Clinical characteristics.

SGCE myoclonus-dystonia (SGCE-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 SGCE-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 alcohol abuse, obsessive-compulsive disorder (OCD), and anxiety disorders. Symptom onset is usually in the first decade of life and almost always by age 20 years, but ranges from age six months to 80 years. Most affected adults report a dramatic reduction in myoclonus in response to alcohol ingestion. SGCE-M-D is compatible with an active life of normal span.

Diagnosis/testing.

The diagnosis of SGCE-M-D is established in a proband with characteristic clinical features by identification of a heterozygous pathogenic variant in SGCE.

Management.

Treatment of manifestations: Class 1 evidence supports the improvement of myoclonus and dystonia with zonisamide. Benzodiazepines (particularly clonazepam) and anti-seizure drugs used to treat myoclonus (especially valproate and levitiracetam) also improve myoclonus in individuals with myoclonus-dystonia. The response to other anti-seizure drugs (e.g., topiramate) is more 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. Deep brain stimulation has improved both myoclonus and dystonia, with most targeting the globus pallidus interna (GPi); however, success with ventral intermediate nucleus of the thalamus (VIM) target has also been reported.

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

Genetic counseling.

SGCE-M-D is inherited in an autosomal dominant manner with penetrance determined by the parental origin of the altered SGCE allele: an SGCE pathogenic variant on the paternally derived (expressed) SGCE allele generally results in disease; a pathogenic variant on the maternally derived (silenced) SGCE allele typically does not result in disease. Most individuals with SGCE-M-D inherited the disorder from a heterozygous parent who may or may not have clinical signs of M-D (as phenotypic expression in the parent would depend on the sex of the transmitting grandparent). Each child of an individual with SGCE-M-D has a 50% chance of inheriting the pathogenic variant. Almost all children who inherit an SGCE pathogenic variant from their father develop symptoms, whereas only ~5% of children who inherit an SGCE pathogenic variant from their mother develop symptoms. Once the SGCE pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis are possible.

Suggestive Findings

SGCE myoclonus-dystonia (SGCE-M-D) should be suspected in individuals with myoclonus alone or with dystonia that begins in the first or second decade of life. It less frequently presents with isolated dystonia. Recently suggested criteria for the diagnosis of M-D require four major criteria and no exclusionary criteria OR three major criteria, two minor criteria, and no exclusionary criteria [Roze et al 2018].

Major criteria

• Myoclonus isolated or predominating over dystonia
• Prominence of the motor manifestations in the upper body
• Absence of truncal dystonia
• Positive family history
• Onset before age 18 years

Minor criteria

• Obsessive-compulsive disorder, anxiety-related disorder, or alcohol dependence
• Spontaneous remission of limb dystonia during childhood or adolescence
• Alcohol responsiveness

Exclusionary criteria

• Other neurologic manifestation in addition to myoclonus and/or dystonia (except seizures, which may be present in some individuals with SGCE-M-D)
• Abnormal brain MRI examination
• Neurophysiologic findings that do not support the diagnosis (defined as muscle contractions shorter than 300 ms that can occur in body parts not affected by dystonia)

Establishing the Diagnosis

The diagnosis of SGCE-M-D is established in a proband with myoclonus and/or dystonia by identification of a heterozygous pathogenic variant in SGCE on molecular genetic testing (see Table 1).

Note: (1) SGCE is maternally imprinted and, therefore, expressed only from the paternal allele. While rare cases of maternal inheritance have been reported (see Penetrance and Molecular Genetics), affected individuals typically have a pathogenic variant on the paternal allele. (2) A small number of individuals have been identified with either microdeletions of SGCE or maternal uniparental disomy resulting in methylation of both SGCE alleles (see Genetically Related Disorders).

Molecular genetic testing approaches can include single-gene testing and a multigene panel. However, for this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1):

• Single-gene testing. Sequence analysis of SGCE detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Single-gene testing is most appropriate in individuals from families with a previously identified SGCE pathogenic variant.
• A dystonia multigene panel that includes SGCE and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

SGCE myoclonus-dystonia (SGCE-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 is most often in the first decade of life or in adolescence.

While most affected adults report a dramatic response of myoclonus to ingestion of alcohol [Quinn 1996], the alleviation of findings following alcohol ingestion varies within and between families. Alcohol dependence may be a comorbidity in those who do respond.

The myoclonic jerks typical of SGCE-M-D are brief, lightning-like movements most often affecting the neck, trunk, and upper limbs, with legs less prominently affected. In children, leg and trunk myoclonus may in rare cases lead to falls [Luciano et al 2009]. Myoclonus is usually the presenting manifestation of SGCE-M-D.

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 et al 2002]. In contrast to primary torsion dystonia [Bressman et al 2000], dystonia in the lower limbs is rare, although it has been reported in individuals with infantile onset [Kyllerman et al 1990]. In addition, the dystonia does not tend to worsen or generalize in the course of the disease. Infrequently, 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 [Kyllerman et al 1990], sudden noise [Asmus et al 2001, Trottenberg et al 2001], caffeine [Nygaard et al 1999], and tactile stimuli [Nygaard et al 1999].

Tremor (postural or other) may be a feature in a subset of individuals [Vidailhet et al 2001].

Psychiatric comorbidities have been reported. One systematic analysis of 307 participants with pathogenic variants in SGCE and M-D found that 65% had one or more psychiatric diagnoses, the most common of which were specific (33%) and social phobias (31%), followed by alcohol dependence (24%) and obsessive-compulsive disorder (OCD) (21%) [Peall et al 2015]. A further comparison of symptomatic and asymptomatic individuals with an SGCE pathogenic variant reported in this study found that OCD and social phobia were ten and 12 times more likely, respectively, in symptomatic individuals. It is unclear if psychiatric features seen in people with SGCE-M-D are a result of the SGCE pathogenic variant or a consequence of living with the disease. One argument against a purely reactive explanation, however, is that OCD is generally not considered a reactive condition.

Other neurologic signs and symptoms including dementia and ataxia are rare in SGCE-M-D [Gasser 1998]. Seizures are also rare, but have been reported in at least three families and are no longer considered exclusionary for diagnosis. However, the significance of this finding remains unclear [Foncke et al 2003, O'Riordan et al 2004, Haugarvoll et al 2014].

SGCE-M-D is compatible with an active life of normal span [Nygaard et al 1999].

Although spontaneous remission of SGCE-M-D has been reported [Roze et al 2008], SGCE-M-D may also be gradually progressive [Trottenberg et al 2001], leading to considerable functional disability and sometimes to early retirement [Hjermind et al 2003, Maréchal et al 2003].

Multiple studies support a different disease mechanism for SGCE-M-D than for isolated dystonia. Currently, the leading hypotheses suggest dysfunction of the cerebello-thalamo-cortical or striato-pallido-thalmo-cortical pathways [Popa et al 2014, Roze et al 2015].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

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 an SGCE pathogenic variant in affected individuals and DNA methylation differences consistent with maternal imprinting [Müller et al 2002, Grabowski et al 2003].
• Because about 5% of affected individuals inherit the SGCE pathogenic variant from their mothers [Zimprich et al 2001, Grabowski et al 2003], the apparent suppression of the M-D phenotype on maternal transmission of the SGCE allele is incomplete. In these instances, the phenotype may be milder. The reasons for loss of the maternal imprint are unknown.

Nomenclature

"Myoclonus-dystonia" is the term used for individuals with an SGCE-like phenotype [Roze et al 2018]. It is distinguished from "myoclonic dystonia," a condition having a primarily dystonic phenotype with longer duration jerks co-occurring in the dystonic body regions. Additional terms used in the past for SGCE-M-D include "inherited myoclonus-dystonia syndrome," "alcohol-responsive myoclonic dystonia," and "hereditary essential myoclonus" [Quinn et al 1988, Quinn 1996, Lang 1997].

Prevalence

Little is known about the prevalence of SGCE-M-D. 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 SGCE myoclonus-dystonia (SGCE-M-D) the following evaluations (if not performed as part of the evaluation that led to the diagnosis) 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.
• Consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Medications may improve myoclonus and/or dystonia:

• While multiple anti-seizure medications have been reported in case series or individual reports, zonisamide is the first to demonstrate class I evidence of improvement of both myoclonus and dystonia in a double-blind study [Hainque et al 2016].
  Valproate and levetiracetam may also be used. Topiramate and carbamazepine have been reported to improve myoclonus [Nygaard et al 1999, Sanjari Moghaddam et al 2018].
• Benzodiazepines, particularly clonazepam, improve mostly myoclonus and tremor [Goetz & Horn 2001].
• Anticholinergic medication may improve dystonia [Goetz & Horn 2001] and botulinum toxin injection may be especially helpful for cervical dystonia [Berardelli & Curra 2002].
• Improvement of dystonia with L-5-hydroxytryptophan has been reported [Scheidtmann et al 2000].
• Improvement with both L-dopa [Luciano et al 2009] and the dopamine-depleting medication tetrabenazine has been reported [Luciano et al 2014].
• One individual with SGCE-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 sodium oxybate may improve myoclonus [Frucht et al 2005].

Note: Although the symptoms of SGCE-M-D usually resolve with ingestion of alcohol, the risk of long-term addiction to alcohol renders it an unacceptable treatment option.

Deep brain stimulation (DBS). Studies of globus pallidus interna (Gpi) and/or ventral intermediate nucleus of the thalamus (VIM) DBS in individuals with M-D determined that both were effective long-term treatments, although GPi is now the more frequently chosen target. Marked improvement in both myoclonus and dystonia as well as good quality of life and social adjustment were seen in a cohort of nine individuals with SGCE-M-D who had GPi DBS for at least five years [Kosutzka et al 2019]. In individuals with a predominant myoclonus phenotype undergoing VIM DBS (3 individuals with SGCE M-D; 2 individuals without an SGCE pathogenic variant), sustained improvement of both myoclonus and dystonia was found over 50 months [Zhang et al 2019].

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].

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.

Surveillance

Agents/Circumstances to Avoid

Use of alcohol to ameliorate symptoms should be avoided due to the risk of alcohol dependence.

Evaluation of Relatives at Risk

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

Pregnancy Management

There is concern about teratogenicity with certain anti-seizure medications that are sometimes used in the treatment of myoclonus-dystonia. These should be avoided in women considering pregnancy or who are known to be pregnant. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Women with M-D should be counseled about abstaining from alcohol during pregnancy, particularly during the first trimester, as alcohol negatively affects fetal development.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SGCE myoclonus-dystonia (SGCE-M-D) is inherited in an autosomal dominant manner with penetrance determined by the parental origin of the altered SGCE allele. An SGCE pathogenic variant on the paternally derived (expressed) SGCE allele generally results in disease; a pathogenic variant on the maternally derived (silenced) SGCE allele typically does not result in disease.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with SGCE-M-D inherited a pathogenic variant from a heterozygous parent who may or may not have clinical signs of M-D. Because SGCE-M-D shows reduced penetrance, the parent of an affected individual may have the pathogenic allele without showing clinical signs [Müller et al 2002, Hedrich et al 2004, Kock et al 2004, Gerrits et al 2009]. The mechanism of reduced penetrance is related to maternal imprinting and, therefore, based on the parental origin of the pathogenic variant. In general, maternally derived alleles are silenced and paternally derived SGCE alleles are expressed.
• A proband with M-D may have the disorder as the result of a de novo SGCE pathogenic variant [Hedrich et al 2004, Asmus et al 2007, Borges et al 2007]; to date only three de novo cases have been reported.
• Molecular genetic testing is recommended for the parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Since the SGCE variant was likely inherited from the father, it may be appropriate to evaluate the father first.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• Although most individuals diagnosed with M-D inherited the pathogenic allele from a parent, the family history may appear to be negative because of either the effects of imprinting or 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. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs 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 pathogenic allele is 50%. Expression of the pathogenic SGCE allele is influenced by the sex of the parent transmitting the allele (imprinting).
  • If the SGCE pathogenic variant is inherited from the father, it is typically expressed and most often the offspring is symptomatic.
  • If the SGCE pathogenic variant 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 pathogenic variant from their mother do develop symptoms, indicating that the apparent suppression of the phenotype by maternal inheritance of a pathogenic SGCE allele is incomplete and loss of the maternal imprint occurs at a low frequency. Symptoms in individuals who have a maternally derived SGCE pathogenic variant may be milder than in those who inherit the pathogenic variant from their fathers.
• Because of intrafamilial clinical variability, symptomatic sibs may be more or less severely affected than the proband and have different M-D-related findings.
• If the proband has a known SGCE pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the risk to sibs of inheriting a pathogenic variant is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the SGCE pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for SGCE-M-D because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SGCE-M-D has a 50% chance of inheriting the pathogenic variant.

• If the proband is male, it is likely that all of his children who inherit the pathogenic variant will develop symptoms.
• If the proband is female, about 5% of her children who inherit the pathogenic variant will develop symptoms.
• Symptomatic offspring of a proband may be more or less severely affected than the proband.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or is known to have an SGCE pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SGCE pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. The results of prenatal testing are not useful in predicting age of onset, severity, type of symptoms, or rate of progression of SGCE-M-D.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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Revision History

• 4 June 2020 (cm) Revision: revised information on GNB1; link to GNB1 Encephalopathy
• 8 August 2019 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 19 December 2005 (me) Comprehensive update posted live
• 11 June 2004 (ljo/cd) Revision: testing
• 21 May 2003 (me) Review posted live
• 5 May 2003 (ljo) Original submission