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- PATIENTS AND METHODS
Myoclonus–dystonia syndrome (MDS) is an inherited movement disorder with clinical and genetic heterogeneity. The epsilon sarcoglycan (SGCE) gene is an important cause of MDS. We report the results of a clinical and genetic study of 20 patients from 11 families. We disclosed six novel and two previously described mutations in nine families. The majority of patients had a phenotype of myoclonus and dystonia in combination, but clinical findings considered atypical, such a very early onset, distal myoclonus, and legs involvement, were detected in a significant proportion of cases. The disease course was variable, from progression to spontaneous remission of the motor symptoms. There were no obvious differences between mutation-positive and -negative cases. © 2007 Movement Disorder Society
Myoclonus–dystonia syndrome (MDS) is an inherited movement disorder with onset in childhood or adolescence. It is characterized by myoclonic jerks and dystonia in variable combination, usually being myoclonus the predominant and most disabling symptom.1 Mutations in the epsilon-sarcoglycan (SGCE) gene on chromosome 7q21 represent the most frequent genetic alteration disclosed in patients with MDS, but other genes and gene loci are known to be involved and still in a variable proportion of patients no genetic alteration can be disclosed, indicating that the disorder is genetically heterogeneous.2–6
We report the results of a clinical and genetic study in 20 patients from 11 unrelated families with MDS to further characterize the clinical spectrum.
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- PATIENTS AND METHODS
Our study confirms that the SGCE gene plays a major role in the pathogenesis of MDS: we disclosed mutations in a high proportion of families (9 of 11, 80%) while the screening of other genes known to be associated to MDS, such as DYT13 and GCH-1,4 resulted negative. The data in the literature regarding the prevalence of SGCE mutations in the different series are variable. Considering patients with MDS as defined according to the established criteria,1 recent studies on large series of patients reported a proportion of positive patients of 20%,9 29%,10 and 22%.11 The higher proportion of SGCE-positive patients in our series is due to the fact that all but one of our patients were familial cases, and it is well known that SGCE mutations are more common in patients with a positive family history.5, 7, 12 Interestingly, the only sporadic patient of our series was mutated, indicating that the absence of family history does not exclude the possibility of mutation in the SGCE gene, due to the reduced penetrance of the mutated genotype and the possible occurrence of de novo mutation as in our case.13 In our SGCE-positive families the reduced penetrance was due to the maternal imprinting of the mutated allele, even if some family members did not follow this imprinting pattern. The autosomal dominant paternal inheritance of the SGCE gene is a very is another very important factor that may help to predict the genetic status in MDS families, however this pattern of inheritance may also be seen in negative families, as in Family 9 of our series.9, 11 In this family, like in other similar reported, undetectable mutations in the SGCE gene may be postulated.7
We found 8 different SGCE mutations, six novel and two previously described. Five of the 6 new mutations are “loss of function” mutations, causing an abnormal or truncating protein, like the majority reported in patients with MDS,10 while the remaining one was a missense mutation. Missense mutations are much rarer. Recently, it has been shown that three missense mutants (H60R, H60P, L1196) produce proteins that are not correctly localized to the plasma membrane and therefore degraded by the proteasome.14
The R102X mutation appears to be one of the most common recurrent mutations, being already described in 10 families including ours from different countries.10 The IVS2–1 mutation described in a French family has been proved to be causative by determining an alternative splicing of exon 2.
The clinical presentation of our MDS patients is overall similar to previously described patients1 with no clear difference between SGCE mutation-positive and -negative cases, but some aspects of the clinical presentation are worthy to be underlined. In 4 patients the symptoms began before 1 year of age; such very early onset has been rarely described, but it may be not exceptional and MDS should be considered in the differential diagnosis of myoclonic conditions in the first year of life. Lightning myoclonic jerks with segmental distribution, involving mainly the upper body part with a predominant proximal distribution, alone or combined with dystonia, is reported to be the typical MDS presentation.7 In our series, distal myoclonus in the upper limbs was also detected in the great majority of patients, and a similar observation has been reported in a large Dutch family.15 Moreover, in 3 patients of our series we have observed an involvement of lower limbs, considered to be a rare feature of MDS.1 One patient of our series had a focal dystonia as the only manifestation of the disease; the phenotype of pure dystonia in MDS, usually a focal dystonia such as writer cramp or cervical dystonia, has been described in very few patients9, 16, 17 and may suggest a wrong diagnosis of primary dystonia.
The course of the disease was variable, from patients with a progressive course to patients in which the disease had improved or completely disappeared. Progression of the symptoms was observed in less than half of the patients, and in all cases correlated with a worsening of myoclonus only; when present dystonia remained unchanged in terms of distribution and severity. In 1 SGCE mutation-positive patient, with clinical phenotype of myoclonus only, a spontaneous remission of symptoms was observed, as already reported.18, 19 Two SGCE mutation-negative patients with onset of symptoms at age 3, showed a marked spontaneous improvement of myoclonus after age 10; the mild dystonic symptom had remained unchanged.
In some families, we observed a striking intrafamilial variability of the clinical presentation (age at onset and clinical features) and the disease course, adding evidence to the absence of genotype–phenotype correlation in SGCE patients.10
The EMG patterns of myoclonus are similar to those reported by other authors, in terms of duration of bursts, temporal profile, circumstances of occurrence and their possible combination with a dystonic activity.7, 20 The electrophysiological results provided in this study are in accordance with a subcortical origin of the myoclonus20, 21 and no difference between mutation-positive and -negative patients were found but extensive neurophysiologic investigations on larger series of mutation-positive and -negative patients may disclose aspects that would help in predicting the genetic status in the single patient and hopefully provide new insights about the pathophysiology of this disorder.