Predominant dystonia with marked cerebellar atrophy
A rare phenotype in familial dystonia
Abstract
Background: Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases.
Objective: To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy.
Methods: We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded.
Results: We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 ± 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 ± 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected.
Conclusion: We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.
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Published online: November 27, 2006
Published in issue: November 28, 2006
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We read the recent article by Le Ber et al describing a likely hereditary, new syndrome of dystonia and slowly progressive ataxia, for which they coined the term 'dystonia with cerebellar atrophy' (DYTCA). [1] Spasmodic dysphonia (SD) was the most frequent presenting feature.
A 22-year old woman with a severe case of SD was referred to our movement disorders clinic. She is the youngest member of a family with SCA17 (39/54 CAG repeats in the SCA17/TBP gene) [video will be made available as a web material when this Correspondence is published in print]. As cited by the authors, we have previously described three other members of this family who all presented with pure focal dystonia before starting to develop ataxia years later. [2] A larger study on the phenotypic spectrum of SCA17 revealed focal dystonia in 7/21 (30%) patients is in progress. (unpublished data).
Although excluded by Le Ber in their patients, SCA17 may be another example of a DYTCA-like syndrome. However, in contrast to the reported DYTCA patients, the rather mild cerebellar atrophy in our family was out of proportion to the marked progression of the ataxia. MRI scans of our patient with SD and of her sister, who had initially presented with writer's cramp at age 20 years, mainly showed a dilated forth ventricle (Figure A). While the sister had become wheelchair-bound due to ataxia at eight-year follow-up, her MRI revealed only a moderate increase of the cerebellar atrophy.
Le Ber et al propose an intriguing link between dystonia and the cerebellum with the cerebellar atrophy contributing to the dystonia. [1] An additional explanation for the dystonia may be subtle morphologic or metabolic changes in the basal ganglia that are not obvious on regular MRI. We confirmed this by demonstrating the involvement of basal ganglia structures in SCA17 patients using voxel-based morphometry (VBM) that negatively correlated with the severity of extrapyramidal signs. [3]
Similarly, two SCA17 patients revealed reduced glucose metabolism and 123I-FP-CIT uptake in the basal ganglia. [4] In addition, we compared the morphometry of basal ganglia structures of the elder sister with SCA17 with that of 11 matched healthy controls employing VBM and ROI- based morphometry (Figure B) that showed a significant global reduction of gray matter density, accentuated in the cerebellum and basal ganglia.
Taken together, a combination of structural, functional, and metabolic changes of both the cerebellum and the basal ganglia likely contribute to 'DYTCA'. Patients with DYTCA provide a unique opportunity to clarify the possible link between the cerebellum and dystonia.
References
1. Le Ber I, Clot F, Vercueil L, et al. Predominant dystonia with marked cerebellar atrophy: A rare phenotype in familial dystonia. Neurology 2006;67:1769-1773.
2. Hagenah J, Zühlke C, Hellenbroich Y, Heide W, Klein C. Focal dystonia as presenting sign of SCA17. Mov Disord 2004;19:217-220.
3. Lasek K, Lencer R, Gaser C, et al. Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17). Brain 2006;129:2341-2352.
4. Minnerop M, Joe A, Lutz M, et al. Putamen dopamine transporter and glucose metabolism are reduced in SCA17. Ann Neurol 2005;58:490-491.
Figure legends
Figure A. At first presentation, the MRI image of the two sisters with SCA17 (Patients 1 and 2) showed mild cerebellar atrophy with characteristic widening of the forth ventricle as compared to an age- and sex-matched control subject. Eight-year follow-up of the elder sister (Patient 2) revealed a mild progression of the cerebellar atrophy and beginning general cortical atrophy.
Figure B. Observer-independent VBM analysis of Patient 2 at follow- up. The pattern of gray matter degeneration is presented in projection on characteristic slices from the MNI Atlas and showed a significant general decrease of gray matter density, accentuated in the cerebellum and the basal ganglia in comparison to 11 age-matched control subjects (below 2 SD of the control mean).
Video legend (video will be made available as a web material when Correspondence is published in print). <
Disclosure: The authors report no conflicts of interest.
Acknowledgments: This study was supported by the BMBF (to FB) and Volkswagen Foundation (to FB and CK) and by intramural grants from the University of Luebeck.
We described twelve patients in eight families with an unusual "dystonia-plus" phenotype characterized by dystonia and cerebellar atrophy on brain MRI. [1] At onset, dystonia was focal or multifocal, mainly affecting vocal cords and upper limbs. During the disease course, spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five.
Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. In response to Klein et al, it is well-known that different genetic subtypes of autosomal dominant cerebellar ataxias are associated with additional movement disorders in general and specifically dystonia. SCA17 and all the other testable SCA genes were excluded in our DYTCA families. Their SCA17 family with focal dystonia and severe cerebellar syndrome--which was already reported--is very different from our patients in several respects. [2]
First, the phenotype in their family is not restricted to dystonia and ataxia but is associated with dementia, chorea, saccadic eye movements and spastic pyramidal syndrome. Second, ataxia in their case is progressive and invalidating and in our patients, if present, mild and progress very slowly. Third, cerebellar atrophy in our patients is global and severe and in their cases minimal and vermian only. Fourth, the transmission is autosomal dominant in their family, whereas our patients were sibs in a single generation, suggesting recessive transmission.
The phenotypes are, therefore, quite different in the family published by Klein et al and our DYTCA patients. However, we agree that the existence of two diseases associating dystonia and cerebellar ataxia suggests that there is a relationship between dystonia and the cerebellum, and that it is important to investigate further this intriguing pathophysiological connection.
Disclosure: The authors report no conflicts of interest.