Sgce Myoclonus-Dystonia
Summary
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 antiepileptics used to treat myoclonus (especially valproate and levitiracetam) also improve myoclonus in individuals with myoclonus-dystonia. The response to other antiepileptics (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 gender 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.
Diagnosis
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 at the most reasonable cost 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.
Table 1.
Molecular Genetic Testing Used in SGCE Myoclonus-Dystonia
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SGCE | Sequence analysis 3 | ~75% 4 |
| Gene-targeted deletion/duplication analysis 5 | ~25% 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Tezenas du Montcel et al [2006], Raymond et al [2008], Roze et al [2008]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
DeBerardinis et al [2003], Asmus et al [2005], Asmus et al [2007], Han et al [2007], Grünewald et al [2008], Ritz et al [2009], Peall et al [2014]
Clinical Characteristics
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.
Differential Diagnosis
Myoclonic dystonia 26 (OMIM 616398), associated with heterozygous pathogenic variants in KCTD17, is closest in phenotype to SGCE myoclonus-dystonia (SGCE-M-D). For further information about myoclonic dystonia 26 and other disorders to consider in the differential diagnosis of SGCE-M-D, see Table 2.
Table 2.
Other Genes of Interest in the Differential Diagnosis of SGCE Myoclonus-Dystonia
| Gene(s) | Disorder | MOI | Key Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/SGCE-M-D | Distinguishing from SGCE-M-D | |||
| ADCY5 | ADCY5-related dyskinesia | AD |
| Typically assoc w/additional features (e.g., chorea, early motor delay, alternating hemiplegia of childhood) |
| ATM | Variant ataxia-telangiectasia 3 | AR | Dystonia only or dystonia w/myoclonus may be present. |
|
| ATN1 | DRPLA | AD | Myoclonus, epilepsy | In children:
|
| ATP7B | Wilson disease | AR | Dystonia |
|
| ATXN3 | Spinocerebellar ataxia type 3 | AD | Dystonia in 1 individual | Cerebellar ataxia, pyramidal signs, pontocerebellar atrophy |
| CSTB | Unverricht-Lundborg disease | AR | Myoclonus, seizures |
|
| EPM2A NHLRC1 | Progressive myoclonus epilepsy, Lafora type | AR | Myoclonus, seizures |
|
| GCH1 | GTP cyclohydrolase 1-deficient dopa-responsive dystonia | AD | M-D in 1 individual 4 |
|
| GNB1 | GNB1 encephalopathy | AD | M-D in 1 individual w/comorbid OCD & mild DD, 5 neurodevelopmental delay, & other features incl dystonia in 46 others 6 | One individual w/M-D:
|
| KCTD17 | Myoclonic dystonia 26 (OMIM 616398) | AD | Early-onset myoclonic jerks; development of dystonia later in life (in 4 individuals) | Early motor delay, severe lingual dystonia, & mild cognitive delay in 2 families w/splice variants 7 |
| mtDNA | MERRF | Mat | Myoclonus; seizures | Ataxia & ragged red fibers on muscle biopsy |
| NKX2-1 8 | Benign hereditary chorea (OMIM 118700) | AD | Myoclonus | Does not demonstrate aggravation of jerks w/complex motor tasks (in contrast to action-induced myoclonus of M-D). |
| PRKCG | Spinocerebellar ataxia type 14 | AD | M-D in 1 individual 9 | Slowly progressive cerebellar ataxia, dysarthria, & nystagmus |
| RELN | RELN myoclonus-dystonia 7 | AD |
|
|
| TOR1A | DYT1 early-onset isolated dystonia | AD | Unusual presentation of alcohol-responsive M-D in 1 individual 11 | Cervical dystonia is uncommon in DYT1 dystonia. |
| TTPA | Ataxia with vitamin E deficiency | AR | Dystonia |
|
| TUBB2B | TUBB2B tubulinopathy (mild form) 12 (see Tubulinopathies Overview) | AD | M-D in 1 individual |
|
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; Mat = maternal inheritance; M-D = myoclonus-dystonia; MOI = mode of inheritance; OCD = obsessive-compulsive disorder
- 1.
Douglas et al [2017]
- 2.
Chen et al [2015]
- 3.
Saunders-Pullman et al [2012], Levy & Lang [2018]
- 4.
Leuzzi et al [2002]
- 5.
Jones et al [2019]
- 6.
Petrovski et al [2016], Steinrücke et al [2016], Lohmann et al [2017], Hemati et al [2018]
- 7.
Mencacci et al [2015], Graziola et al [2019], Marcé-Grau et al [2019]
- 8.
Because of the association of hypothyroidism with pathogenic variants in NKX2-1, thyroid hormone screening should be considered in affected individuals. See OMIM 118700, 610978, 600635.
- 9.
Foncke et al [2010]
- 10.
Groen et al [2015]
- 11.
A male with alcohol-responsive M-D who had the typical three-base pair deletion in TOR1A and no pathogenic variant in SGCE was reported [Tezenas du Montcel et al 2006]. His mother was Ashkenazi Jewish and had only writer's cramp.
- 12.
Geiger et al [2017]
Myoclonic dystonia 15 (OMIM 607488). A clinically similar M-D phenotype in a large Canadian family without an identifiable SGCE pathogenic variant 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 chromosome region [Schüle et al 2004]. The overall contribution of this locus to M-D cannot be determined until the gene is identified.
For a review of various genetic and secondary forms of dystonia, see Hereditary Dystonia Overview.
Management
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 antiepileptic 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
Table 3.
Recommended Surveillance for Individuals with Myoclonus-Dystonia
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Neurologic | Neurologic exam to assess burden of myoclonus & dystonia & review therapy & side effects | Annually |
| Psychiatric | Eval for psychiatric features | Annually |
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 antiepileptic 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 antiepileptic 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.