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Delayed Diagnoses of SGCE Myoclonus-Dystonia.

ABSTRACT: Background:Myoclonus-dystonia due to SGCE mutations (OMIM: 159900) most commonly presents during childhood with mainly upper body myoclonus, and mild dystonia affecting the neck and arms. Case reports:Herein, we report patients misdiagnosed during childhood with Tourette syndrome and dyskinetic cerebral palsy, and, during adulthood, found to harbor SGCE frameshift mutations. Discussion:Myoclonus-dystonia may be underdiagnosed due to phenotypic misclassification during childhood. SGCE mutations should be included in the differential diagnosis of childhood movement disorders that ostensibly manifest with tics, myoclonus, or abnormal posturing secondary to dystonia and/or spasticity. Highlights:Due to pleiotropy, variable penetrance, broad differential, and hereditary effects of imprinting, the diagnosis of a disorder of childhood onset, myoclonus-dystonia due to SGCE mutations, may be delayed until adulthood, often compromising appropriate clinical management and genetic counseling.

SUBMITTER: Varga MG

PROVIDER: S-EPMC7394200 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Delayed Diagnoses of <i>SGCE</i> Myoclonus-Dystonia.

Varga M Georgeta MG Nand Nikita P NP LeDoux Mark S MS

Tremor and other hyperkinetic movements (New York, N.Y.) 20200728

<h4>Background</h4>Myoclonus-dystonia due to <i>SGCE</i> mutations (OMIM: 159900) most commonly presents during childhood with mainly upper body myoclonus, and mild dystonia affecting the neck and arms.<h4>Case reports</h4>Herein, we report patients misdiagnosed during childhood with Tourette syndrome and dyskinetic cerebral palsy, and, during adulthood, found to harbor <i>SGCE</i> frameshift mutations.<h4>Discussion</h4>Myoclonus-dystonia may be underdiagnosed due to phenotypic misclassificatio ...[more]

PMID: 32775037

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Project description:Loss-of-function mutations in SGCE, which encodes ε-sarcoglycan (ε-SG), cause myoclonus-dystonia syndrome (OMIM159900, DYT11). A "major" ε-SG protein derived from CCDS5637.1 (NM_003919.2) and a "brain-specific" protein, that includes sequence derived from alternative exon 11b (CCDS47642.1, NM_001099400.1), are reportedly localized in post- and pre-synaptic membrane fractions, respectively. Moreover, deficiency of the "brain-specific" isoform and other isoforms derived from exon 11b may be central to the pathogenesis of DYT11. However, no animal model supports this hypothesis. Gene-trapped ES cells (CMHD-GT_148G1-3, intron 9 of NM_011360) were used to generate a novel Sgce mouse model (C57BL/6J background) with markedly reduced expression of isoforms derived from exons 3' to exon 9 of NM_011360. Among those brain regions analyzed in adult (2month-old) wild-type (WT) mice, cerebellum showed the highest relative expression of isoforms incorporating exon 11b. Homozygotes (SgceGt(148G1)Cmhd/Gt(148G1)Cmhd or SgceGt/Gt) and paternal heterozygotes (Sgcem+/pGt, m-maternal, p-paternal) showed 60 to 70% reductions in expression of total Sgce. Although expression of the major (NM_011360) and brain-specific (NM_001130189) isoforms was markedly reduced, expression of short isoforms was preserved and relatively small amounts of chimeric ε-SG/β-galactosidase fusion protein was produced by the Sgce gene-trap locus. Immunoaffinity purification followed by mass spectrometry assessments of Sgcem+/pGt mouse brain using pan- or brain-specific ε-SG antibodies revealed significant reductions of ε-SG and other interacting sarcoglycans. Genome-wide gene-expression data using RNA derived from adult Sgcem+/pGt mouse cerebellum showed that the top up-regulated genes were involved in cell cycle, cellular development, cell death and survival, while the top down-regulated genes were associated with protein synthesis, cellular development, and cell death and survival. In comparison to WT littermates, Sgcem+/pGt mice exhibited "tiptoe" gait and stimulus-induced appendicular posturing between Postnatal Days 14 to 16. Abnormalities noted in older Sgcem+/pGt mice included reduced body weight, altered gait dynamics, and reduced open-field activity. Overt spontaneous or stimulus-sensitive myoclonus was not apparent on the C57BL/6J background or mixed C57BL/6J-BALB/c and C57BL/6J-129S2 backgrounds. Our data confirm that mouse Sgce is a maternally imprinted gene and suggests that short Sgce isoforms may compensate, in part, for deficiency of major and brain-specific Sgce isoforms.

Dataset Information

Delayed Diagnoses of SGCE Myoclonus-Dystonia.

Publications

Delayed Diagnoses of <i>SGCE</i> Myoclonus-Dystonia.

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