Our finding confirm that SGCE mutations can occur in sporadic patients when the phenotype is consistent with M-D. Further functional studies are needed to show how changes in SGCE protein function lead to the M-D phenotype.
The objective of this study was to assess the long-term clinical outcome, quality of life, and social adjustment of GPi-DBS in patients with ε-sarcoglycan (DYT11)-positive myoclonus-dystonia.
In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described.
Recent research has highlighted the role of the cerebellum in the pathophysiology of myoclonus-dystonia syndrome as a result of mutations in the ɛ-sarcoglycan gene (DYT11).
Our phenotypic characterization highlights the suitability of iPSC-derived cortical neurons with SGCE mutations for myoclonus-dystonia research and, in more general terms, prompts the use of iPSC-derived cellular models to study epigenetic mechanisms impacting on health and disease.
Physical symptoms of myoclonus dystonia due to epsilon-sarcoglycan mutations are well documented; however, the progression of neuropsychiatric and cognitive symptoms remains unclear.
Clinical and genetic heterogeneity also characterizes myoclonus-dystonia, which includes not only the classical phenotype associated with epsilon-sarcoglycan mutations but rarely also presentation of ANO3 gene mutations, TITF1 gene mutations typically underlying benign hereditary chorea, and some dopamine synthesis pathway conditions due to GCH1 and TH mutations.
After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family.
Two siblings with M-D due to the same SGCE deletion mutation were evaluated with the Global Dystonia Rating Scale (GDRS), Fahn-Marsden Rating Scale (FM) and Unified Myoclonus Rating Scale (UMRS) on and off tetrabenazine.