GAG deletion in the DYT1 gene in early limb-onset idiopathic torsion dystonia in Germany

TheDYT1 GAG deletion is infrequent in sporadic and familial writer's cramp

“…Although focal hand dystonia is more likely to be associated with the GAG deletion than other focal dystonia subtypes, 4,5,8,9 our data further confirm previous findings [3][4][5][6]9 that this mutation only rarely manifests as focal dystonia. To our knowledge, only six mutation carriers with focal dystonia other than writer's cramp have been reported to date: cervical dystonia and laryngeal dystonia, 9 cervical dystonia, 7 postural hand tremor, 14 stutter, 14 and involuntary movements of the lower face.…”

“…Presuming that the GAG deletion acts in a dominant-negative manner, the underlying molecular mechanism might be disruption of an oligomeric protein complex. 13 The phenotypic spectrum of this mutation has been delineated in North American, 3 British, 4 French, 5 German, 6,7 and Russian 14 patients with dystonia, thus extending the originally described phenotype of the Ashkenazi Jewish founder population. 9 This includes spread of symptoms with involvement of craniocervical, especially cranial, muscles (after limb onset), which is not unusual in European patients.…”

“…This mutation accounts for most cases of typical early limb-onset primary dystonia, regardless of ethnic background. [3][4][5][6][7] It results in the loss of one of a pair of glutamic acid residues near the carboxy terminus of a novel ATP-binding protein, termed torsinA. 3 This protein belongs to the AAA+ superfamiliy of chaperonelike proteins 3 and is expressed selectively in specific regions of the brain underlying movement control, with highest levels in the dopaminergic neurons of the substantia nigra.…”

“…9 This includes spread of symptoms with involvement of craniocervical, especially cranial, muscles (after limb onset), which is not unusual in European patients. [4][5][6] In addition, in some patients, the mutation is associated with isolated unilateral or bilateral brachial dystonia, 4,5 particularly in familial cases of juvenile onset associated with the occurrence of "mirror movements." 8 The phenotype associated with the GAG deletion may be influenced by other modifying genes or environmental factors.…”

“…2 Recently, a GAG deletion in the DYT1 gene 3 has been found to be responsible for most cases of early-onset primary generalized dystonia in genetically distinct populations. [3][4][5][6][7] Several lines of evidence point to an association between focal hand dystonia, among other focal dystonias, and the DYT1 GAG deletion. First, this mutation was found to be responsible for juvenile onset writer's cramp associated with the occurrence of "mirror movements" in a gentile German family with five affected patients without further spread of dystonic symptoms, 8 a phenotype that is distinct from the typical early-onset, generalized dystonia seen in the Ashkenazi Jewish population with this mutation.…”