The present study expands previous findings of the presence of dystonia in a considerable number of relatives of index patients with MD with an autosomal dominant pattern of transmission.12
Affected relatives were identified both of index FH+ and FH− patients. Although none of the 14 FH− index patients reported any cases of dystonia in their families, 5 of them (36%) had affected relatives with dystonia on clinical examination. Several clinical studies on other forms of focal dystonia based on examination of family members revealed similar numbers of familial cases (23% to 27%).5-7
MD, however, has long served as a textbook example of a purely occupational dystonia, even more so than other forms of FTSD such as WC. Due to the large number of familial cases observed also in MD, the concept of MD as a sporadic and solely environmentally acquired type of dystonia needs to be reconsidered.
The present study focuses on clinical genetic data of MD based upon systematic family history taking and neurologic examination of both index patients and relatives. This approach resulted in a significant increase of familial cases compared to previous data based on family history interview,1
clearly indicating that the family history method is of limited use in genetic studies of primary adult-onset dystonia including MD.
The detection of a larger number of affected relatives in the present study compared to previous reports is largely the result of systematic history taking with the BIDS. Although superior to family history alone, we cannot fully exclude that a case with dystonia was not detected with the BIDS. While the utility of the BIDS as a screening tool was previously described to identify family members with cervical dystonia only,13
it is a computer-assisted telephone interview designed to detect many forms of dystonia. The present study demonstrated that the BIDS appears to be an excellent screening instrument also for genetic studies of FTSD but further validation is advisable.
An important goal for genetic studies of all types of focal dystonia is ascertainment and examination of as many affected cases as possible. The complex rating procedure of the videos was employed to ensure accurate diagnosis of dystonia. Establishing a diagnosis of MD requires specific expertise including experience in professional instrument playing. In some cases, a diagnosis is based only on hearing of subtle changes of complex sensorimotor skills, making it difficult to diagnose MD in some cases even for movement disorder specialists.
The majority of affected relatives had FTSD including MD and WC. Interestingly, most of them were not aware of the presence of dystonia, although all reported symptoms such as technical problems when playing an instrument or difficulties when writing. Only 7 of the 19 cases were previously diagnosed with dystonia. In addition, few relatives related their difficulties during motor performance to the dystonia of the index patients.
Surprisingly, a considerable number of identified patients with MD or WC displayed additional types of dystonia. In addition, an unexpected number of other hypokinetic and hyperkinetic movement disorders, some of them unusual, were present in a considerable number of participants. As a broad intrafamilial and interfamilial phenotypic spectrum is known for many genetic movement disorders, it is tempting to speculate that at least part of the observed additional movement disorders in our patients are due to a shared underlying genetic cause.
In a similar vein, the intrafamilial accumulation of MD and WC found in our families raises the question whether these disorders are indeed related or distinct entities. Recent studies comparing MD and WC patients using transcranial magnetic stimulation suggested pathophysiologic differences between the two conditions.16,17
Given a possible common genetic cause of MD and WC in at least a subset of patients as confirmed by the present study, however, these neurophysiologic differences could be interpreted as a secondary rather than a primary phenomenon.
Several environmental risk factors have been described as potential triggers for the development of MD, such as an increase of practice time spent on the instrument,1,3
or local pain or intensified sensory input due to various causes1,3,18
before the onset of dystonia. On the basis of a given, most probably genetic susceptibility, these factors were hypothesized to trigger the manifestation of MD.19
Triggers for the development of a genetic movement disorder have recently been identified in patients with rapid-onset dystonia-parkinsonism (DYT12
Although in our families some patients reported the aforementioned triggers before the onset of dystonia, no significant difference was observed compared to the unaffected family members, some of whom also reported potential triggers at different times of their lives. In view of these findings and the fact that triggers may be subject to substantial recall bias, the role of potential triggers in the pathophysiology of MD should be revisited.
Based on the results of the present study, our main hypothesis is that at least some cases of MD, other forms of FTSD, and possibly even other types of movement disorders may have a shared underlying genetic cause. A recent review article addressed the question whether the various types of focal dystonia may have a common etiologic background.21
Interestingly, available clinical genetic studies indicated that all types of focal dystonia are likely related disorders that share a common etiologic, most probably genetic background.21
Not surprisingly, none of our patients carried the GAG deletion in the DYT1
gene, which has only rarely been linked to focal dystonia.8
Owing to the relatively small number of affected family members, linkage to the DYT7
gene locus that has been described in two families with focal dystonia10,11
could not be definitively excluded in all but one family. To perform meaningful linkage analyses, the identification of large families with MD/FTSD suitable for a classic genome scan is needed. In addition, modern methods of genome-wide linkage in large numbers of MD/FTSD cases may lead to the identification of the genetic factors that cause or contribute to focal dystonia, the most common form of dystonia.