Myoclonus-dystonia is a genetically heterogeneous disorder characterized by myoclonic jerks affecting mostly proximal muscles. Dystonia, usually torticollis or writer's cramp, is observed in most patients, but occasionally can be the only symptom of the disorder. Onset of the ... Myoclonus-dystonia is a genetically heterogeneous disorder characterized by myoclonic jerks affecting mostly proximal muscles. Dystonia, usually torticollis or writer's cramp, is observed in most patients, but occasionally can be the only symptom of the disorder. Onset of the disorder is usually in the first or second decade. Symptoms often respond to alcohol, and patients can also have psychiatric abnormalities (Valente et al., 2003; Schule et al., 2004). See also HETEROGENEITY below for other forms of the disorder that do not map to 7q21, including DYT15 (607488), which maps to 18p11.
Myoclonic dystonia, or myoclonus-dystonia, has dystonia as the core feature, but tremor or rapid jerky movements resembling myoclonus may also be present. The age of onset, pattern of body involvement, presence of myoclonus, and response to alcohol are ... Myoclonic dystonia, or myoclonus-dystonia, has dystonia as the core feature, but tremor or rapid jerky movements resembling myoclonus may also be present. The age of onset, pattern of body involvement, presence of myoclonus, and response to alcohol are all variable. Essential myoclonus is a relatively mild condition starting in the first or second decade, and is inherited as an autosomal dominant trait with incomplete penetrance. Some patients with essential myoclonus also have dystonia, but there are usually no other neurologic symptoms, and there may be a dramatic response to alcohol (Nemeth, 2002). In a family of French-Canadian background, a father and 5 of his 9 children showed onset of myoclonus in the first or second decade and a benign course without seizures, dementia, or neurologic signs other than myoclonus (Mahloudji and Pikielny, 1967). Because of the uncertainty of the nature of the case, on the basis of which Friedreich in 1881 introduced the term paramyoclonus multiplex, these cases might best be called hereditary essential myoclonus. Daube and Peters (1966) reported 2 families with hereditary essential myoclonus in each of which affected members occurred in at least 4 generations, with male-to-male transmission but some skipped generations. Symonds (1953) described nocturnal myoclonus in a man and 5 of his 6 children. Muller and Kupke (1990) interpreted the family reported by Mahloudji and Pikielny (1967) as an instance of what they termed myoclonic dystonia, i.e., the association of torsion dystonia with myoclonus (muscle jerks). They pointed to families with the same disorder reported by Benedek and Rakonitz (1940), Quinn et al. (1988), and Kurlan et al. (1988). Unlike other forms of dystonia (e.g., 128100), myoclonic dystonia may be highly responsive to ethanol ingestion and frequently also to clonazepam therapy and usually pursues a benign course. Kyllerman et al. (1990) described a 6-generation Swedish family with alcohol-responsive hereditary myoclonus. After clinical examination of 20 affected persons, myoclonus was found in the arms, shoulders, and neck of 17. The onset of myoclonus was between 2 and 3 years of age. The onset of leg dystonia was from 6 to 18 months of age. Nygaard et al. (1999) reported a large American kindred of European and Native American ancestry with essential familial myoclonic dystonia that was responsive to alcohol. There were 10 definitely affected living individuals. Four had both myoclonus and dystonia, 5 had myoclonus alone, and 1 had brachial dystonia only. However, among the 5 judged to have only myoclonus, 4 had occasional sustained contractions and subtle posturing that might suggest mild dystonia. Mean age at onset of symptoms was 6.5 years (range, 4 to 15 years) in the 8 individuals able to recall onset. All affected individuals who tried alcohol reported relief of symptoms. Several family members had sought medical attention; levodopa was ineffective, and clonazepam or valproate gave mild benefit. Nine out of the 10 affected family members reported psychiatric problems, including diagnoses and treatment for depression, anxiety, and obsessive-compulsive disorder. Asmus et al. (2002) reported 24 affected patients from 9 families, confirmed by genetic analysis of the SGCE gene (1 previously known and 6 novel heterozygous mutations were identified). The clinical presentation was homogeneous, with myoclonus affecting primarily the neck, trunk, and upper extremities at a mean age of onset of 5.4 years (range 0.5 to 20 years). Dystonia presented mostly in a focal distribution as cervical dystonia and/or writer's cramp at a mean age of onset of 8.8 years (range 1 to 38 years), often occurring in parallel with worsening of myoclonus. Myoclonus was improved by alcohol in 21 of 24 affected, and 5 affected members of 3 families had a history of panic attacks, depression, and agoraphobia. Pedigree analysis showed reduced penetrance of the phenotype upon maternal inheritance of the mutated allele, indicating genomic imprinting. Doheny et al. (2002) described in detail the motor symptoms, psychiatric disorders, and neuropsychologic deficits in 3 families with myoclonus-dystonia syndrome who carried mutations in the SGCE gene. One family also carried a mutation in the DRD2 gene. Motor expression was variable, with onset of myoclonus or dystonia or both affecting the upper body and progression to myoclonus and dystonia in most cases. Psychiatric profiles revealed depression, obsessive-compulsive disorder, substance abuse, anxiety/panic/phobic disorders, and psychosis in 2 families, and depression only in the third family. Averaged scores from cognitive testing showed impaired verbal learning and memory in 1 family, impaired memory in the second family, and no cognitive deficits in the third family. Doheny et al. (2002) concluded that cognitive deficits may be associated with myoclonus-dystonia and that psychiatric abnormalities correlated with motor symptoms in affected individuals. In a large family with myoclonus-dystonia syndrome and a mutation in the SGCE gene (604149.0008), Hjermind et al. (2003) reported prominent involvement of the legs, leading to disability in some, and laryngeal involvement causing vocal myoclonus. Valente et al. (2005) identified SGCE mutations in 6 (21%) of 29 patients with essential myoclonus and myoclonic dystonia; no SGCE mutations were identified in another 29 patients with a broader myoclonus/dystonia phenotype. The patients with mutations typically had early onset of predominant myoclonus and milder dystonia, with an upper body predilection. Dystonia tended to have a later onset than that of myoclonus. Most patients' symptoms improved with alcohol. Autosomal dominant paternal inheritance was observed. Valente et al. (2005) noted the clinical phenotypic overlap of myoclonic dystonia, essential myoclonus, 'jerky' dystonia, Ramsay Hunt syndrome (159700), and benign hereditary chorea (118700). Gerrits et al. (2006) reported 31 unrelated patients with a clinical diagnosis of myoclonus-dystonia, of whom 7 were found to have mutations in the SGCE gene. Clinical comparisons between mutation-positive and mutation-negative patients showed that the former had earlier disease onset before age 20 years. Mutation carriers first presented mostly with both myoclonus and dystonia, whereas mutation-negative patients usually presented with 1 or the other symptom. Those with mutations also tended to have a family history of the disorder, as well as truncal myoclonus and axial dystonia. There were no significant differences between the 2 groups regarding alcohol sensitivity or psychiatric symptoms. Roze et al. (2008) reviewed the features of 41 patients from 22 French families with SGCE mutation-positive myoclonus dystonia. The mean age at onset was 6 years (range, 1 to 18 years). Myoclonus was the presenting feature in 29 patients, 5 of whom also presented with dystonia. Ten patients presented with isolated dystonia, and 2 patients from the same family presented with hypotonia. Dystonia was axial, mostly cervical, in 13 patients, in the upper limbs in 18 patients, and in the lower limbs in 9 patients. One patient had laryngeal dystonia. Myoclonus involved the axis in 90% of cases, most commonly with cervical and upper limb involvement. Myoclonus of the face and voice occurred in 27% and 24%, respectively, and involved the lower limbs in 34% of patients. Myoclonus was present at rest in 70% of patients, and increased with posture and action in 95%. Neurophysiologic studies showed that myoclonus could be synchronous or asynchronous, isolated, and mostly arrhythmic. The studies indicated a subcortical origin: myoclonus was stimulus insensitive; the mean duration of myoclonus was 95 seconds, which is longer than that observed in cortical myoclonus; and there were no features of cortical hyperexcitability, as reflected by a negative C-reflex response. Nine patients had spontaneous remission of the dystonia during childhood or adolescence. Eight patients had associated psychiatric disturbances, including obsessive-compulsive disorder, severe anxiety and depression, attention-deficit hyperactivity disorder, and phobic disorder. There were no clear genotype/phenotype correlations.
Using a positional cloning approach, Zimprich et al. (2001) identified 5 different heterozygous loss-of-function mutations in the gene encoding epsilon-sarcoglycan (SGCE; 604149). SGCE was found to be expressed in all brain regions ... - Mutations in SGCE Using a positional cloning approach, Zimprich et al. (2001) identified 5 different heterozygous loss-of-function mutations in the gene encoding epsilon-sarcoglycan (SGCE; 604149). SGCE was found to be expressed in all brain regions examined. Pedigree analysis showed a marked difference in penetrance depending on the parental origin of the disease allele. This was indicative of a maternal imprinting mechanism, which had been demonstrated in the case of the mouse epsilon-sarcoglycan gene. Using bisulfite genomic sequencing to study methylation patterns of the SGCE gene in samples from MDS patients, Grabowski et al. (2003) found strong evidence for maternal imprinting of the SGCE gene. In a Dutch family with myoclonus-dystonia syndrome spanning 5 generations, previously reported by Doheny et al. (2002), Foncke et al. (2003) identified a mutation in the SGCE gene (604149.0007). In addition to the typical motor symptoms, 3 of 5 living affected members also had EEG abnormalities and seizures. Seizures consisted of episodes of reduced consciousness and staring, amnesia, and panic-like feelings, suggestive of temporal-limbic origin. Foncke et al. (2003) suggested that epilepsy should not be considered an exclusion criterion for the clinical diagnosis of myoclonus-dystonia syndrome. Asmus et al. (2005) identified 2 different large heterozygous deletions in the SGCE gene (604149.0010 and 604149.0011) in affected members from 2 unrelated families with myoclonic dystonia. The deletion was paternally inherited in all cases with motor symptoms. In 1 family, a man who inherited the mutation maternally did not have motor symptoms but did have alcohol dependence. Tezenas du Montcel et al. (2006) identified 13 different mutations in the SGCE gene in 16 of 76 unrelated French Caucasian patients with myoclonus-dystonia or essential myoclonus. In 12 families (75%), at least 1 other family member was affected. Penetrance was complete in paternal transmissions and null in maternal transmissions. None of the patients had severe psychiatric disorders. In affected members of a large Dutch family with myoclonus-dystonia syndrome reported by Korten et al. (1974), Foncke et al. (2006) identified a heterozygous mutation in the SGCE gene (604149.0012). The mutation was identified in all 19 symptomatic relatives, all 5 'possibly affected' relatives, and in 9 clinically unaffected relatives. All symptomatic individuals inherited the mutation from their father, and all asymptomatic individuals inherited it from their mother. Foncke et al. (2006) noted that subtle distal myoclonus of the fingers was a prominent feature in this family. - Mutations in DRD2 In a family containing 8 members with myoclonic dystonia, Klein et al. (1999) found heterozygosity for a variation in the DRD2 gene (V154I; 126450.0001). However, Klein et al. (2002) later identified a 5-bp deletion in the SGCE gene (604149.0005) in all 8 affected members. There were 2 unaffected carriers of both mutations. The contribution of each mutation to the clinical phenotype could not be determined, but was the phenotype most likely resulted from the SGCE mutation, as Klein et al. (2000) showed that the V154I DRD2 mutant protein was similar to wildtype and did not show impaired activity in in vitro studies. (See also Furukawa and Rajput, 2002). By direct sequencing, Klein et al. (2000) excluded DRD2 mutations in 5 unrelated probands with myoclonus dystonia. Four additional families were excluded by linkage analysis. Durr et al. (2000) excluded mutations in the DRD2 gene in 9 unrelated families with myoclonic dystonia or essential myoclonus and variable responses to alcohol. The authors concluded that DRD2 mutations are rare in these disorders. - Mutations in DYT1 In a family first classified as having early-onset dystonia (128100), Leung et al. (2001) identified a heterozygous 18-bp deletion in the DYT1 gene (TOR1A; 605204.0002). However, in 2 sibs of this same family, Klein et al. (2002) identified a missense mutation in the SGCE gene (604149.0006). The sibs had inherited the DYT1 deletion from their mother, who showed dystonic features, and the SGCE mutation from their father, who showed myoclonic features. The contribution of each mutation to the clinical phenotype could not be determined, but the molecular studies indicated coincidence inheritance of 2 different disorders. (See also Furukawa and Rajput, 2002).
The following diagnostic criteria for myoclonus-dystonia (M-D), modified from Mahloudji & Pikielny [1967] and Gasser [1998], were proposed by Klein [2002] based on families with proven linkage to DYT11 or an SGCE mutation. ...
DiagnosisClinical DiagnosisThe following diagnostic criteria for myoclonus-dystonia (M-D), modified from Mahloudji & Pikielny [1967] and Gasser [1998], were proposed by Klein [2002] based on families with proven linkage to DYT11 or an SGCE mutation. Onset of myoclonus, usually in the first or second decade of life; dystonic features are also observed in more than half of affected individuals in addition to myoclonus; rarely, dystonia may be the only manifestation of the disorder.Males and females about equally affectedA relatively benign course, often variable but compatible with an active life of normal span in most casesAutosomal dominant mode of inheritance with variable severity and incomplete penetrance, which is dependent on the parental origin of the disease allele; in most cases a symptomatic individual inherits the disease-causing mutation from his/her father.Absence of dementia, gross ataxia, and other neurologic deficitsNormal somatosensory evoked potentials (SSEP)Normal neuroimaging studies (CT or MRI). Note: Degenerative changes may be seen as a result of chronic alcohol use.Optional diagnostic criteria:Alleviation of symptoms (particularly of the myoclonus and to a lesser degree of the dystonia) with alcohol useVarious psychiatric symptomsNote: Normal EEG was a diagnostic criterion; however, two reports have associated mutation-positive familial M-D with epilepsy and/or EEG abnormalities [Foncke et al 2003, O'Riordan et al 2004]. Therefore, EEG changes and epilepsy should no longer be considered exclusion criteria.TestingIn general, all laboratory tests are normal in individuals with M-D. Abnormal liver function tests may be the result of chronic alcohol use.Molecular Genetic TestingGenes. SGCE (locus DYT11), encoding the protein epsilon-sarcoglycan, is the only gene in which mutations are known to cause M-D. Evidence for locus heterogeneity. An SGCE mutation or deletion is detected in approximately 30%-40% of persons having the typical M-D phenotype (see Table 1). Simplex and familial cases without identifiable SGCE mutations have been reported [Han et al 2003, Valente et al 2003, Grundmann et al 2004, Hedrich et al 2004, Schule et al 2004, Valente et al 2005, Tezenas du Montcel et al 2006, Grünewald et al 2008, Ritz et al 2009], suggesting locus heterogeneity. Mutations in two other genes have been associated with M-D in a few individuals/families.DRD2. It is unclear if the DRD2 missense mutation found in a single family is disease-causing, disease-modifying, or a rare polymorphism [Klein et al 1999], as further analysis in this family also identified a 5-bp deletion in SGCE (c.835_839delACAAA) [Klein et al 2002]. DYT1, the gene associated with early-onset primary dystonia (DYT1):An 18-bp deletion in DYT1 was found in one family [Leung et al 2001]. However, a p.Leu196Arg missense SGCE mutation was subsequently identified [Klein et al 2002]; the significance of the combination of these two variants is unknown.A male with alcohol-responsive M-D who was found to have the typical three-base pair deletion in DYT1 and no mutation in SGCE was reported [Tezenas du Montcel et al 2006]. His mother was Ashkenazi Jewish but only had writer's cramp. Maternal uniparental disomy (mUPD) of chromosome 7. Two persons with M-D and Russell-Silver syndrome (RSS) associated with mUPD of chromosome 7 have been reported. Patient 1. Only maternal chromosome 7 markers were present; both SGCE alleles were methylated; and SGCE expression was absent. The RSS phenotype in this individual is presumably attributable to mUPD of another imprinted gene on chromosome 7 [Guettard et al 2008]. Patient 2. An atypical RSS phenotype was accompanied by myoclonus. Maternal iso/heterodisomy of chromosome 7 was present and may account for the atypical presentation [Stark et al 2010]. DYT15 locus. A clinically similar M-D phenotype in a large Canadian family without an identifiable SGCE mutation showed significant evidence for linkage to markers on chromosome 18p (locus DYT15) [Grimes et al 2002, Han et al 2007]. The M-D phenotype of two other families may also be linked to this chromosomal region [Schule et al 2004]. The overall contribution of this locus to M-D cannot be determined until the gene is identified.Table 1. Summary of Molecular Genetic Testing Used in Myoclonus-DystoniaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFamilial 2Simplex 3, 4, 5 SGCESequence analysisSequence variants 6, 7~30%-50%~10%-15%ClinicalDeletion / duplication analysis 8Exonic or whole-gene deletionsUnknown 9 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. The mutation detection rate among familial cases ranges from 0% to 100% with the high range biased by linkage studies; on average, the overall rate based on the literature is close to 50%. The mutation detection rate increases when there is paternal transmission [Zimprich et al 2001, Asmus et al 2002, Klein 2002, Muller et al 2002, Hjermind et al 2003, Marechal et al 2003, Hedrich et al 2004, Schule et al 2004, Valente et al 2005, Tezenas du Montcel et al 2006, Grünewald et al 2008, Nardocci et al 2008, Raymond et al 2008, Ritz et al 2009].3. The mutation detection rate among simplex cases (i.e., individuals with no family history of M-D) averages about 12%-13% overall [Asmus et al 2002, Han et al 2003, Valente et al 2003, Grundmann et al 2004, Hedrich et al 2004, Schule et al 2004, Valente et al 2005, Tezenas du Montcel et al 2006].4. 85 mutations are listed in HGMD (see Table A. Genes and Databases); a few are confirmed de novo mutations [Nardocci et al 2008].5. In two probands who appeared to represent simplex cases, the mutation was subsequently identified in the fathers [Muller et al 2002, Hedrich et al 2004, Kock et al 2004].6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.7. To date, the vast majority (~95%) of SGCE mutations have been found in exons 1-7; the remaining approximately 5% have been found in exon 9.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 9. Exonic and whole-gene deletions are likely to account for a relatively small percentage of SGCE mutations [DeBerardinis et al 2003, Asmus et al 2005, Asmus et al 2007, Han et al 2007, Grünewald et al 2008, Ritz et al 2009]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo establish the diagnosis in a probandThe diagnosis of myoclonus-dystonia is made clinically. Molecular genetic testing of SGCE may be helpful for clarifying an equivocal diagnosis and for genetic counseling purposes. Sequence analysis is performed first. If a mutation is not identified, deletion/duplication analysis is considered. Testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotype is known to be associated with mutations in SGCE. Microdeletion 7q21. However, at least six persons with interstitial deletions that include SGCE have been described: five had typical M-D and one, a nine-year old who had no signs of M-D, had split-hand/split-foot malformation and sensorineural hearing loss. This child and one other had facial dysmorphism and cognitive delay. Additional findings noted in these six individuals included short stature (4), joint laxity (3), bone fractures (2), severe early generalized osteoporosis with necrosis of the femoral head and cartilage defects leading to hip and knee replacement by age 25 years (1), blue sclerae and cavernous cerebral malformations (1), and hypodontia (1). These findings are most likely the result of deletion of a number of contiguous genes including COL1A2 and KRIT1 [DeBerardinis et al 2003, Asmus et al 2007, Grünewald et al 2008]. One additional individual with M-D, language delay, dysmorphic features, and a seemingly balanced de novo reciprocal translocation was subsequently found to have microdeletions of 7q21 and 9q23 [Bonnet et al 2008].
Myoclonus-dystonia (M-D) is a movement disorder characterized by a combination of rapid, brief muscle contractions (myoclonus), and/or sustained twisting and repetitive movements that result in abnormal postures (dystonia). Onset usually occurs in childhood or early adolescence, particularly in families with an SGCE mutation, but ranges from six months to more than 80 years for all M-D whether or not a causative mutation has been identified [Foncke et al 2006, Gerrits et al 2006, Tezenas du Montcel et al 2006, Nardocci et al 2008, Raymond et al 2008, Ritz et al 2009]. ...
Natural HistoryMyoclonus-dystonia (M-D) is a movement disorder characterized by a combination of rapid, brief muscle contractions (myoclonus), and/or sustained twisting and repetitive movements that result in abnormal postures (dystonia). Onset usually occurs in childhood or early adolescence, particularly in families with an SGCE mutation, but ranges from six months to more than 80 years for all M-D whether or not a causative mutation has been identified [Foncke et al 2006, Gerrits et al 2006, Tezenas du Montcel et al 2006, Nardocci et al 2008, Raymond et al 2008, Ritz et al 2009]. Although most affected adults report a dramatic response of myoclonus to alcohol ingestion [Mahloudji & Pikielny 1967, Kyllerman et al 1990, Quinn 1996], the alleviation of findings following alcohol ingestion varies within and between families The myoclonic jerks typical of M-D are brief, lightning-like movements most often affecting the neck, trunk, and upper limbs with legs affected less prominently. Myoclonus is usually the presenting manifestation of M-D. Laryngeal myoclonus has been reported [Hjermind et al 2003].Approximately half of affected individuals (54%) have focal or segmental dystonia that manifests as cervical dystonia and/or writer's cramp [Asmus et al 2002, Klein 2002]. In contrast to primary torsion dystonia [Bressman et al 2000], involvement of lower limbs is rare and usually does not occur at onset. In addition, the dystonia does not tend to worsen or generalize in the course of the disease. Rarely, dystonia is the only disease manifestation.The involuntary movements are frequently precipitated or worsened by active movements of the affected body parts. Other factors eliciting or enhancing the movements include stress [Korten et al 1974, Kyllerman et al 1990], sudden noise [Korten et al 1974, Kurlan et al 1988, Asmus et al 2001, Trottenberg et al 2001], caffeine [Nygaard et al 1999], and tactile stimuli [Kurlan et al 1988, Nygaard et al 1999].Additional neurologic features mainly include postural and other forms of tremor [Korten et al 1974, Kurlan et al 1988, Kyllerman et al 1990, Vidailhet et al 2001].The most prominent non-motor features have been psychiatric disease reported in some [Kyllerman et al 1990, Klein et al 1999, Nygaard et al 1999], but not all families [Asmus et al 2001]. However, systematic study for psychiatric illness was not performed in these families with M-D and it is unknown whether these features segregated with the M-D mutation. Reported psychiatric problems include:Depression, anxiety, and obsessive-compulsive disorder (OCD) [Nygaard et al 1999, Doheny et al 2002, Saunders-Pullman et al 2002a, Marechal et al 2003, Hess et al 2007, Misbahuddin et al 2007]; Depression, personality disorders, and addiction [Klein et al 1999]; Panic attacks [Scheidtmann et al 2000]. Saunders-Pullman et al [2002a] studied psychiatric features in detail in three families linked to chromosome 7q and found an association between OCD and M-D. This finding was supported by Doheny et al [2002] and Marechal et al [2003] and was confirmed in mutation-positive cases by Hess et al [2007], who reported OCD in combination with M-D in several other families.Other neurologic signs and symptoms including dementia and ataxia are rare in M-D [Gasser 1998]. Seizures have been reported in two families, but the significance of this finding remains unclear [Foncke et al 2003, O'Riordan et al 2004]. M-D is compatible with an active life of normal span [Nygaard et al 1999]. Although spontaneous remission of M-D has been reported [Korten et al 1974, Fahn & Sjaastad 1991, Roze et al 2008], in some cases M-D may be gradually progressive [Kurlan et al 1988, Quinn 1996, Borges et al 2000, Trottenberg et al 2001] and may lead to considerable functional disability and result in early retirement [Borges et al 2000, Trottenberg et al 2001, Hjermind et al 2003, Marechal et al 2003]. Neurophysiology and NeuroimagingNeurophysiologic studies in persons with M-D, including routine electroencephalography (EEG), polymyography, and somatosensory evoked potentials (SEPs), were normal [Chokroverty et al 1987, Quinn et al 1988]. Roze et al [2008] noted short jerks of subcortical origin in persons with M-D while at rest, with activity, or while standing. Marelli et al [2008] found neurophysiologic signs suggesting the dysfunction of systems including brain stem and neocortex. Li et al [2008] identified normal intracortical inhibition in persons with M-D with dystonia and suggested that the role of cortical dysfunction may be less prominent and that the mechanisms for dystonia in M-D may be different from those in other dystonic disorders. Another neurophysiologic study showed that globus pallidus interna (GPi) deep brain stimulation (DBS) resulted in substantial decrease in the frequency and amplitude of myoclonus and suppression of dystonia, suggesting that in M-D the pallidum plays a role in generation, or at least modulation, of both these hyperkinetic features [Kurtis et al 2010]. Functional MRI studies support subcortical activation [Nitschke et al 2006]:In an 18F-FDG PET performed on an individual with genetically confirmed M-D, Tai et al [2009] noted significant bilateral hypermetabolism in the thalamus and cerebellum. Functional MRI in a five-year old girl with genetically confirmed M-D revealed specific activations within the thalamus and dentate nucleus [Nitschke et al 2006]. Reduced striatal D2 receptor binding in M-D has been demonstrated [Beukers et al 2009] as well as frontotemporal and striatal SPECT abnormalities [Papapetropoulos et al 2008].
Familial conditions with dystonia, including Wilson disease, spinocerebellar ataxia type 3 (SCA3), ataxia with vitamin E deficiency and other secondary forms of dystonia, can generally be differentiated from M-D based on laboratory tests and neuroimaging studies (including MRI) (for a review of various genetic and secondary forms of dystonia, see Dystonia Overview and de Carvalho Aguiar & Ozelius [2002]). ...
Differential DiagnosisFamilial conditions with dystonia, including Wilson disease, spinocerebellar ataxia type 3 (SCA3), ataxia with vitamin E deficiency and other secondary forms of dystonia, can generally be differentiated from M-D based on laboratory tests and neuroimaging studies (including MRI) (for a review of various genetic and secondary forms of dystonia, see Dystonia Overview and de Carvalho Aguiar & Ozelius [2002]). One individual with genetically confirmed dopa-responsive dystonia [Leuzzi et al 2002] and one with genetically confirmed spinocerebellar ataxia type 14 (SCA14) [Foncke et al 2010] presented with findings of myoclonus dystonia.Most other conditions in which myoclonus is a prominent feature are characterized by a variety of neurologic signs and symptoms that generally are not associated with a diagnosis of M-D. Genetic disorders with myoclonus as a major component include the following:Unverricht-Lundborg disease (also known as EPM1 or progressive myoclonus epilepsy), caused by mutations in CSTB (the gene encoding cystatin B) [Pennacchio et al 1996]Progressive myoclonus epilepsy, Lafora type associated with mutations in either EPM2A or NHLRC1 [Minassian et al 1998, Ganesh et al 2002]Myoclonus epilepsy with ragged red fibers (MERRF), caused by mutations in mitochondrial DNADentatorubral-pallidoluysian atrophy (DRPLA) [Naito & Oyanagi 1982]The findings in benign hereditary chorea (BHC) caused by mutations in NKX2-1 may be somewhat similar to those in M-D; however, in contrast to the action induced myoclonus of M-D, BHC does not demonstrate aggravation of jerks with complex motor tasks. Because of the association of hypothyroidism with mutations in this gene, thyroid hormone screening should be considered in affected individuals. See OMIM 118700, 610978, 600635. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with myoclonus-dystonia (M-D) the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with myoclonus-dystonia (M-D) the following evaluations are recommended:Clinical examination to evaluate the location, severity, and progression of dystonia and the severity and progression of myoclonus. This is best done by a neurologic specialist in movement disorders. MRI Medical genetics consultationTreatment of ManifestationsMedications may improve either the myoclonus or the dystonia or both:Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [Kurlan et al 1988, Bressman & Greene 1990, Kyllerman et al 1990, Nygaard et al 1999, Goetz & Horn 2001].Antiepileptic drugs (AEDs), typically valproate but also topiramate, may improve myoclonus [Bressman & Greene 1990, Nygaard et al 1999].Anticholinergic medication may improve dystonia [Bressman & Greene 1990, Goetz & Horn 2001] and botulinum toxin injection may be especially helpful for cervical dystonia [Bressman & Greene 2000, Goetz & Horn 2001, Berardelli & Curra 2002].Improvement of dystonia with L-5-hydroxytryptophan [Scheidtmann et al 2000] and with L-dopa [Leuzi et al 2002, Raymond et al 2008, Luciano et al 2009] has been reported. One individual with M-D who represented a simplex case (i.e., a single occurrence of M-D in the family) showed a robust response to zolpidem [Park et al 2009].Gamma-hydroxybutyrate [Priori et al 2000] and the sodium oxybate may improve myoclonus [Frucht et al 2005].Note: Although the symptoms of M-D usually resolve with ingestion of alcohol, the risk of long-term addiction to alcohol renders it an unacceptable treatment option.Surgery. Stereotactic thalamotomy can improve myoclonus, but caused dysarthria in one individual and mild hemiparesis in another [Gasser et al 1996]. In two others, myoclonus improved, but without significant gain in function [Suchowersky et al 2000].Deep brain stimulation (DBS). In a recent study, ten persons with M-D (9 with an identifiable SGCE mutation) had DBS of the internal segment of the globus pallidus (GPi) only (1 person), of the ventral intermediate thalamic nucleus (VIM) only, or of both GPi and VIM (8 persons). All experienced substantial improvement of both myoclonus (61.5%) and dystonia (48.2%). No adverse effects on cognition or affect were noted. VIM DBS was associated with a slightly higher incidence of reversible adverse events, possibly accounting for the slightly less robust improvement noted in those treated with VIM vs GPi DBS. The authors also note that quadruple VIM/GPi stimulation may be slightly more effective than VIM or GPi alone [Gruber et al 2010].The results of case studies are summarized below:Improvement of M-D was reported in a 63-year old with symptoms from age two years, suggesting that the findings are responsive to DBS, even after more than 50 years [Kurtis et al 2010]. Neurostimulation of the ventral intermediate thalamic nucleus (VIM) in an individual with medically intractable and progressive inherited M-D resulted in an 80% reduction of myoclonus score, but no significant effect on dystonia. A second individual who had genetically confirmed M-D had a 14% reduction of myoclonus score following VIM stimulation [Trottenberg et al 2001, Kuncel et al 2009]. DBS of the internal segment of the globus pallidus (GPi) improved myoclonus and dystonia in two individuals [Cif et al 2004, Magarinos-Ascone et al 2005], one of whom had a confirmed SGCE mutation [Cif et al 2004]. DBS of the medial globus pallidus improved both myoclonus and dystonia at an eight-week follow-up [Liu et al 2002]. Prevention of Secondary ComplicationsAs self-treatment with alcohol is common, proper treatment and counseling regarding alcohol abuse may decrease alcohol-related toxicities, particularly in adolescents.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Myoclonus-Dystonia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDSGCE7q21.3Epsilon-sarcoglycanSGCEData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Myoclonus-Dystonia (View All in OMIM) View in own window 159900MYOCLONIC DYSTONIA 604149SARCOGLYCAN, EPSILON; SGCENormal allelic variants. SGCE comprises 12 exons with exon 10 being differentially spliced and absent from most transcripts [McNally et al 1998]. Other alternative splice variants in mouse brain that affect the C-terminal end of the encoded protein have been identified [Nishiyama et al 2004, Yokoi et al 2005].Pathologic allelic variants. All types of mutations have been reported in SGCE: nonsense and missense mutations, deletions, and insertions leading to frame shifts and splicing errors [Zimprich et al 2001, Asmus et al 2002, Doheny et al 2002, Klein et al 2002, Muller et al 2002, DeBerardinis et al 2003, Foncke et al 2003, Han et al 2003, Hjermind et al 2003, Marechal et al 2003, Hedrich et al 2004, Kock et al 2004, Schule et al 2004, Valente et al 2005]. Exonic deletions in SGCE may also cause M-D [Asmus et al 2005].Most of the mutations described to date have been localized to exons 3-7 and 9, implicating this region of the gene as important for function. Four nonsense mutations, p.Arg97X, p.Trp100X, p.Arg102X (all in exon 3), and p.Arg372X (in exon 9) as well as two small deletions (in exons 4 and 7) [Grünewald et al 2008] have been found in more than one proband and appear to be recurrent mutations. (For more information, see Table A.)Table 2. Selected SGCE Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change (Alias 1)Reference Sequences c.289C>Tp.Arg97XNM_001099401.1 NP_001092871.1c.587T>Gp.Leu196Argc.300G>Ap.Trp100Xc.304C>Tp.Arg102Xc.771_772delATp.C258Xc.835_839delACAAAp.Thr279Alafs*17 (Lys278fs295X)c.1114C>Tp.Arg372X See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventionsSee Table 3 for a summary of all mutations known to date.Normal gene product. SGCE encodes epsilon-sarcoglycan. SGCE is a member of a gene family that also includes alpha, beta, gamma, delta, and zeta sarcoglycans. Recessive mutations in these other sarcoglycan family members result in various types of limb-girdle muscular dystrophies (see Hack et al [2000] for review). In muscles, these genes encode transmembrane components of the dystrophin-glycoprotein complex, which link the cytoskeleton to the extracellular matrix. However, SGCE is widely expressed in many tissues of the body [Ettinger et al 1997, McNally et al 1998] including various regions of the brain [Zimprich et al 2001, Xiao & LeDoux 2003, Nishiyama et al 2004, Chan et al 2005] both during development and adulthood. The function of epsilon-sarcoglycan in the brain is unknown.Abnormal gene product. It is speculated that because maternal imprinting transcriptionally silences SGCE and the vast majority of affected individuals inherit their disease allele from their fathers, the disease is caused by loss of function of this protein. However, about 5% of affected individuals inherit their mutated allele from their mothers and presumably also express the wild-type allele from their fathers. Therefore, the mechanism of disease pathogenesis is not entirely clear.