregapede F, Travaglini L, Garone G, Verardo M, Bosco L, et al
. A novel KCTD17 mutation is associated with childhood early-onset hyperkinetic movement disorder. Parkinsonism Relat Disord 2019;61:4-6.
Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, et al
. The wide spectrum of tubulinopathies: What are the key features for the diagnosis? Brain 2014;137:1676-700.
Cushion TD, Dobyns WB, Mullins JG, Stoodley N, Chung SK, Fry AE, et al
. Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain 2013;136:536-48.
Geiger JT, Schindler AB, Blauwendraat C, Singer HS, Scholz SW. TUBB2B mutation in an adult patient with myoclonus-dystonia. Case Rep Neurol 2017;9:216-21.
Groen JL, Andrade A, Ritz K, Jalalzadeh H, Haagmans M, Bradley TE, et al
. CACNA1B mutation is linked to unique myoclonus-dystonia syndrome. Hum Mol Genet 2015;24:987-93.
Gorman KM, Meyer E, Grozeva D, Spinelli E, McTague A, Sanchis-Juan A, et al
. Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia. Am J Hum Genet 2019;104:948-56.
Mencacci NE, R'bibo L, Bandres-Ciga S, Carecchio M, Zorzi G, Nardocci N, et al
. The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort. Hum Mol Genet 2015;24:5326-9.
Balint B, Guerreiro R, Carmona S, Dehghani N, Latorre A, Cordivari C, et al
. KCNN2 mutation in autosomal-dominant tremulous myoclonus-dystonia. Eur J Neurol 2020;27:1471-7.
Augustine EF, Blackburn J, Pellegrino JE, Miller R, Mink JW. Myoclonus- dystonia syndrome associated with Russell Silver syndrome. Mov Disord 2013;28:841-2.
Guettard E, Portnoi MF, Lohmann-Hedrich K, Keren B, Rossignol S, Winkler S, et al
. Myoclonus- dystonia due to maternal uniparental disomy. Arch Neurol 2008;65:1380-4.
Sheridan MB, Bytyci Telegrafi A, Stinnett V, Umeh CC, Mari Z, Dawson TM, et al
. Myoclonus-dystonia and Silver-Russell syndrome resulting from maternal uniparental disomy of chromosome 7. Clin Genet 2013;84:368-72.
Shpiner DS, Bardos J, Barbouth DS, Moore HP. Uniparental disomy causing myoclonus dystonia associated with Russell Silver syndrome. Mov Disord Clin Pract 2019;6:409-10.
Abu-Amero S, Monk D, Frost J, Preece M, Stanier P, Moore GE. The genetic aetiology of Silver-Russell syndrome. J Med Genet 2008;45:193-239.
Peall KJ, Kurian MA, Wardle M, Waite AJ, Hedderly T, Lin JP, et al
. SGCE and myoclonus dystonia: Motor characteristics, diagnostic criteria and clinical predictors of genotype. J Neurol 2014;261:2296-304.
Asmus F, Devlin A, Munz M, Zimprich A, Gasser T, Chinnery PF. Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia. Mov Disord 2007;22:2104-9.
Armstrong MJ, Shah BB, Chen R, Angel MJ, Lang AE. Expanding the phenomenology of benign hereditary chorea: Evolution from chorea to myoclonus and dystonia. Mov Disord 2011;26:2296-7.
Balicza P, Grosz Z, Molnár V, Illés A, Csabán D, Gézsi A, et al
. NKX2-1 new mutation associated with myoclonus, dystonia, and pituitary involvement. Front Genet 2018;9:335.
Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, et al
. Benign hereditary chorea: Phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry 2012;83:956-62.
Farrenburg M, Gupta HV. Levodopa-responsive chorea: A review. Ann Indian Acad Neurol 2020;23:211-4. [Full text]
Vijiaratnam N, Bhatia KP, Lang AE, Raskind WH, Espay AJ. ADCY5-related dyskinesia: Improving clinical detection of an evolving disorder. Mov Disord Clin Pract 2019;6:512-20.
Agarwal PA, Ramprasad VL. Adult-onset myoclonus-dystonia syndrome preceding characteristic facial myoclonus in Indian ADCY5-related dyskinesia. Mov Disord Clin Pract 2019;6:267-8.
Bohlega SA, Abou-Al-Shaar H, AlDakheel A, Alajlan H, Bohlega BS, Meyer BF, et al
. Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders. Parkinsonism Relat Disord 2019;64:145-9.
Douglas AG, Andreoletti G, Talbot K, Hammans SR, Singh J, Whitney A, et al
. ADCY5-related dyskinesia presenting as familial myoclonus-dystonia. Neurogenetics 2017;18:111-7.
Saraf U, Chandarana M, Divya KP, Krishnan S. ADCY5-related dyskinesia with myoclonus-dystonia syndrome: Clues to diagnosis. Ann Mov Disord 2021;4:86-8. [Full text]
Barrett MJ, Williams ES, Chambers C, Dhamija R. Autosomal recessive inheritance of ADCY5-related generalized dystonia and myoclonus. Neurol Genet 2017;3:193.
Chang FC, Westenberger A, Dale RC, Smith M, Pall HS, Perez-Dueñas B, et al
. Phenotypic insights into ADCY5-associated disease. Mov Disord 2016;31:1033-40.
Stamelou M, Mencacci NE, Cordivari C, Batla A, Wood NW, Houlden H, et al
. Myoclonus-dystonia syndrome due to tyrosine hydroxylase deficiency. Neurology 2012;79:435-41.
Clot F, Grabli D, Cazeneuve C, Roze E, Castelnau P, Chabrol B, et al
. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia. Brain 2009;132:1753-63.
Leuzzi V, Carducci C, Carducci C, Cardona F, Artiola C, Antonozzi I. Autosomal dominant GTP-CH deficiency presenting as a dopa-responsive myoclonus-dystonia syndrome. Neurology 2002;59:1241-3.
Geoghegan AR, Al Hussona M, Beauchamp NJ, Hutchinson M, Sean O'Riordan MB, Lynch T, et al
. A novel GNAL mutation in familial dystonia presenting with childhood tremor and myoclonus. Mov Disord 2019;34:923-4.
Carecchio M, Panteghini C, Reale C, Barzaghi C, Monti V, Romito L, et al
. Novel GNAL mutation with intra-familial clinical heterogeneity: Expanding the phenotype. Parkinsonism Relat Disord 2016;23:66-71.
McGovern E, Hutchinson M, Lynch T, Webb D. PO090 Familial early-onset dystonia and myoclonus due to a novel gnal mutation (dyt25). J Neurol Neurosurg Psychiatry 2017;88:A35.
Steinrucke S, Lohmann K, Domingo A, Rolfs A, Bäumer T, Spiegler J, et al
. Novel GNB1 missense mutation in a patient with generalized dystonia, hypotonia, and intellectual disability. Neurol Genet 2016;2:e106.
Jones HF, Morales-Briceño H, Barwick K, Lewis J, Sanchis-Juan A, Raymond FL, et al
. Myoclonus-dystonia caused by GNB1 mutation responsive to deep brain stimulation. Mov Disord 2019;34:1079-80.
Groen JL, Ritz K, Jalalzadeh H, van der Salm SM, Jongejan A, Mook OR, et al
. RELN rare variants in myoclonus-dystonia. Mov Disord 2015;30:415-9.
Van Iseghem V, McGovern E, Apartis E, Keren B, Vidailhet M, Roze E, et al
. Subcortical myoclonus and associated dystonia in 22q11.2 syndrome. Tremor Other Hyperkinet Mov (N Y) 2020;10. doi: 10.7916/tohm.v0.729.
Baralle D. Myoclonic movement disorder associated with microdeletion of chromosome 22q11. J Neurol Neurosurg Psychiatry 2002;73:600-1.
Cherian A, Chandarana M, Susvirkar AA, Divya KP, Saraf UU, Krishnan S. Abnormal saccades differentiate adolescent onset variant ataxia telangiectasia from other myoclonus dystonia. Ann Indian Acad Neurol 2021;24:630-2. [Full text]
Angelini L, Erba A, Mariotti C, Gellera C, Ciano C, Nardocci N. Myoclonic dystonia as unique presentation of isolated vitamin E deficiency in a young patient. Mov Disord 2002;17:612-4.
Lagarde J, Roze E, Apartis E, Pothalil D, Sedel F, Couvert P, et al
. Myoclonus and dystonia in cerebrotendinous xanthomatosis. Mov Disord 2012;27:1805-10.
Van Gaalen J, Giunti P, van de Warrenburg BP. Movement disorders in spinocerebellar ataxias. Mov Disord 2011;26:792-800.
Foncke EM, Beukers RJ, Tijssen CC, Koelman JH, Tijssen MA. Myoclonus-dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes: Trunk tremor, myoclonus, and dystonia. Parkinsonism Relat Disord 2010;16:288-9.
Christensen CK, Walsh L. Movement disorders and neurometabolic diseases. Semin Pediatr Neurol 2018;25:82-91.
Ebrahimi-Fakhari D, Van Karnebeek C, Münchau A. Movement disorders in treatable inborn errors of metabolism. Mov Disord 2019;34:598-613.
Verma R, Holla VV, Pandey S, Rizvi I. Multifocal myoclonus as a heralding manifestation of Wilson disease. J Pediatr Neurosci 2016;11:358-60.
] [Full text]
Kumar N, Kumar D. Teaching Video NeuroImages: Myoclonus as the presenting feature of Wilson disease. Neurology 2019;92: e1667-8.
Batla A, Gaddipati C. Neurodegeneration with brain iron accumulation. Ann Indian Acad Neurol 2019;22:267-76.
] [Full text]
Raut TP, Singh MK, Garg RK, Rai D. Evolution of certain typical and atypical features in a case of subacute sclerosing panencephalitis. BMJ Case Rep 2012;2012:bcr2012007052.
Dimova P, Bojinova V. Subacute sclerosing panencephalitis with atypical onset: Clinical, computed tomographic, and magnetic resonance imaging correlations. J Child Neurol 2000;15:258-60.
Reyes AJ, Ramcharan K, Perot S, Giddings SL, Rampersad F, Gobin R. Subacute sclerosing panencephalitis causing rapidly progressive dementia and myoclonic jerks in a sexagenarian woman. Tremor Other Hyperkinet Mov (N Y) 2019;9. doi: 10.7916/tohm.v0.680.
Bally JF, Méneret A, Roze E, Anderson M, Grabli D, Lang AE. Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease. Mov Disord 2018;33:1700-11.
Rodriguez-Porcel F, Ciarlariello VB, Dwivedi AK, Lovera L, Da Prat G, Lopez-Castellanos R, et al
. Movement disorders in prionopathies: A systematic review. Tremor Other Hyperkinet Mov (N Y) 2019;9. doi: 10.7916/tohm.v0.712.
Balint B, Vincent A, Meinck HM, Irani SR, Bhatia KP. Movement disorders with neuronal antibodies: Syndromic approach, genetic parallels and pathophysiology. Brain 2018;141:13-36.
Zutt R, van Egmond ME, Elting JW, van Laar PJ, Brouwer OF, Sival DA, et al
. A novel diagnostic approach to patients with myoclonus. Nat Rev Neurol 2015;11:687-97.
Klawans HL, Goetz C, Bergen D. Levodopa-induced myoclonus. Arch Neurol 1975;32:331-4.
Pandey S, Srivanitchapoom P. Levodopa-induced dyskinesia: Clinical features, pathophysiology, and medical management. Ann Indian Acad Neurol 2017;20:190-8.
] [Full text]
Truong DD, Bhidayasiri R. Myoclonus and parkinsonism. Handb Clin Neurol 2007;84:549-60.
Caviness JN, Adler CH, Newman S, Caselli RJ, Muenter MD. Cortical myoclonus in levodopa-responsive parkinsonism. Mov Disord 1998;13:540-4.
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al
. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670-6.
Vanacore N, Suzzareddu G, Maggini M, Casula A, Capelli P, Raschetti R. Pisa syndrome in a cohort of Alzheimer's disease patients. Acta Neurol Scand 2005;111:199-201.
Caviness JN. Myoclonus and neurodegenerative disease-what's in a name? Parkinsonism Relat Disord 2003;9:185-92.
Cronin T, Rosser A, Massey T. Clinical presentation and features of juvenile-onset Huntington's disease: A systematic review. J Huntingtons Dis 2019;8:171-9.
[Figure 1], [Figure 2], [Figure 3]