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.

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.
  • 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) Disorders

No 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].

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:

• 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].

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].

• Consistent with this hypothesis, two studies demonstrated both paternal transmission of the SGCE mutant allele in affected individuals and DNA methylation differences consistent with maternal imprinting [Muller et al 2002, Grabowski et al 2003].
• Because about 5% of affected individuals inherit the mutant allele from their mothers [Zimprich et al 2001, Grabowski et al 2003], the apparent suppression of the M-D phenotype on maternal transmission of the disease-causing SGCE allele is incomplete. In these instances, the phenotype may be milder. The reasons for loss of the maternal imprint are unknown.

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.

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:

• 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 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.

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.

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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]
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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