SGCE – Myoclonus-Dystonia Syndrome (DYT11)

Myoclonus-dystonia syndrome (MDS, DYT11; Disease Name) is an autosomal dominant movement disorder with reduced penetrance due to maternal imprinting of the SGCE gene (Gene Symbol). It manifests in childhood or adolescence with brief, alcohol-sensitive myoclonic jerks predominantly of the neck and upper limbs, often combined with focal or segmental dystonia (HP:0001336; HP:0001332) ({PMID:12325078}).

Genetic evidence for the SGCE–MDS association is robust and definitive. Heterozygous loss-of-function SGCE variants have been identified in over 24 affected individuals across 9 unrelated families with clear cosegregation of mutations and phenotype, and consistent paternal transmission due to maternal imprinting ({PMID:12325078}; {PMID:12444570}). Large multiexonic deletions and point mutations spanning nonsense, frameshift, splice-site, and missense changes confirm haploinsufficiency as the primary pathogenic mechanism.

The variant spectrum includes recurrent founder and hotspot alleles such as c.942C>A (p.Tyr314Ter) in a French twin pedigree ({PMID:19147379}), c.289C>T (p.Arg97Ter), and multiple other truncating and splicing mutations. Large 7q21 microdeletions encompassing SGCE have been reported in patients with additional features (short stature, microcephaly, intellectual disability) emphasizing phenotypic variability ({PMID:20425829}).

Phenotypic expressivity is wide, with onset typically in childhood but ranging from infancy to adulthood. While myoclonus and dystonia are universal, up to 30% of mutation carriers develop seizures (febrile, absence, or generalized tonic-clonic), and neuropsychiatric comorbidities (anxiety, depression, OCD) are seen in >60% of adults ({PMID:24297365}; {PMID:23332219}). Sporadic cases harbor SGCE mutations in 30–50% of genetically undiagnosed patients.

Functional studies corroborate the clinical phenotype: imprinting analyses demonstrate exclusive expression of the paternal SGCE allele in affected individuals, with methylation of the maternal allele ({PMID:12444570}). Human iPSC-derived cortical neurons carrying SGCE mutations exhibit increased intrinsic excitability and disrupted synaptic adhesion molecule expression ({PMID:36204995}), while Sgce mutant mice display impaired striatal long-term depression that is corrected by adenosine A2A receptor inhibition ({PMID:28823931}).

Therapeutically, deep brain stimulation of the globus pallidus internus yields significant and sustained improvement in myoclonus and dystonia, even in long-standing disease, and anticholinergics or sodium oxybate may benefit select patients.

References

• Annals of Neurology • 2002 • Myoclonus-dystonia syndrome: epsilon-sarcoglycan mutations and phenotype. PMID:12325078
• European Journal of Paediatric Neurology • 2009 • Myoclonus in fraternal twin toddlers: a French family with a novel mutation in the SGCE gene. PMID:19147379
• American Journal of Human Genetics • 2002 • Evidence that paternal expression of the epsilon-sarcoglycan gene accounts for reduced penetrance in myoclonus-dystonia. PMID:12444570
• Brain • 2023 • Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia. PMID:36204995
• Neurobiology of Disease • 2017 • Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition. PMID:28823931

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