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Myoclonus-Dystonia

Synonyms: Dystonia 11, Hereditary Essential Myoclonus, Myoclonic Dystonia

, MS and , PhD.

Author Information
, MS
Department of Neurology
Beth Israel Medical Center
New York, New York
, PhD
Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine
New York, New York

Initial Posting: ; Last Update: January 26, 2012.

Summary

Disease characteristics. 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). The myoclonic jerks typical of M-D most often affect the neck, trunk, and upper limbs with less common involvement of the legs. Approximately 50% of affected individuals have additional focal or segmental dystonia, presenting as cervical dystonia and/or writer's cramp. Non-motor features may include obsessive-compulsive disorder (OCD), depression, anxiety, personality disorders, alcohol abuse, and panic attacks. Symptom onset is usually in childhood or early adolescence but ranges from age six months to 80 years. Most affected adults report a dramatic reduction in myoclonus in response to alcohol ingestion. M-D is compatible with an active life of normal span.

Diagnosis/testing. The diagnosis of myoclonus-dystonia is based on clinical findings, family history, absence of other neurologic deficits, and normal neuroimaging studies. Mutations in SGCE are associated with most cases of familial M-D. Although mutations in two other genes, DRD2 and DYT1, have been associated with M-D, the significance of mutations in these genes is unknown. Molecular testing includes both sequence and deletion/duplication analyses of the coding region of SGCE.

Management. Treatment of manifestations: Benzodiazepines (particularly clonazepam) used to treat myoclonus-dystonia improve both myoclonus and tremor. Antiepileptic drugs (valproate, topiramate) may improve myoclonus, but the response is variable. Anticholinergic medication may improve dystonia; botulinum toxin injection may be especially helpful for cervical dystonia. Improvement with L-5-hydroxytryptophan, L-dopa and the salt of sodium oxybate has been reported. Stereotactic thalamotomy can improve myoclonus but has caused dysarthria and hemiparesis. Deep brain stimulation has improved both myoclonus and dystonia in several individuals; it is unclear whether targeting the globus pallidus interna (GPi) is more effective than targeting the ventral intermediate nucleus of the thalamus (VIM).

Other: Symptoms of M-D often improve short term with ingestion of alcohol, but the risk of addiction recommends against its long term use.

Genetic counseling. Myoclonus-dystonia is inherited in an autosomal dominant manner. A proband with M-D may have inherited the disorder from a parent or have it as the result of a de novo mutation; the proportion of cases caused by de novo mutations is unknown. Each child of an individual with M-D has a 50% chance of inheriting the mutation. In general, maternally derived SGCE alleles are not expressed and paternally derived SGCE alleles are expressed. Thus, almost all children who inherit an SGCE mutation from their father develop symptoms, whereas close to 95% of children who inherit an SGCE mutation from their mother do not. Prenatal testing and preimplantation genetic diagnosis are possible for families in which the disease-causing mutation is known

Diagnosis

Clinical Diagnosis

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.

  • 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 affected
  • A relatively benign course, often variable but compatible with an active life of normal span in most cases
  • Autosomal 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 deficits
  • Normal 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 use
  • Various psychiatric symptoms

Note: 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.

Testing

In 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 Testing

Genes. 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.

Table 1. Summary of Molecular Genetic Testing Used in Myoclonus-Dystonia

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Familial 2Simplex 3, 4, 5
SGCESequence analysisSequence variants 6, 7~30%-50%~10%-15%
Deletion / 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 gene

2. 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 Strategy

To establish the diagnosis in a proband

  • The 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.

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.

Clinical Description

Natural History

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].

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:

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 Neuroimaging

Neurophysiologic 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for SGCE are known.

Penetrance

Reduced penetrance on maternal transmission of the disease allele has been observed, suggesting that maternal genomic imprinting of SGCE suppresses expression of the maternally inherited SGCE allele [Zimprich et al 2001].

Anticipation

Anticipation is not observed in M-D.

Nomenclature

Terms used in the past for myoclonus-dystonia include myoclonic dystonia, inherited myoclonus dystonia syndrome, alcohol-responsive myoclonic dystonia, hereditary essential myoclonus, and DYT11 dystonia [Quinn et al 1988, Quinn 1996, Lang 1997, Saunders-Pullman et al 2002b].

When myoclonic movements were reported in individuals with DYT1 or other forms of primary dystonia, it was called myoclonic dystonia syndrome [Obeso et al 1983].

Prevalence

Little is known about the prevalence of M-D; however, the disease has been described in families of many nationalities including mixed European, German, Irish, Turkish, Brazilian, and Canadian.

Differential Diagnosis

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]).

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:

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 consultation

Treatment of Manifestations

Medications may improve either the myoclonus or the dystonia or both:

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 Complications

As 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Myoclonus-dystonia is inherited in an autosomal dominant manner with reduced penetrance. Penetrance is related to maternal imprinting and, therefore, is based on the parental origin of the mutation. In general, maternally derived SGCE alleles are not expressed and paternally derived SGCE alleles are expressed.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with M-D have an affected parent.
  • Because M-D shows reduced penetrance, the parent of an affected individual may have the disease-causing allele without showing clinical signs. The mechanism of reduced penetrance is related to maternal imprinting and, therefore, based on the parental origin of the mutation. In general, maternal imprinting suppresses expression of a maternally derived SGCE allele, whether it is normal or has a disease-causing mutation. Paternally derived SGCE alleles are expressed.
    • More than 95% of individuals who inherit the disease-causing allele from their mothers do not have clinical signs. Approximately 5% of individuals who inherit the disease-causing allele from their mothers do develop M-D. This indicates that the apparent suppression of the phenotype by maternal inheritance of a disease-causing SGCE allele is incomplete; it appears that loss of the maternal imprint occurs at a low frequency.
    • As expected, the majority of individuals who inherit the disease-causing allele from their fathers have clinical symptoms. In addition, persons who were initially thought to be simplex cases (i.e., a single occurrence of M-D in their family) have been shown to have an SGCE mutation that was inherited from an asymptomatic father [Muller et al 2002, Hedrich et al 2004, Kock et al 2004, Gerrits et al 2009].
  • A proband with M-D may have the disorder as the result of a de novo SGCE mutation [Hedrich et al 2004]; the proportion of cases caused by de novo mutations is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include obtaining a detailed medical and family history, examination by a neurologist specializing in movement disorders, and molecular genetic testing if the family-specific SGCE mutation has been identified.

Sibs of a proband

  • The risk to the sib of a proband depends on the genetic status of the parents.
  • If a parent of the proband is affected, the risk to the sibs of inheriting the disease-causing allele is 50%.
  • Expression of a disease-causing SGCE allele is influenced by the sex of the parent transmitting the disease-causing allele (imprinting).
    • If the SGCE disease-causing allele is inherited from the father, it is typically expressed and most often the offspring is symptomatic.
    • If the SGCE disease-causing allele is inherited from the mother, most often it is not expressed and the child remains symptom-free. However, about 5% of individuals who inherit the mutation from their mothers do develop symptoms. These symptoms may be milder than those in individuals who inherit the mutation from their fathers.
  • Because of variable expressivity, sibs may be more or less severely affected with findings different from those of the proband.
  • If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband

  • Each child of an individual with M-D has a 50% chance of inheriting the mutation.
  • Almost all children who inherit the mutation from their fathers develop symptoms.
  • About 5% of children who inherit the mutation from their mothers develop symptoms.
  • Symptomatic offspring of a proband may be more or less severely affected than the proband.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a disease-causing allele, his or her family members are at risk.

Related Genetic Counseling Issues

Although most individuals diagnosed with M-D have inherited the disease-causing allele from a parent, the family history may appear to be negative either because of the effects of imprinting or because of failure to recognize the disorder in family members. Since it is possible for affected family members to self-medicate with alcohol, a family history of alcoholism may be indicative of additional affected relatives.

Non-medical considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has a disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members. Testing of at-risk asymptomatic family members for myoclonus-dystonia is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. However, adults are unlikely to become symptomatic, particularly when inheriting the gene through a mother. When testing at-risk individuals for myoclonus-dystonia, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystonia Medical Research Foundation
    One East Wacker Drive
    Suite 2810
    Chicago IL 60601-1905
    Phone: 800-377-3978 (toll-free); 312-755-0198
    Fax: 312-803-0138
    Email: dystonia@dystonia-foundation.org
  • Dystonia Society
    89 Albert Embankment
    3rd Floor
    London SE1 7TP
    United Kingdom
    Phone: 0845 458 6211; 0845 458 6322 (Helpline)
    Fax: 0845 458 6311
    Email: support@dystonia.org.uk
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Dystonia International Patient Registry (DIPR)
    Email: contact@dipregistry.com

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SGCE7q21​.3Epsilon-sarcoglycanSGCE homepage - Leiden Muscular Dystrophy pagesSGCE

Data 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)

159900MYOCLONIC DYSTONIA
604149SARCOGLYCAN, EPSILON; SGCE

Normal 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

DNA Nucleotide Change Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.289C>Tp.Arg97XNM_001099401​.1 NP_001092871​.1
c.587T>Gp.Leu196Arg
c.300G>Ap.Trp100X
c.304C>Tp.Arg102X
c.771_772delATp.C258X
c.835_839delACAAAp.Thr279Alafs*17
(Lys278fs295X)
c.1114C>Tp.Arg372X

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

See 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.

References

Literature Cited

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  95. Zimprich A, Grabowski M, Asmus F, Naumann M, Berg D, Bertram M, Scheidtmann K, Kern P, Winkelmann J, Muller-Myhsok B, Riedel L, Bauer M, Muller T, Castro M, Meitinger T, Strom TM, Gasser T. Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome. Nat Genet. 2001;29:66–9. [PubMed: 11528394]

Suggested Reading

  1. Bressman SB. Genetics of dystonia: an overview. Parkinsonism Relat Disord. 2007;13 Suppl 3:S347–55. [PubMed: 18267263]
  2. Esapa CT, Waite A, Locke M, Benson MA, Kraus M, McIlhinney RA, Sillitoe RV, Beesley PW, Blake DJ. 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. [PubMed: 17200151]
  3. Han F, Racacho L, Yang H, Read T, Suchowersky O, Lang AE, Grimes DA, Bulman DE. Large deletions account for an increasing number of mutations in SGCE. Mov Disord. 2008;23:456–60. [PubMed: 18098280]
  4. Kinugawa K, Vidailhet M, Clot F, Apartis E, Grabli D, Roze E. Myoclonus-dystonia: an update. Mov Disord. 2009;24:479–89. [PubMed: 19117361]
  5. Klein C, Gurvich N, Sena-Esteves M, Bressman S, Brin MF, Ebersole BJ, Fink S, Forsgren L, Friedman J, Grimes D, Holmgren G, Kyllerman M, Lang AE, de Leon D, Leung J, Prioleau C, Raymond D, Sanner G, Saunders-Pullman R, Vieregge P, Wahlstrom J, Breakefield XO, Kramer PL, Ozelius LJ, Sealfon SC. Evaluation of the role of the D2 dopamine receptor in myoclonus dystonia. Ann Neurol. 2000;47:369–73. [PubMed: 10716258]
  6. Klein C, Schilling K, Saunders-Pullman RJ, Garrels J, Breakefield XO, Brin MF, deLeon D, Doheny D, Fahn S, Fink JS, Forsgren L, Friedman J, Frucht S, Harris J, Holmgren G, Kis B, Kurlan R, Kyllerman M, Lang AE, Leung J, Raymond D, Robishaw JD, Sanner G, Schwinger E, Tabamo RE, Tagliati M. A major locus for myoclonus-dystonia maps to chromosome 7q in eight families. Am J Hum Genet. 2000;67:1314–9. [PMC free article: PMC1288573] [PubMed: 11022010]
  7. Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol. 2002;192:245–58. [PubMed: 12124770]
  8. Weinstein LS. The role of tissue-specific imprinting as a source of phenotypic heterogeneity in human disease. Biol Psychiatry. 2001;50:927–31. [PubMed: 11750888]
  9. Yokoi F, Dang MT, Li J, Li Y. Myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism in epsilon-sarcoglycan deficient mice. J Biochem. 2006;140:141–6. [PubMed: 16815860]

Chapter Notes

Revision History

  • 26 January 2012 (me) Comprehensive update posted live
  • 19 December 2005 (me) Comprehensive update posted to live Web site
  • 11 June 2004 (ljo/cd) Revision: testing
  • 21 May 2003 (me) Review posted to live Web site
  • 5 May 2003 (ljo) Original submission
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