Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes

Service de Biostatistique et Information Medicale, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
Journal of Medical Genetics (Impact Factor: 6.34). 06/2006; 43(5):394-400. DOI: 10.1136/jmg.2005.036780
Source: PubMed


Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21.
We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested.
Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders.
This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

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Available from: Philippe Damier, Oct 04, 2015
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    • "Both nonsense and missense mutations have been found in DYT11 M-D patients. The missense mutations usually result in a shift of translational reading frame and introduce premature termination codon [3], [11]. Several SGCE missense mutations in extracellular domain of ε-SG impair membrane trafficking of the mutant proteins in cultured cells [12]. "
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    ABSTRACT: DYT11 myoclonus-dystonia (M-D) syndrome is a neurological movement disorder characterized by myoclonic jerks and dystonic postures or movement that can be alleviated by alcohol. It is caused by mutations in SGCE encoding ε-sarcoglycan (ε-SG); the mouse homolog of this gene is Sgce. Paternally-inherited Sgce heterozygous knockout (Sgce KO) mice exhibit myoclonus, motor impairment and anxiety- and depression-like behaviors, modeling several clinical symptoms observed in DYT11 M-D patients. The behavioral deficits are accompanied by abnormally high levels of dopamine and its metabolites in the striatum of Sgce KO mice. Neuroimaging studies of DYT11 M-D patients show reduced dopamine D2 receptor (D2R) availability, although the possibility of increased endogenous dopamine, and consequently, competitive D2R occupancy cannot be ruled out. The protein levels of striatal D2R, dopamine transporter (DAT), and dopamine D1 receptor (D1R) in Sgce KO mice were analyzed by Western blot. The striatal dopamine release after amphetamine injection in Sgce KO mice were analyzed by microdialysis in vivo. The striatal D2R was significantly decreased in Sgce KO mice without altering DAT and D1R. Sgce KO mice also exhibited a significant increase of dopamine release after amphetamine injection in comparison to wild-type (WT) littermates. The results suggest ε-SG may have a role in the regulation of D2R expression. The loss of ε-SG results in decreased striatal D2R, and subsequently leads to increased discharge of dopamine which could contribute to the behavioral impairment observed in DYT11 dystonia patients and in Sgce KO mice. The results suggest that reduction of striatal D2R and enhanced striatal dopamine release may contribute to the pathophysiology of DYT11 M-D patients.
    PLoS ONE 03/2012; 7(3):e33669. DOI:10.1371/journal.pone.0033669 · 3.23 Impact Factor
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    • "Myoclonus could only be detected in both adult patients. Because M–D has been shown to have an almost complete penetrance after paternal transmission by the age of 25 years, patient 3 is still at risk of developing M–D in the future (Asmus et al., 2002; Tezenas du Montcel et al., 2006). "
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    ABSTRACT: Myoclonus-dystonia (M-D, DYT11) is a dystonia plus syndrome characterized by brief myoclonic jerks predominantly of neck and upper limbs in combination with focal or segmental dystonia. It is caused by heterozygous mutations of the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21.3. We present three patients with heterozygous large deletions in the 7q21.13-21.3 region. By quantitative analysis of single nucleotide polymorphism (SNP) oligonucleotide arrays, the deletion size was determined to range from 1.63 to 8.78 Mb. All deletions contained the maternally imprinted SGCE gene and up to 43 additional neighbouring genes. Two of the patients presented with typical M-D, whereas one paediatric patient with split-hand/split-foot malformation and sensorineural hearing loss (SHFM1D, OMIM 220600) had not developed M-D at the age of 9 years. This patient had the largest deletion of 8.78 Mb (7q21.13-21.3) containing also SHFM1, DLX6 and DLX5, which had been previously shown to be deleted in SHFM1D. In two patients, the deletions removed the paternal allele of the KRIT1 gene, which is a major cause of cavernous cerebral malformations type 1 (CCM1). Only the adult patient showed asymptomatic cavernous cerebral malformations on cranial MRI, underlining age-dependent penetrance and haploinsufficiency as pivotal features of patients with KRIT1 mutations. All three deletions contained the COL1A2 gene. In contrast to dominant negative point mutations, which cause osteogenesis imperfecta with bone fractures, haploinsufficiency of COL1A2 resulted only in subtle symptoms like recurrent joint subluxation or hypodontia. Assessing copy number variations by SNP arrays is an easy and reliable technique to delineate the size of human interstitial deletions. It will therefore become a standard technique to study patients, in whom heterozygous whole gene deletions are detected and information on neighbouring deleted genes is required for comprehensive genetic counselling and clinical management.
    Brain 11/2007; 130(Pt 10):2736-45. DOI:10.1093/brain/awm209 · 9.20 Impact Factor
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