SGCE-Related Myoclonus-Dystonia (DYT-SGCE) and Other Myoclonus-Dystonia Syndromes

Combined dystonia usually beginning in childhood, with brief myoclonic jerks of the upper body, response to alcohol and frequent psychiatric comorbidity, caused mainly by loss of function of epsilon-sarcoglycan, a maternally imprinted gene expressed only from the paternal allele

Literature and regulatory information update: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. From hereditary essential myoclonus to myoclonus-dystonia

The association of brief myoclonic jerks with dystonic postures, transmitted within families and attenuated by alcohol intake, was described for decades under different names. In 1996, Quinn reviewed the history of the terms “essential myoclonus” and “myoclonic dystonia” and proposed that hereditary essential myoclonus and dominantly transmitted myoclonic dystonia, both with lightning-like jerks and a marked response to alcohol, were the same disease, a hypothesis that only genetic studies could confirm [22]. GeneReviews also lists the designations “hereditary myoclonus-dystonia syndrome”, “alcohol-sensitive myoclonic dystonia” and “hereditary essential myoclonus” as historical synonyms [1].

Family descriptions are, however, much older. Friedreich introduced the term “paramyoclonus multiplex” in 1881 on the basis of a case of uncertain nature; in 1966, Daube and Peters described two families with hereditary essential myoclonus over at least four generations, with father-to-son transmission and apparently skipped generations; in 1967, Mahloudji and Pikielny reported a French-Canadian family in which the father and five of the nine children had myoclonus beginning in the first or second decade, with a benign course and without seizures or dementia [3]. In 1990, Müller and Kupke reinterpreted these families as “myoclonic dystonia”, an association of torsion dystonia with muscle jerks, and Kyllerman and colleagues described a six-generation Swedish family with alcohol-sensitive hereditary myoclonus, in which 17 of 20 affected individuals had myoclonus of the arms, shoulders and neck beginning between 2 and 3 years of age, and some had dystonia of the legs from 6 to 18 months [3]. Linkage to the TOR1A locus at 9q34 was excluded in that Swedish family and in a German family, indicating a gene different from that of early-onset torsion dystonia [3].

The first molecular step came in 1999, when Nygaard and colleagues studied a large family with “essential” myoclonus-dystonia, without other neurological signs or laboratory abnormalities, and mapped the locus to a 28-centimorgan region at 7q21–q31 [23]. In that North American family of European and Native American ancestry, the mean age at onset was 6.5 years (4 to 15), everyone who tried alcohol reported relief, levodopa was ineffective, clonazepam and valproate gave slight benefit, and 9 of the 10 affected individuals had psychiatric problems such as depression, anxiety and obsessive-compulsive disorder (OCD) [3]. In 2000, Klein and colleagues confirmed linkage to 7q21 in eight families, with a combined multipoint LOD score (logarithm of the odds) of 11.71 in a 14 cM region [3]. In 2001, Zimprich and colleagues identified, by positional cloning in a critical region of about 3.2 Mb, five heterozygous loss-of-function variants in the epsilon-sarcoglycan gene (SGCE), expressed in all brain regions studied; pedigree analysis showed a marked difference in penetrance depending on the transmitting parent, consistent with the maternal imprinting already demonstrated in the murine gene [13]. In the combined analysis of pedigrees with SGCE variants or linkage to 7q21, 49 of the 62 affected individuals had inherited the disease from the father and only 4 from the mother (9 undetermined), whereas 14 of the 18 asymptomatic carriers had inherited it from the mother and only 3 from the father [3]. In 2002, Müller and colleagues showed, in families with apparent recessive inheritance or sporadic cases, that the variant came from clinically unaffected parents, that affected individuals expressed only the altered allele and unaffected carriers only the normal one, and identified a differentially methylated region in the promoter [14]. In 2003, Grabowski and colleagues confirmed by bisulfite sequencing that, in leucocytes, the maternal SGCE allele is methylated and the paternal allele is not, that the maternal allele is probably fully methylated in the brain, and that cell lines with maternal uniparental disomy of chromosome 7 express the gene very weakly, unlike lines with paternal disomy [24].

1.2. Nomenclature and classification

Dystonia is defined, in the 2025 revision of the international consensus, as a movement disorder characterised by sustained or intermittent abnormal movements and/or postures, usually patterned and repetitive, which may be tremulous or jerky, are often initiated or worsened by voluntary action and are frequently accompanied by overflow movements [25]. The classification retains two axes: axis I describes age at onset, family history, body distribution, temporal pattern, phenomenology and whether the dystonia is isolated or combined with other neurological or systemic manifestations; axis II organises aetiology (genetic, acquired, anatomical) and common mechanisms [25]. In this classification, myoclonus-dystonia is a combined dystonia, because myoclonus is a second movement disorder with equal or greater weight than the dystonia. The Oxford Desk Reference, in its 2017 edition, still places it among the “dystonia-plus” syndromes, with a variable degree of dystonia and myoclonus, marked improvement with alcohol, autosomal dominant inheritance with reduced penetrance and more than one locus [26].

GeneReviews distinguishes “myoclonus-dystonia”, the phenotype similar to that caused by SGCE, from “myoclonic dystonia”, a predominantly dystonic picture with longer-lasting jerks in the dystonic regions themselves [1]. The MDS task force on the nomenclature of genetic movement disorders proposed in 2016, and updated in 2022, a system that combines a phenotypic prefix with the gene symbol; the update added 89 genes and created the category of mixed movement disorders [4]. Recent literature uses “DYT-SGCE” and, when it wishes to stress the equal weight of myoclonus, “MYC/DYT-SGCE” [5, 27]. The old numerical designation DYT11 remains that of OMIM entry 159900 [3].

1.3. Entities covered in this article

The central entity is SGCE-related myoclonus-dystonia, defined by the presence of myoclonus and/or dystonia with a heterozygous pathogenic variant in SGCE, a deletion including the gene or a maternal uniparental disomy of chromosome 7 that silences both alleles [1, 28]. The same syndromic class includes KCTD17 myoclonic dystonia 26 (OMIM 616398) [6], KCNN2 myoclonic dystonia 34 (OMIM 619724, gene-phenotype relationship still provisional, based on a single family) [8, 9] and the DYT15 locus at 18p11, whose gene has not been identified [1, 10]. According to Krygier and colleagues, SGCE, KCTD17 and KCNN2 are the only genes that OMIM links to the designation “myoclonic dystonia”, although other genes, such as NUS1, may broaden the spectrum [12]. An additional set of disorders, including ADCY5 dyskinesias, GNB1 encephalopathy, variant ataxia-telangiectasia and DYT-TOR1A dystonia, sometimes produces a myoclonus-dystonia picture and enters the differential diagnosis [1].

2. Molecular Genetics and Pathophysiology

2.1. The SGCE gene and epsilon-sarcoglycan

SGCE is located at 7q21.3 and encodes epsilon-sarcoglycan [1, 29]. The sarcoglycan family includes the alpha, beta, gamma, delta, epsilon and zeta forms; in striated muscle they are transmembrane components of the dystrophin-glycoprotein complex, which links the actin cytoskeleton to the extracellular matrix [1]. Alpha-, beta-, gamma- and delta-sarcoglycan are the proteins whose absence causes the sarcoglycanopathy limb-girdle muscular dystrophies [30]. Epsilon-sarcoglycan stands apart in having ubiquitous expression, including several brain regions during development and in adulthood, and its loss produces a movement disorder of central origin rather than a myopathy; its function in the brain remains unknown [1, 31].

The predicted protein has a signal peptide, a large extracellular domain with four conserved cysteines and a glycosylation site, a transmembrane domain and a short cytoplasmic domain, and shares 43% identity with alpha-sarcoglycan [14]. In the mouse, the isoform containing exon 8 is widely expressed and concentrated in postsynaptic membranes, whereas the brain isoform containing exon 11b, which encodes a C-terminus with a PDZ domain-binding motif, is concentrated in presynaptic membranes; in the human brain, the exon 11b transcript is expressed in the sensorimotor cortex, putamen, thalamus, hippocampus and cerebellum, and the imprinting pattern observed in blood and muscle is maintained in brain tissue [14].

The gene has 13 exons according to GeneReviews; the OMIM entry, based on the original 1998 description, which predates the identification of brain exon 11b in 2004, counts 12 [1, 14]. Exon 10 is alternatively spliced and absent from most transcripts, exon 11b is brain-specific and exon 8 is rarely expressed in the brain [1]. Variant nomenclature uses the MANE Select transcript NM_003919.3, which encodes the protein NP_003910.1 [11]. GeneGuidance gives NM_001099400 as the reference RefSeq, which corresponds to another isoform; reports should state the transcript used [11, 31].

2.2. Maternal imprinting and disease mechanism

Genomic imprinting is the mechanism by which a gene is expressed only from the allele inherited from one of the parents; the epigenetic marks, mainly DNA methylation, are erased and re-established in the germline according to the sex of the individual, and imprinting disorders result from variants in the imprinted gene, deletions or duplications, uniparental disomy or epimutations [29]. The Oxford Desk Reference includes SGCE in the list of imprinted genes with an associated disease, as a paternally expressed gene at 7q21.3, alongside GRB10 (7p, maternally expressed) and PEG1/MEST (7q32.2, paternally expressed), linked to Silver-Russell syndrome [29].

In the case of SGCE, the maternal allele is methylated at the CpG island of the promoter and first exon and the paternal allele is not [24]. Because the disease arises almost only when the variant is on the paternal allele, the mechanism is thought to be loss of function of epsilon-sarcoglycan [1, 13]. Functional studies support this interpretation: proteins with the missense substitutions p.His60Arg, p.His60Pro and p.Leu196Arg (historical nomenclature) are retained in the endoplasmic reticulum or distributed diffusely in the neuron, instead of reaching the plasma membrane, and are ubiquitinated and degraded in the proteasome; co-expression with normal torsinA reduces the levels of the mutant protein [14]. Maternal uniparental disomy of chromosome 7 reinforces this interpretation: in a 36-year-old man with typical myoclonus-dystonia and Silver-Russell syndrome, loss of the paternal chromosome 7 left both SGCE alleles methylated, with no unmethylated allele after bisulfite treatment and no expression of the gene on reverse transcription, in the absence of any sequence variant [28]. The mechanism is not, however, fully understood. About 5% of patients inherit the variant from the mother and presumably express the normal paternal allele [1]; in one such patient, Grabowski and colleagues found only the normal paternal transcript in blood, with no transcript from the altered maternal allele [24]. In an affected patient with a maternally inherited variant, Müller and colleagues found biallelic expression associated with partial loss of methylation at several CpG dinucleotides of the promoter [14]. The reasons for the occasional loss of maternal imprinting are unknown [1].

2.3. Variant spectrum

The Human Gene Mutation Database (HGMD) lists more than 100 pathogenic SGCE variants: nonsense, missense, small frameshift deletions and insertions, splicing alterations and deletions of exons or of the whole gene [1]. Among probands with a causal variant, sequencing identifies about 75% and targeted deletion/duplication analysis the remaining 25%, proportions that measure the distribution of variant types and not the clinical sensitivity of the test [1]. The intragenic deletions described by Asmus and colleagues, of 15,020 bp (exon 5) in a German family and 6872 bp (exon 6) in a Danish family, truncate the protein before the transmembrane domain and probably result from non-homologous end joining; in the Danish family, the father, who had inherited the deletion from his mother, had no motor symptoms but had alcohol dependence [14]. Variants described in older series often use historical nomenclature (for example p.Arg97Ter, p.Arg102Ter or 974delC) that was not converted to the MANE transcript in the sources consulted [14]. No founder variants are described in the sources consulted, and GeneReviews identifies no genotype-phenotype correlations [1].

The c.406T>G p.(Cys136Gly) variant, not described before 2026, was classified as pathogenic under the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria with the codes PM1, PM2, PM5, PP1 at strong level, PP2 and PP3, because it co-segregated with the disease in all affected individuals tested and was absent from population databases [33]. This example contrasts with LeDoux’s warning: in the Genome Aggregation Database (gnomAD) v2, with 125,748 exomes and 15,708 genomes, there were 56, 408 and 1250 SGCE alleles with a CADD score (Combined Annotation Dependent Depletion, a measure of predicted deleteriousness) above 30, 25 and 20, respectively, which corresponds to about one in every 348 people in the USA carrying a variant with a CADD score of at least 25 [16]. The frequency of variants predicted to be deleterious far exceeds the prevalence of the disease, so a rare missense SGCE variant is not considered causal without a co-segregation study and neurological examination of relatives [16].

2.4. Contiguous deletions and uniparental disomy

7q21 deletions that include SGCE cause myoclonus-dystonia usually accompanied by other features. The first case, described by DeBerardinis and colleagues in 2003, was a 32-month-old child with an interstitial deletion of 9 to 15 Mb on the paternal chromosome, myoclonus, microcephaly, short stature, facial dysmorphism and language delay [14]. At least 15 patients had been described by 2020, most with typical myoclonus-dystonia and, in variable combinations, short stature, facial dysmorphism, intrauterine growth restriction, microcephaly, cognitive impairment, language delay, psychosis, joint laxity and fractures [1]. In the UK and Ireland cohort, five probands had contiguous deletions of 0.7 to 2.3 Mb, with short stature, joint laxity and microcephaly, features that were not always predictable from the size of the deletion or the genes included [34]. In one family, two siblings had myoclonus-dystonia and cognitive impairment, and the father and three of his siblings had adult-onset psychosis without a movement disorder [1]. A patient with myoclonus-dystonia, language delay, dysmorphism and an apparently balanced de novo reciprocal translocation in fact had microdeletions at 7q21 and 9q23 [1]. The 7q21 region also includes the split hand-foot malformation locus associated with DLX5, an anomaly that occurs in 1 in every 8000 to 25,000 newborns and accounts for about 15% of limb reduction defects [35]; the sources consulted do not describe how often deletions including SGCE involve that locus.

Maternal uniparental disomy of chromosome 7 has been found in three people with myoclonus-dystonia and Silver-Russell syndrome [1, 28]. In Silver-Russell syndrome, maternal disomy 7 accounts for 5 to 10% of cases and is associated with a phenotype meeting fewer clinical criteria, which is why molecular testing is recommended with as few as three of the six cardinal criteria [36].

2.5. Circuit pathophysiology

SGCE myoclonus-dystonia appears to have a mechanism different from that of the isolated dystonias, and the main hypotheses point to dysfunction of the cerebello-thalamo-cortical or striato-pallido-thalamo-cortical pathways [1]. Roze and colleagues summarised the evidence of an altered cerebello-thalamic pathway, possibly linked to a GABAergic deficit due to Purkinje cell dysfunction, and added alterations of striatal plasticity and of serotonin homeostasis [37]. In a fluorodeoxyglucose positron emission tomography study of 23 patients (11 with an SGCE variant and 12 without) and 23 controls, the supplementary motor area had different metabolism in patients, and severity correlated negatively with cerebellar and caudate nucleus metabolism, a pattern consistent with a more excitable motor cortex owing to reduced cerebellar and striatal inhibition [38].

In cellular models derived from patient induced pluripotent stem cells and from edited lines, cortical glutamatergic neurons with SGCE variants had a hyperexcitable phenotype, and GABAergic interneurons with a medial ganglionic eminence pattern showed dysregulation of genes involved in axonal organisation and synaptic signalling, simpler dendritic arbours, a reduced calcium response to gamma-aminobutyric acid (GABA) and reduced network activity [39]. These results are preclinical and reinforce the hypothesis of an imbalance between excitation and inhibition in motor circuits, without therapeutic application to date [39].

2.6. Class of myoclonus-dystonia syndromes: types and genes

Mencacci and colleagues estimated that SGCE accounts for 30 to 50% of familial myoclonus-dystonia and described KCTD17 as a gene highly expressed in the putamen, part of a co-expression network rich in dystonia genes and associated with alterations of endoplasmic reticulum-dependent calcium signalling in fibroblasts [6]. KCNN2 encodes the SK2 subunit of a small-conductance calcium-activated potassium channel, highly expressed in the cerebellum and involved in neuronal excitability and synaptic plasticity; the original variant, absent from gnomAD and with a CADD score of 29.7, co-segregated over three generations [8, 12]. Krygier and colleagues described two Polish families in 2026: a five-year-old girl with KCTD17 c.461T>A p.(Met154Lys), gait disturbance, postural instability, myoclonus and tongue dyskinesia; and a 38-year-old mother and her 17-year-old daughter with KCNN2 c.1780-2A>G, tremor, myoclonus, dystonia, psychiatric symptoms and episodic memory impairment [12]. The KCTD17 and KCNN2 variants cited were transcribed from the publication and were not normalised in VariantValidator.

2.7. Penetrance, expressivity and modifiers

Penetrance depends on the sex of the parent transmitting the variant: almost all children who inherit the variant from the father become symptomatic, and only about 5% of those who inherit it from the mother develop symptoms, sometimes milder [1]. Expressivity varies within families. In the French family with the p.(Cys136Gly) variant, the spectrum ranged from mild stress-triggered myoclonus in the women to early myoclonus with cervical dystonia and response to alcohol in the men, which the authors attributed to imprinting and sex-linked modifiers [33]. In the study of 89 probands from the UK and Ireland, 19 (21.3%) had an SGCE variant, more often when onset occurred by 10 years of age and the picture was pure myoclonus-dystonia of the upper body [34]. In myoclonus-dystonia without an SGCE variant, truncal dystonia during action and the coexistence of myoclonus and dystonia in the same body region are more frequent and suggest another genetic cause [40].

No other phenotypes are associated with intragenic SGCE variants [1]. Conversely, SGCE variants occur rarely in patients with isolated dystonia: in exome sequencing of 1924 patients with undiagnosed dystonia, mostly late-onset and isolated, recruited from two international registries, pathogenic or likely pathogenic variants were identified in 163 patients (yield of 8.1% in index cases), and SGCE was one of the most frequent genes, with 12 index cases, including the variants p.Met174Lys and c.233-1G>A with demonstrated co-segregation [41]. The GeneReviews chapter on monogenic isolated dystonias records the same phenomenon for GCH1, PRKN, SGCE, SLC2A1 and CACNA1A [42].

The genetic heterogeneity of myoclonus-dystonia became evident early: studies in 2003 and 2004 found no SGCE variants in 16 patients and in 5 of 7 autosomal dominant families, and a three-generation family with myoclonus-dystonia and Gilles de la Tourette syndrome showed no linkage to SGCE, DYT15, TOR1A or DRD2 [3]. A DRD2 missense variant initially proposed as causal turned out to coexist with an SGCE deletion in all affected members of the family, and DRD2 variants were later considered rare in this disease [3].

3. Clinical Spectrum and Manifestations by System

3.1. Myoclonus

The myoclonus of the SGCE-related form consists of brief, lightning-like jerks that mainly affect the neck, trunk and upper limbs, with proximal predominance; the lower limbs are less affected [1, 12]. It is usually the first manifestation [1]. The jerks are triggered or worsened by active movement of the affected region and by sustained postures, and also by stress, sudden noises, caffeine and touch [1, 12]. In children, myoclonus of the legs and trunk may rarely cause falls [1]. Some patients have postural or other tremor [1].

In the French series of Roze and colleagues, with 41 patients from 22 families with an SGCE variant and a mean age at onset of 6 years (1 to 18), the myoclonus involved the axis in 90% of cases, the face in 27%, the voice in 24% and the lower limbs in 34%; it was present at rest in 70% and increased with posture and action in 95% [3]. Neurophysiological studies showed synchronous or asynchronous, isolated and mostly arrhythmic jerks, insensitive to stimuli, without signs of cortical hyperexcitability (negative C reflex), pointing to a subcortical origin [3]. Other families had marked involvement of the legs, with disability in some members, and vocal myoclonus due to laryngeal involvement, or subtle distal myoclonus of the fingers as a prominent feature [3].

3.2. Dystonia

In the German series of Asmus and colleagues (24 patients from 9 families), myoclonus began at a mean age of 5.4 years (6 months to 20 years) and dystonia, mainly cervical or writer’s cramp, at 8.8 years (1 to 38), often in parallel with worsening of the myoclonus; alcohol improved the myoclonus in 21 of the 24 [3]. About half of patients (54% in the 2002 series) have focal or segmental dystonia, in the form of cervical dystonia, writer’s cramp, or both [1]. Unlike primary torsion dystonia, lower limb dystonia is rare in adults, although it has been described with childhood onset, and the dystonia does not tend to generalise [1]. Isolated dystonia, without myoclonus, is uncommon [1]. In the French series, 10 of the 41 patients began with isolated dystonia and 2 with hypotonia; the dystonia was axial, mainly cervical, in 13, of the upper limbs in 18, of the lower limbs in 9 and laryngeal in 1, and 9 had spontaneous remission of the dystonia in childhood or adolescence [3]. In the UK and Ireland cohort, Peall and colleagues recognised three motor patterns: myoclonus and dystonia of the upper body with onset in early childhood; early-onset lower limb dystonia progressing to myoclonus and upper body involvement; and myoclonus and dystonia of the upper body with later childhood onset, with evident cervical involvement [34]. In children, action dystonia appears mainly during writing and walking [43].

3.3. Response to alcohol

Most adults report a marked reduction in myoclonus after alcohol intake, but the intensity of this response varies between and within families [1]. The response to alcohol aids diagnosis and explains the risk of self-medication and alcohol dependence [1, 26]. Lack of response to alcohol is the rule in the KCTD17 form, and in the KCNN2 form improvement is seen only early in the disease [12].

3.4. Psychiatric and cognitive manifestations

Psychiatric comorbidity is frequent. In the international study of Peall and colleagues, with data from 307 participants from the Netherlands, the UK, the USA and Germany (140 men and 167 women; mean age 42.5 years), about two thirds of carriers with motor symptoms had at least one psychiatric diagnosis, and affected patients had significantly higher rates than non-carrier relatives (p<0.001), particularly of alcohol dependence, obsessive-compulsive disorder (OCD) and social and specific phobias [17]. According to GeneReviews, which reanalysed this cohort, 65% had one or more psychiatric diagnoses, with specific phobia in 33%, social phobia in 31%, alcohol dependence in 24% and OCD in 21%, and OCD and social phobia were 10 and 12 times more likely in symptomatic than in asymptomatic carriers [1]. In a study of five families with 64 members, alcohol dependence was more frequent in symptomatic carriers (35%) than in asymptomatic carriers and controls (11.4%), OCD occurred in 16.7% of carriers and 3.0% of non-carriers, none of the 10 asymptomatic carriers had OCD, and motor symptoms preceded OCD by about 10 years; the authors interpreted alcohol dependence as self-medication and OCD as a possible expression of the altered gene [3]. It is not known whether these disorders result directly from the loss of epsilon-sarcoglycan or from the experience of living with the disease; OCD, which is not usually considered reactive, is an argument in favour of a direct effect [1, 17].

Among the children and adolescents of the Spanish cohort, 26 of 32 had a psychiatric diagnosis: anxiety in 13, OCD in 9 and attention deficit hyperactivity disorder (ADHD) in 8 [43]. In the European survey of patients and carers, all but one of the 84 participants reported psychiatric symptoms, such as anxiety, depression or OCD, but few had had a formal psychiatric assessment [44]. In three families studied in detail, neuropsychological assessment showed a deficit in verbal learning and memory in one, a memory deficit in another and no deficit in the third, and two of the families also had cases of psychosis [3]. Cognition is usually normal in the SGCE form, unlike the KCNN2 form, in which cognitive dysfunction is common [12].

3.5. Other manifestations

Dementia and ataxia are rare [1]. Seizures have been described in at least three families and are no longer an exclusion criterion, although their significance remains uncertain [1]. In a five-generation Dutch family, three of the five living affected individuals had electroencephalographic abnormalities and seizures with impaired consciousness, staring, amnesia and a feeling of panic, suggestive of a temporolimbic origin [3]. 7q21 deletions add short stature, dysmorphism, growth restriction, microcephaly, cognitive impairment, language delay, psychosis, joint laxity and fractures, and maternal disomy 7 adds the Silver-Russell phenotype [1, 28, 34].

3.6. Natural history by age

Onset occurs in most patients in the first decade and almost always by 20 years, with a reported range of 6 months to 80 years [1]. In the prospective study of De Francesch and colleagues, carried out between 2014 and 2023 in Barcelona and Groningen, 38 patients with an SGCE variant (21 boys and 17 girls) were assessed on video, with blinded rating, at a mean age of 10 years (2 to 21 years) and again at 14 years and 2 months (4 to 25 years), after a mean follow-up of 4 years and 1 month; six patients operated on with pallidal stimulation were excluded [43]. Myoclonus was the initial symptom in 58%, dystonia in 13% and both in 29%; myoclonus began at a mean age of 2 years and 7 months (6 months to 10 years) and dystonia at 3 years (11 months to 12 years) [43]. Action myoclonus, global dystonia and writing dystonia worsened on average by 1.356 points per year on the Unified Myoclonus Rating Scale (UMRS), 0.226 on the Burke-Fahn-Marsden scale (BFMDRS) and 0.518 on the writer’s cramp scale, and patients perceived worsening of speech, writing and gait [43]. The authors concluded that, contrary to what is described in adults, the disease is progressive in childhood and adolescence [43].

In adults, the disease is compatible with an active life of normal length [1]. Spontaneous remissions have been described, mainly of limb dystonia in childhood or adolescence, but also gradual progression with functional disability and early retirement [1]. In the ERN-RND survey, with 84 patients and carers from 12 countries and a mean age of 30.8 years (3 to 75), 69% had been diagnosed in childhood, 70% had a family history, the disease limited the daily activities of 80% (writing, drinking, eating, walking and speech), school difficulties were poorly recognised and unemployment was high [44]. These data describe patients treated with various therapies and not untreated natural history.

3.7. Comparison between the forms of the class

Source: comparative table of Krygier and colleagues, 2026 [12].

4. Clinical Recognition and Red Flags

SGCE myoclonus-dystonia should be considered in the presence of isolated myoclonus or myoclonus with dystonia beginning in the first or second decade, and less often in early-onset isolated dystonia [1]. The most valuable clues are myoclonus predominating over dystonia, involvement of the upper body, absence of truncal dystonia, associated anxiety or compulsivity and a family history [37]. When taking the history, asking about the response to alcohol is useful, and a family history of alcoholism may conceal affected relatives who self-medicate [1, 26]. A negative family history does not exclude the disease, because carriers who inherited the variant from the mother usually remain asymptomatic [1].

In infants and young children, isolated myoclonus raises the differential diagnosis of benign myoclonus of infancy, epilepsies and metabolic disorders, and myoclonus that is persistent, progressive or functionally disabling warrants investigation [15]. In children, dystonia may be subtle at first and reveal itself as writer’s cramp, mirror dystonia while drawing or peculiar gait abnormalities [15, 43].

Red flags for another cause are: a neurological manifestation other than myoclonus and dystonia (for example ataxia, spasticity, cognitive decline), abnormal brain magnetic resonance imaging, truncal action dystonia and myoclonus coexisting with dystonia in the same body region [1, 40]. The features that the Oxford Desk Reference associates with non-primary dystonia, such as an abnormal perinatal history, dysmorphism, developmental delay, hemidystonia, sudden onset or rapid progression, prominent oro-bulbar dystonia, signs of other neurological systems or extraneurological signs (hepatomegaly or splenomegaly), also point to other aetiologies [26]. In a movement disorder, suspicion of an inborn error of metabolism increases when several types of abnormal movement, other neurological signs, orofacial dystonia or bilateral basal ganglia lesions coexist [45]. Associated short stature, growth restriction, microcephaly or cognitive impairment should prompt a search for a 7q21 deletion or maternal disomy of chromosome 7 [1, 34].

There is no newborn screening. The disease does not cause emergencies of its own; the relevant acute risks are alcohol intoxication or dependence through self-medication, especially in adolescence, and the complications of drugs and surgery [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no diagnostic criteria validated by a scientific society. In 2018, Roze, Lang and Vidailhet proposed clinical criteria, reproduced by GeneReviews, which serve to decide when the picture matches the typical SGCE phenotype [1, 37]. The clinical diagnosis is probable with four major criteria, or three major and two minor, in the absence of any exclusion criterion [1].

Source: Roze and colleagues, 2018, as reported by GeneReviews [1, 37].

The phenomenological framework follows the 2025 dystonia classification: axis I records age at onset, distribution, temporal course and whether the dystonia is combined; in myoclonus-dystonia, the dystonia is combined with myoclonus and, in many patients, with tremor [25]. Comparative series show that clinical features discriminate only partially. In the series of Gerrits and colleagues, 7 of 31 Dutch patients with a clinical diagnosis of myoclonus-dystonia had an SGCE variant; carriers had onset before 20 years, simultaneous presentation of myoclonus and dystonia, a family history and truncal myoclonus, with no difference in alcohol sensitivity or psychiatric symptoms [3]. Valente and colleagues found variants in 6 of 29 patients (21%) with essential myoclonus or myoclonic dystonia and in none of 29 patients with a broader phenotype of myoclonus and dystonia [3]. Zutt and colleagues, comparing 20 patients with and 20 without an SGCE variant who met clinical criteria, found that the negative patients had more severe disease, more truncal dystonia during action and more coexistence of myoclonus and dystonia in the same body region [40].

5.2. Neurophysiology and imaging

Neurophysiology confirms the myoclonic nature of the jerks and helps to exclude other causes. The jerks of the SGCE form are subcortical, without an electroencephalographic correlate, insensitive to stimuli and with a negative C reflex, and discharges lasting less than 300 ms in non-dystonic regions support the diagnosis, whereas their absence is an exclusion criterion [1, 3]. In the Portuguese case described in 2025, video-electroencephalography recorded dozens of episodes of multifocal positive myoclonus lasting 100 to 200 ms without concomitant electroencephalographic change [15]. Brain magnetic resonance imaging is normal, and a structural abnormality excludes the typical clinical diagnosis [1]. Fluorodeoxyglucose positron emission tomography showed group differences in the supplementary motor area but has no individual diagnostic use [38].

5.3. Laboratory tests for exclusion

There is no biochemical biomarker of myoclonus-dystonia, and GeneGuidance notes the absence of a measurable metabolic defect [31]. In young children, the initial work-up usually includes thyroid function, ammonia, caeruloplasmin, copper, creatine kinase, lactate, pyruvate, amino acids, organic acids and acylcarnitines, mainly to exclude treatable causes such as Wilson disease, hypothyroidism and mitochondrial disorders [1, 15]. A slightly low caeruloplasmin, as in the Portuguese case (18.8 mg/dl, reference 21.7 to 43.3 mg/dl), should be interpreted in the clinical context and does not replace molecular diagnosis [15].

5.4. Genetic tests and order of use

The molecular diagnosis is established by identifying a heterozygous pathogenic SGCE variant. GeneReviews recommends a multigene movement disorder panel including SGCE and other genes in the differential diagnosis, with deletion/duplication analysis; single-gene testing, with sequencing followed by dosage analysis, is reserved for relatives of a patient with a known variant [1]. The Oxford Desk Reference recommends a panel, exome or genome depending on the context, DNA storage with consent and genomic microarray in children, particularly when there is dysmorphism or delay [26]. A 2026 international Delphi consensus included DYT-SGCE among the 16 genetic movement disorders with 100% consensus on the need for genetic testing in the adult clinic [27]. Before deep brain stimulation, the ERN-RND review recommends that genetic testing form part of the preoperative assessment [5].

The 75% and 25% figures describe the distribution of variant types among patients in whom a cause was found; they are not the clinical sensitivity. Only about half of patients with a clinical myoclonus-dystonia phenotype have an SGCE variant, a proportion that rises when there is recognised paternal transmission [1]. In the UK and Ireland series, the proportion was 21.3% (19 of 89 probands) [34], and in the 2006 French series, 16 of 76 unrelated patients with myoclonus-dystonia or essential myoclonus [3]. A negative result does not exclude the disease or the forms of the class still without an identified gene, such as DYT15 [1].

5.5. Interpretation and report content

The report should state the gene, the transcript with version (NM_003919.3 for MANE Select), the variant in Human Genome Variation Society (HGVS) nomenclature for DNA and protein, the zygosity, the class according to the ACMG/AMP criteria and the criteria applied [11, 33]. Truncating variants and deletions can usually be classified as pathogenic, because loss of function is the established mechanism [1]. Rare missense variants require caution: the population frequency of SGCE variants predicted to be deleterious (about 1 in 348 people with a CADD score of at least 25) far exceeds the prevalence of the disease, and classification depends on co-segregation, examination of relatives and absence from population databases [16, 33]. Segregation analysis has a particular feature: an asymptomatic carrier does not contradict pathogenicity if they inherited the variant from the mother, so the report and counselling should take into account the parental origin of each allele [1, 14].

5.6. Practical algorithm

In the presence of myoclonus, with or without dystonia, beginning before 20 years and predominating in the upper body, the first step is phenomenological characterisation by a movement disorder specialist, with video recording and, when in doubt, neurophysiological study [1, 26]. This is followed by exclusion of treatable acquired and metabolic causes, with magnetic resonance imaging and targeted tests [1, 45]. The first-line genetic test is a movement disorder panel or exome with CNV analysis [1, 26]. If there is dysmorphism, short stature, microcephaly or delay, microarray is added, and if there are Silver-Russell features, chromosome 7 methylation analysis [1, 36]. If the result is negative, the phenotype is reassessed for features of KCTD17, KCNN2, ADCY5, GCH1 or other causes and exome or genome sequencing is considered [1, 12].

5.7. Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are technically possible, but they do not predict age at onset, severity or progression, and penetrance depends on the sex of the transmitting parent [1]. The decision requires targeted genetic counselling.

6. Differential Diagnosis

6.1. Comparative table

AD, autosomal dominant; AR, autosomal recessive. Rows from ADCY5 to TUBB2B according to table 2 of GeneReviews [1].

6.2. Forms of the same class

The KCTD17 form is the closest. In the original British family, seven affected individuals began between 5 and 20 years with jerks or jerky tremor of the upper limbs and later developed dystonia of the upper limbs and craniocervical region, with spasmodic dysphonia, facial myoclonus, blepharospasm, torticollis and dystonic head jerks; the older individuals were more affected, and none improved with alcohol [7]. The proband of the German family, with arm jerks and writing difficulty since childhood and torticollis from 40 years of age, underwent pallidal stimulation at 58 years with marked improvement [7]. The p.(Arg145His) variant was found in one of 87 additional probands with familial myoclonus-dystonia and in none of 358 sporadic patients screened for exon 4, suggesting that KCTD17 is a rare cause [6, 7]. In the KCNN2 form, eight affected individuals over three generations had dystonia of the hands and neck beginning between 5 and 12 years, high-frequency tremor with stimulus-insensitive myoclonus, saccadic ocular pursuit, rotatory nystagmus on extreme gaze and mild difficulty with tandem gait [9]. In the DYT15 family, 12 members over four generations had alcohol-sensitive myoclonus-dystonia, mainly of the upper limbs, hands and axial muscles, and the 18p11 haplotype was also present in unaffected obligate carriers, a sign of reduced penetrance [10].

6.3. Other genetic dystonias and myoclonus

TOR1A dystonia usually results from the GAG deletion, has a penetrance of 30 to 40% and responds to deep brain stimulation; GCH1 dopa-responsive dystonia responds markedly and sustainedly to levodopa, which is why a therapeutic trial is recommended in all children with dystonia of unknown cause [26]. Variants in combined dystonia genes, including GCH1 and SGCE, may rarely present as isolated dystonia [41, 42]. The coexistence of variants in two dystonia genes in the same family, such as SGCE and TOR1A in two siblings who inherited each variant from a different parent, makes it difficult to attribute the phenotype to each gene [14]. The progressive myoclonic epilepsies (Unverricht-Lundborg, Lafora, MERRF, DRPLA) are distinguished by a course with seizures, ataxia and cognitive decline, and Wilson disease should be excluded in any young-onset dystonia [1].

6.4. Differential diagnosis in childhood and non-genetic causes

In infants and young children, isolated myoclonus raises the differential diagnosis of benign myoclonus of infancy, epileptic and metabolic disorders and secondary causes, such as infections or toxins, and video-electroencephalography without an electrographic correlate of the jerks is useful to separate epileptic causes [15]. The presence of dysmorphism, short stature or delay shifts the diagnosis towards a contiguous 7q21 deletion or maternal disomy of chromosome 7, rather than the intragenic form [1, 34]. Acquired causes and inborn errors of metabolism are ruled out by the history, magnetic resonance imaging and targeted tests [15, 45].

7. Treatments and Risk Management Strategies

7.1. Principles and sources of recommendations

There is no treatment directed at the cause, nor a formal guideline from a scientific society dedicated to myoclonus-dystonia. The available recommendations come from GeneReviews (2020 revision), the clinical synthesis of Roze and colleagues (2018), the only randomised trial (zonisamide, 2016) and the ERN-RND systematic review of deep brain stimulation in monogenic dystonias (2026), which makes recommendations for the SGCE form [1, 5, 18, 37]. Treatment is symptomatic and stepwise: initial assessment by a movement disorder specialist and the genetics clinic, oral drugs when myoclonus or dystonia limit function, botulinum toxin for focal dystonia and deep brain stimulation when non-invasive treatments fail [1, 5]. The 2025 European survey showed that botulinum toxin and deep brain stimulation were considered more effective than oral drugs but were little used, and that formal psychiatric assessment was rare despite the frequency of symptoms [44].

No drug is authorised for myoclonus-dystonia in the USA or the European Union; all the uses described below are off-label, and the doses come from the zonisamide trial or, in the absence of disease data, from the labels of analogous indications (myoclonic seizures, focal epilepsy, cervical dystonia), which constitutes an extrapolation [18, 47–49].

7.2. Oral drugs

Zonisamide is the only drug with class I evidence. In the double-blind, placebo-controlled crossover trial of Hainque and colleagues, 24 patients received zonisamide at a target dose of 300 mg/day, with six weeks of titration and three weeks at a fixed dose in each period and a five-week washout between periods; in the intention-to-treat analysis (23 patients, 11 men and 12 women), zonisamide reduced action myoclonus (median −5 points on UMRS section 4; 95% confidence limits −9.25 to −1.44; p=0.003), myoclonus-related functional disability (−2; −2.58 to −2.46, an interval published as such in the trial abstract that does not contain the median; p=0.007) and dystonia on the Burke-Fahn-Marsden movement scale (−3; −8.46 to 0.03; p=0.009), with no difference in clinical global impression (−1; −1.31 to 0.09; p=0.1), and was well tolerated [18]. The mechanism of action relevant to myoclonus has not been established; in the summary of product characteristics (SmPC), zonisamide, an antiepileptic drug with a sulfonamide structure, is described as acting on voltage-dependent sodium and calcium channels [47]. In practice, the response is variable: in the Spanish and Dutch paediatric cohort, 12 of 38 children took zonisamide and discontinuation for lack of efficacy or adverse effects was frequent, and in the Portuguese case zonisamide brought no benefit [15, 43].

Clonazepam mainly improves myoclonus and tremor [1]. Valproate and levetiracetam may be used for myoclonus; topiramate and carbamazepine have been described as useful in individual patients [1]. Anticholinergics, such as trihexyphenidyl, may improve dystonia [1]. With evidence only from series or case reports, improvements have also been described with L-5-hydroxytryptophan, levodopa, tetrabenazine, zolpidem (one case), gamma-hydroxybutyrate and sodium oxybate [1]. In a Saudi family with the c.341-2A>G variant, a 13-year-old girl with disabling refractory axial dystonic spasms and myoclonus showed improvement in axial dystonia, less so in myoclonus, and in quality of life with sodium oxybate 1 g twice daily, with three years of follow-up [50]. In the paediatric cohort, the drugs most used were zonisamide (12), clonazepam (12), levodopa (9), trihexyphenidyl (8), levetiracetam (5) and piracetam (2), in 22 of the 38 children (58%) [43].

7.3. Botulinum toxin

Botulinum toxin is useful in cervical dystonia and focal limb dystonia [1]. Doses follow the cervical dystonia labels, the closest approved indication. According to the Portuguese SmPC for Botox®, the first session should not exceed 200 units in total, with a maximum of 50 units per site and 100 units in the sternocleidomastoid, avoiding bilateral injection of this muscle; the maximum per session is 300 units, the minimum interval between sessions is 10 weeks, the effect begins in about 2 weeks, peaks at 6 and usually lasts 12 weeks; the SmPC sets 12 years as the minimum age for this indication [49]. In the US label, the mean dose in the cervical dystonia trial was 236 units (25th–75th percentiles: 198–300), and limiting the sternocleidomastoid dose to 100 units reduces dysphagia; the boxed warning refers to distant spread [57]. For Dysport®, the initial dose in adult cervical dystonia is 500 units, with retreatment between 250 and 1000 units at intervals of at least 12 weeks; the units of the different products are not interchangeable [58]. In Portugal, Botox® and Xeomin® are available [59].

7.4. Alcohol

Alcohol reduces symptoms, but the risk of dependence makes it unacceptable as a treatment [1]. Self-medication is frequent and explains part of the alcohol dependence observed in symptomatic carriers, and counselling on alcohol use is part of treatment, especially in adolescents [1, 3].

7.5. Deep brain stimulation

Deep brain stimulation is the treatment with the greatest reported effect in patients with refractory disability. The ERN-RND systematic review, published in 2026, gathered 1544 patients with monogenic dystonia attributable to a gene, of whom 196 (12.7%) had an SGCE variant [5]. In 22 patients with individual scores before and after surgery (20 with stimulation of the globus pallidus internus and 2 of the ventral intermediate nucleus of the thalamus), the median improvement on the Burke-Fahn-Marsden motor scale was 71.8% (interquartile range 57.2–76.6); 18 (81.8%) were good responders, 4 of them with improvement above 80%, 3 were partial responders and 1 a non-responder, a woman operated on at 42 years, with onset at 12, prior exposure to first-generation antipsychotics and electrode revision [5]. For myoclonus, the 16 patients assessed were all good responders, with a median UMRS improvement of 67.5% (interquartile range 56–78.9), and the benefit was maintained for 7 to 20 years in the 7 patients with long follow-up [5]. The ERN-RND recommendation is pallidal stimulation for generalised or segmental dystonia and myoclonus due to SGCE, after non-invasive treatments have not brought sufficient improvement, with case-by-case decision and systematic assessment before and after surgery (at least one dystonia scale, one scale for each other movement disorder present and one patient-reported scale) [5].

Individual studies agree with this synthesis. In nine patients with pallidal stimulation followed for 8.7 ± 3.1 years, myoclonus improved by 94.1% ± 4%, dystonia by 71.4% ± 28.3%, motor disability by 88.3% ± 20% and involuntary movements by 71.1% ± 15%, without speech or gait disturbances or permanent adverse effects, and eight of the nine had full social adjustment [60]. In the individual patient data meta-analysis of 71 patients from 31 studies, the UMRS improved by 79.5% ± 18.2%, 94.1% of patients had myoclonus improvement above 50%, results were better with later onset and shorter disease duration, and the globus pallidus internus was associated with fewer stimulation-induced effects than the thalamus [61]. In seven patients operated on in the thalamus (ventral intermediate nucleus) alone or combined with the pallidum, myoclonus improved by 62% in the short term and 68% between 5 and 20 years, cervical dystonia by 54%, and global dystonia improved in a sustained way only with the pallidal target, which led the authors to prefer the globus pallidus internus [62]. GeneReviews also mentions five patients with predominant myoclonus, three with an SGCE variant, with sustained improvement over 50 months with thalamic stimulation [1].

In children and adolescents, a series of 10 patients with an SGCE variant, operated on at 12.8 ± 3.4 years (none before 9), showed on blinded assessment improvements of 68.1% in myoclonus, 63.2% in generalised dystonia, 48.1% in writing, 70.3% in gait and 44.2% in running, after 3.8 ± 2.4 years, with psychiatric stability and reduced anxiety, fatigue and stigma; there were three device-related adverse events (two atrophic scars and one wound infection with Cutibacterium acnes), resolved with further surgery, and no potentially fatal complications [32]. The parameters used were generally between about 1.9 and 3.5 mA, 60 to 80 µs and 120 to 200 Hz [32].

The psychiatric effect deserves monitoring. In a French series of five patients, the median improvement was 85% in dystonia and 83% in myoclonus at 6–9 months, without psychiatric adverse effects over 18 months; in a Dutch series of five patients, four had worsening of untreated pre-existing psychiatric disorders despite motor improvement, and the authors recommended psychiatric assessment before and after surgery [3]. Stereotactic thalamotomy improved myoclonus in older cases, but with dysarthria in one patient and mild hemiparesis in another, and without functional gain in two more, so it is no longer a usual option [1]. In the other forms of the class, pallidal stimulation gave a good response in the KCTD17 form, with limited long-term data, and conflicting results in the KCNN2 form: insufficient effect in one patient and prolonged efficacy in another [12, 19, 20].

The zonisamide trial is small, short and crossover, and the improvement in motor scales was not accompanied by a difference in clinical global impression; there are no comparative trials between drugs [18]. Deep brain stimulation data come from series and case reports (about 70% of the studies included in the ERN-RND review), without a control group, with heterogeneous scales and probable publication bias, and percentages from different studies should not be compared directly [5]. A search of ClinicalTrials.gov on 1 November 2026 found no active therapeutic trials specific to myoclonus-dystonia; the registered studies were observational [63, 64].

7.6. Regulatory status

It was not possible to consult the drug label database of the Brazilian Health Regulatory Agency (ANVISA) for these drugs; the sources consulted do not describe their registration status in Brazil.

7.7. Developments in the last 12 months

Between 2025 and 2026, up to the reference date of 1 November 2026, the new data were mainly observational and preclinical. The ERN-RND systematic review (2026) formalised the recommendation of pallidal stimulation in the SGCE form [5]. The paediatric pallidal stimulation series (2025) extended the favourable results to patients operated on in childhood and adolescence [32]. The prospective paediatric study of De Francesch and colleagues (2025) documented annual worsening in childhood, an argument for earlier intervention [43]. Krygier and colleagues (2026) compared the three genetic forms of the class and added new KCTD17 and KCNN2 families [12]. A new missense variant with co-segregation in 10 affected individuals was published in 2026 [33]. At the preclinical level, stem cell-derived GABAergic interneurons with SGCE variants showed reduced network activity [39], and a positron emission tomography study identified alterations of motor and cerebellar metabolism [38]. A 2026 review summarised the path from gene to symptoms [65]. No medicine received an authorisation or regulatory opinion for myoclonus-dystonia in this period, according to the sources consulted.

7.8. Pregnancy, lactation and special populations

Antiepileptic drugs with teratogenic potential should be avoided in women planning a pregnancy or who are pregnant, and the therapeutic decision should be discussed before conception; abstinence from alcohol is recommended during pregnancy, especially in the first trimester [1]. With zonisamide, the SmPC recommends effective contraception during treatment and for one month afterwards, and registry data showed, compared with lamotrigine monotherapy, an increase in the proportion of low birth weight newborns from about 5% to 8%, of preterm births from about 8% to 10% and of small-for-gestational-age newborns from about 7% to 12%; the SmPC states that zonisamide should not be used in pregnancy unless clearly necessary [47]. Since 2018, valproate has been restricted in the EU to situations without an alternative and, in girls and women of childbearing potential, to a pregnancy prevention programme [54]. The MotherToBaby service is listed by GeneReviews as an information resource on drug exposure in pregnancy [1]. The sources consulted contain no data on the course of myoclonus-dystonia during pregnancy or on lactation.

In children, zonisamide has an approved paediatric dose in the EU only from 6 years and 20 kg, and the risk of oligohidrosis and heatstroke requires attention to hydration [47]. Valproate carries a higher risk of hepatotoxicity below 2 years and in POLG mitochondrial disease [53].

7.9. Perioperative care, adolescence and transition

Preoperative assessment for deep brain stimulation includes genetic testing, standardised motor scales and psychiatric assessment, given the comorbidity and the reported risk of psychiatric worsening after surgery [3, 5]. In adolescence, counselling about alcohol, detection of anxiety, OCD and ADHD and school support are components of treatment, because the European survey identified poorly recognised academic difficulties and high unemployment in adulthood [1, 43, 44]. Transition to the adult clinic should maintain annual neurological and psychiatric surveillance [1].

8. Reproductive Options and Family Counselling

8.1. Inheritance and parent-of-origin-dependent penetrance

SGCE myoclonus-dystonia is transmitted in an autosomal dominant manner, but penetrance depends on the parent transmitting the variant: the paternal allele is expressed and causes disease in most carriers, whereas the maternal allele is silenced and usually does not cause disease [1]. Most probands inherited the variant from a heterozygous parent, who may or may not have signs depending on the sex of the transmitting grandparent [1]. In the 2006 French series, penetrance was complete in paternal transmissions and nil in maternal ones [3]; in other families, about 5% of those who inherit the variant from the mother become symptomatic, sometimes more mildly [1], and in a large family 3 of 12 carriers (25%) had no symptoms [14]. Variability within the same family is wide, with milder pictures in women and fuller pictures in men in a recent French family [33].

8.2. Recurrence risks by scenario

8.3. Parental evaluation and cascade testing

In a proband without a family history, testing of both parents is recommended, starting with the father, because an apparently negative family history often results from imprinting or from failure to recognise symptoms [1]. A family history of alcoholism may indicate affected relatives who self-medicate [1]. De novo variants are rare, with only three cases described by 2020 [1]. In the Portuguese case, the variant had been inherited from the father, who was asymptomatic, and the mother did not carry it, a pattern explained by maternal transmission of the variant in the previous generation or by incomplete penetrance [15]. Cascade testing should follow the paternal line of transmission, because it is in the offspring of male carriers that the risk of disease is high [1]. If the variant is not found in either parent, there may be non-medical explanations, such as non-paternity or non-maternity or adoption, which should be addressed with care [1].

8.4. Contiguous deletions and uniparental disomy

In 7q21 deletions, the risk depends on whether the deletion is de novo or inherited, and the clinical consequences of a paternal deletion include the extraneurological features; the sources consulted do not provide specific recurrence risks [1, 34]. In maternal uniparental disomy of chromosome 7, counselling incorporates that for the associated Silver-Russell syndrome, and the sources consulted do not provide specific recurrence risks [28, 36]. The KCTD17 and KCNN2 forms follow autosomal dominant inheritance with no described parent-of-origin effect, with a 50% risk for offspring [6, 8].

8.5. Reproductive options and counselling of minors

Genetic counselling should take place before pregnancy and include affected or at-risk young adults [1]. When the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; their usefulness is greater when the carrier parent is the father, but no test predicts age at onset, severity or progression [1, 26]. Testing of asymptomatic minors raises the usual issues of disorders with variable onset; in myoclonus-dystonia, onset is usually in childhood and effective symptomatic treatments exist, but the sources consulted make no specific recommendation on predictive testing of asymptomatic minors.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

The prevalence of myoclonus-dystonia is not well established. Orphanet gives for Europe a point prevalence class of 1 to 9 per 1,000,000, without an exact value [2]. A 2025 European article cites an estimate of about 2 per 1,000,000 in Europe, based on earlier studies [15]. The frequency of SGCE variants predicted to be deleterious in gnomAD (about 1 in 348 people in the USA with a CADD score of at least 25) does not measure the prevalence of the disease, because many of these variants are not pathogenic and maternally derived carriers have no symptoms; the authors nevertheless suggest that the disease is underdiagnosed [16]. For comparison, the prevalence of dystonia in general lies between 127 and 329 per million, probably an underestimate [26].

9.2. Geographical distribution and populations studied

Families of many origins have been described, including mixed European, German, Irish, Turkish, Brazilian and Canadian [1]. The main series come from France, Germany, the Netherlands, the UK and Ireland, Spain and the USA [3, 17, 34, 43]. The frequency of SGCE among the genetic causes of dystonia, in a large exome series of mostly European and North American patients, was 12 index cases among 153 with a diagnosis [41]. In the ERN-RND review, SGCE accounted for 12.7% of patients with monogenic dystonia treated with deep brain stimulation [5]. No SGCE founder variants have been described in the sources consulted. In Portugal, the case of a child followed in Porto has been published [15]; the sources consulted contain no Portuguese or Brazilian epidemiological data, which does not mean that none exist.

9.3. Special populations

Children are the group in which the disease manifests and in which annual worsening has been documented, and detection of neurodevelopmental and psychiatric disorders (anxiety, OCD, ADHD) is part of follow-up [43]. Women of reproductive age require a choice of drugs compatible with pregnancy planning [1, 54]. Adolescents are at particular risk of self-medication with alcohol [1].

9.4. Reference networks and patient organisations

The relevant European reference network is ERN-RND, with its group for dystonias, paroxysmal disorders and neurodegeneration with brain iron accumulation (NBIA) [21]. ERN-RND promoted the European survey of neurologists, patients and carers and the systematic review of deep brain stimulation [5, 44]. Dystonia Europe brings together national patient associations and took part in the European survey [44, 66]. GeneReviews lists the Dystonia Medical Research Foundation, Dystonia UK, the National Institute of Neurological Disorders and Stroke (NINDS) and the Global Dystonia Registry as resources [1].

10. Illustrative Clinical Case

Pissarra and colleagues, from Porto, published in 2025 the case of a girl referred to the paediatric neurology clinic at 2 years of age, in March 2022, for involuntary movements noticed since 12 months [15]. The movements were sudden and transient, affected the neck and upper limbs, occurred during wakefulness, especially while eating or playing, and were not accompanied by loss of consciousness. The perinatal history was normal, as was psychomotor development (walking at 18 months), and the family history included a maternal cousin with a neuromuscular disease and another with chronic motor tics [15].

At 2 years, examination showed spontaneous multifocal myoclonus, predominantly in the neck, shoulders and upper limbs; dystonia was not recognised at that time, although retrospective review of the videos showed a mild dystonic posture of the upper limbs [15]. Video-electroencephalography recorded dozens of episodes of multifocal positive myoclonus lasting 100 to 200 ms, without an electroencephalographic correlate, and brain magnetic resonance imaging was normal [15]. Laboratory investigation showed normal thyroid function (thyroid-stimulating hormone 1.37 µIU/ml; free thyroxine 1.05 ng/dl) with negative antithyroid antibodies, ammonia 56 µmol/l, caeruloplasmin 18.8 mg/dl (reference 21.7–43.3), creatine kinase 83 U/l, aspartate aminotransferase 44 U/l (reference below 36), alanine aminotransferase 15 U/l, lactate dehydrogenase 282 U/l, and normal amino acids, organic acids, acylcarnitines, pyruvate (0.09 mmol/l) and lactate (0.6 mmol/l) [15].

Clinical exome sequencing identified the heterozygous variant NM_003919.3:c.158C>G p.(Ser53Ter) in SGCE, classified as pathogenic; the mother did not carry the variant and the asymptomatic father was a carrier [11, 15]. At 3 years, the myoclonus became mainly action-induced, while drawing and eating; zonisamide and carbamazepine brought no benefit [15]. At 5 years, assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) gave a verbal intelligence quotient of 99, performance of 92 and full scale of 95; the child had hyperactivity and distractibility, cervical and upper limb action myoclonus and, while drawing, laterocollis and mirror dystonia of the contralateral limb, as well as dystonic postures of one upper limb and reduced arm swing when walking and running [15]. Valproate had no effect and clonazepam caused agitation and worsening of myoclonus, so it was stopped; the child began follow-up with psychology [15]. At 6 years, the parents reported less frequent and more subtle myoclonus, without significant interference with daily activities, with worsening during intercurrent infections; it was agreed to try other drugs or other options if functional disability arose [15]. The article includes a video (video 1) documenting the myoclonus and dystonia at different points of follow-up; no static figures were published [15].

The case illustrates the very early onset, the difficulty of recognising dystonia in the young child, inheritance from an asymptomatic father and the poor and variable response to oral drugs. The authors stress that the response to alcohol, an important clue in adolescents and adults, has no role in childhood, and that the later appearance of behavioural problems warrants psychiatric and neurodevelopmental surveillance [15]. The lack of response to zonisamide in this case contrasts with the average result of the adult trial and is consistent with the frequent discontinuation of drugs described in the paediatric cohort [18, 43].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Life expectancy is normal and most adults maintain an active life [1]. The course varies: there are spontaneous remissions, mainly of limb dystonia in childhood or adolescence, and there is gradual progression with functional disability and early retirement [1]. In childhood and adolescence, the prospective study of 38 patients showed a mean annual worsening of 1.356 points on the action UMRS, 0.226 on the Burke-Fahn-Marsden scale and 0.518 on the writer’s cramp scale [43]. In the European survey, the disease limited the daily activities of 80% of participants and unemployment was high [44]. Psychiatric comorbidity, present in about two thirds of symptomatic carriers, weighs on the functional prognosis [1, 17]. With pallidal stimulation, the motor benefit is maintained for up to 20 years in patients with long follow-up and is accompanied by good social adjustment in most [5, 60]. In the KCTD17 form, dystonia tends to progress and generalise, and in the KCNN2 form myoclonus and tremor become disabling in some patients [12].

11.2. Surveillance

Annual neurological and psychiatric follow-up is the GeneReviews recommendation; the other intervals apply the same periodicity to the dimensions identified in recent cohorts, without a validated protocol [1, 43]. Patients with deep brain stimulation are followed by the centre that operated on them for programming and device checks, with reassessment of motor scales and psychiatric status [3, 5].

12. Summary and Final Considerations

SGCE-related myoclonus-dystonia is a combined dystonia usually beginning in the first decade, in which brief myoclonic jerks of the neck, trunk and upper limbs predominate over a focal or segmental dystonia, usually cervical or in the form of writer’s cramp [1, 37]. The response of symptoms to alcohol and psychiatric comorbidity, particularly OCD, phobias, anxiety and alcohol dependence, complete the picture and influence the functional prognosis as much as the motor manifestations [1, 17]. The cause is loss of function of epsilon-sarcoglycan, encoded by a maternally imprinted gene: almost all carriers who inherit the variant from the father become ill, and only a small fraction of those who inherit it from the mother, which explains the apparently skipped generations, the asymptomatic parents and the need to consider the sex of the parent in every risk calculation [1, 13, 24].

Diagnosis rests on clinical suspicion guided by the criteria of Roze and colleagues and on molecular confirmation by panel, exome or genome with deletion/duplication analysis, supplemented by microarray and chromosome 7 studies when there are syndromic features [1, 37]. Only about half of patients with the clinical phenotype have an SGCE variant, and the class includes the KCTD17 form, with progressive craniocervical dystonia and no response to alcohol, the KCNN2 form, with rapid tremor, cerebellar signs and cognitive impairment, and the DYT15 locus still without a gene [1, 12]. The abundance of rare SGCE variants in the population requires co-segregation studies before attributing causality to missense variants [16].

Treatment is symptomatic. Zonisamide is the only drug with randomised trial evidence, but the individual response is variable; clonazepam, levetiracetam, valproate, anticholinergics and botulinum toxin have a complementary role, almost always off-label, and alcohol should be discouraged [1, 18]. Stimulation of the globus pallidus internus, recommended by ERN-RND for disabling myoclonus and dystonia that do not respond to non-invasive treatments, produces median improvements of the order of 70% in dystonia and myoclonus, sustained for up to two decades, including in children and adolescents [5, 32, 60]. The demonstration that the disease worsens during childhood and the frequency of psychiatric and school difficulties justify annual neurological and psychiatric surveillance, educational support and counselling about alcohol from adolescence [1, 43, 44].

13. References

1. Raymond D, Saunders-Pullman R, Ozelius L. SGCE Myoclonus-Dystonia. 2003 May 21 [updated 2019 Aug 8; revised 2020 Jun 4]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1414/
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