Functional Magnetic Resonance Imaging Evidence of Incomplete Maternal Imprinting in Myoclonus-Dystonia

Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder characterized by myoclonic jerks, dystonic posturing mainly of the limbs, and psychiatric comorbidity, ie, depression, anxiety, and/or obsessive compulsive disorder.¹ It is frequently caused by a mutation in the DYT-11 gene encoding epsilon-sarcoglycan (SGCE), a membrane protein whose function is yet to be elucidated.¹ An interesting feature of the inheritance pattern in this disorder is maternal imprinting; ie, only patients who inherit the mutated allele from their father develop clinical symptoms, although a few patients with symptoms who inherited the disease from their mother have been described.^2,3 In a mouse model, the maternal SGCE allele is weakly expressed in the brain but not in other tissues.⁴ This is consistent with a case report of a French patient with the full clinical picture of M-D who inherited the mutation from her mother and only expressed the paternal allele in peripheral leucocytes.² A functional magnetic resonance imaging study by our group showed hyperresponsiveness of the right cerebellum, right premotor cortex, and left secondary somatosensory cortex and hyporesponsiveness in the left insula in clinically affected DYT-11 carriers during a finger tapping task,⁵ supporting the hypothesis of defective sensorimotor integration in dystonia.⁶ Functional changes in neuroimaging studies in other inherited forms of dystonia, eg, DYT-1, have been described in both clinically affected and unaffected gene mutation carriers.^7-9 The mode of inheritance in these other monogenetic forms of dystonia is autosomally dominant with reduced penetrance but without the maternal imprinting phenomenon.

In the present functional magnetic resonance imaging study, we compared 8 clinically affected DYT-11 mutation carriers from our previous study who inherited the mutation from their fathers with 8 DYT-11 mutation carriers who inherited the gene from their mothers. Of these 8 mutation carriers, none reported symptoms of myoclonus or dystonia. On careful neurological examination, however, 4 of them showed very slight signs of dystonia, inconsistent with a strict monoallelic expression mechanism of the disease, but rather suggesting incomplete maternal imprinting or a biased gene expression based on a parent-of-origin effect, also known as preferential expression mechanism. Separate analyses were performed without these slightly affected patients, using only data from the 4 clinically unaffected mutation carriers. Eleven healthy control subjects were also scanned. We focused on the regions of interest detected in our previous study in clinically affected DYT-11 carriers. We hypothesized that the maternal imprinting mechanism is not complete and that we would detect mild abnormalities in responsiveness in the subjects who inherited the mutation from their mothers, comparable with the mild clinical phenotype.

Eight paternally inherited DYT-11 mutation carriers (median age, 50 years; range, 22-64 years; 6 male), 8 maternally inherited DYT-11 mutation carriers (median age, 52 years; range, 35-65 years; 3 male), and 11 healthy control subjects (median age, 45 years; range, 23-71 years; 6 male) underwent a functional magnetic resonance imaging scanning session in which a finger tapping task was performed, using methodology described previously.⁵ Data were analyzed in SPM2 (Wellcome Department of Cognitive Neurology, http://www.fil.ion.ucl.ac.uk/spm). For the analyses regarding only the 4 clinically unaffected mutation carriers, functional magnetic resonance imaging data were analyzed using a nonparametric approach (SnPM version 3b, Wellcome Department of Cognitive Neurology) in MatLab 2006b (The MathWorks, Natick, Massachusetts). In addition, although the number of clinically unaffected subjects was too small to perform reliable parametric analyses, we explored the blood oxygen level–dependent response of this group of patients compared with controls and symptomatic patients with M-D in regions of interest identified in our previous study: the right cerebellum, right premotor cortex, and contralateral secondary somatosensory cortex and left insula (Figure). All DYT-11 mutation carriers were clinically scored using the Burke-Fahn-Marsden dystonia rating scale¹⁰ and the Unified Myoclonus rating scale.¹¹ Clinical characteristics are summarized in Table 1. Informed consent was obtained for all subjects, and the study was approved by the local medical ethics committee.

When subjects with the paternally inherited mutations were compared with subjects with maternally inherited mutations, hyperresponsiveness was seen in the contralateral secondary somatosensory cortex. When subjects with maternally inherited mutations were compared with control subjects, hyperresponsiveness was found in the supplementary motor area and ipsilateral cerebellum (Table 2).

Nonparametric analysis between clinically unaffected patients with maternally inherited mutations (n = 4) and control subjects and, subsequently, between clinically unaffected subjects with maternally inherited mutations and subjects with paternally inherited mutations revealed no significant differences.

Contrast estimates were plotted in SPM2 for the right cerebellum, right premotor cortex, left secondary somatosensory cortex, and left insula. Blood oxygen level–dependent responses of the maternally inherited DYT-11 mutation carriers fell between the paternal mutation carriers and control subjects in all 4 areas (Figure, B). When contrast estimates were plotted for the same areas, omitting the 4 maternally inherited mutation carriers showing slight dystonia, similar results were obtained (Figure, C). The paternally inherited mutation carriers and control subjects are the same in both parts B and C.

In our previous study involving the clinically affected DYT-11 carriers, clear differences in activation patterns were found between patients and control subjects. In the current study, we found that the maternally inherited mutation carriers showed activation patterns that were intermediate between paternally inherited mutation carriers and control subjects. When only clinically unaffected, maternally inherited mutation carriers were compared with the same paternally inherited mutation carriers and control subjects, the results were similar in all 4 regions of interest. Although these differences failed to reach statistical significance in the nonparametric analyses regarding only the clinically asymptomatic mutation carriers, probably owing to the limited number of patients, our results nevertheless suggest mild functional brain abnormalities in clinically asymptomatic, maternally inherited DYT-11 mutation carriers. These results therefore suggest biased gene expression based on parent of origin rather than a strictly dichotomous maternal imprinting mechanism. This conclusion is compatible with clinical observations, as several patients have been described with a mild M-D phenotype who inherited the gene from their mother.² We also detected these mild phenotypes in our M-D pedigrees.³ In one study of a clinically affected woman who inherited the mutation from her mother, only the wild-type paternal allele was detectable in complement DNA in peripheral leucocytes.² A possible explanation for this result as well as ours would be the existence of brain-specific isoforms of SGCE that are not detectable by standard amplification in peripheral leucocytes. This would be consistent with the previously described mouse model, weakly expressing the maternal SGCE allele in the brain.⁴

We realize that the major drawback of this study is the small number of patients, but as all the regions of interest showed a similar pattern, we consider our results reliable. However, larger groups of nonmanifesting carriers who inherited the gene from their mother should be studied before definite conclusions can be drawn.

Correspondence: Marina A. J. de Koning-Tijssen, MD, PhD, Department of Neurology, Academic Medical Centre, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands (m.a.tijssen@amc.nl).

Accepted for Publication: December 8, 2010.

Published Online: February 14, 2011. doi:10.1001/archneurol.2011.23

Author Contributions:Study concept and design: Foncke and Tijssen. Acquisition of data: Beukers, Foncke, and van der Meer. Analysis and interpretation of data: Beukers, van der Meer, Veltman, and Tijssen. Drafting of the manuscript: Beukers and Tijssen. Critical revision of the manuscript for important intellectual content: Foncke, van der Meer, Veltman, and Tijssen. Statistical analysis: Beukers, van der Meer, and Veltman. Obtained funding: Tijssen. Administrative, technical, and material support: Beukers, van der Meer, and Veltman. Study supervision: Veltman and Tijssen.

Financial Disclosure: None reported.

Funding/Support: This study was supported by a VIDI grant NWO-VIDI (project 016.056.333) from the Netherlands Organisation for Scientific Research (Drs Beukers and Koning-Tijssen) and the Onderzoeksschool Neurowentenschappen Amsterdam–meetfonds (ABIP).