Metabolic changes in DYT11 myoclonus-dystonia

Abstract

Objective: To identify brain regions with metabolic changes in DYT11 myoclonus-dystonia (DYT11-MD) relative to control subjects and to compare metabolic abnormalities in DYT11-MD with those found in other forms of hereditary dystonia and in posthypoxic myoclonus.

Methods: [(18)F]-fluorodeoxyglucose PET was performed in 6 subjects with DYT11-MD (age 30.5 ± 10.1 years) and in 6 nonmanifesting DYT11 mutation carriers (NM-DYT11; age 59.1 ± 8.9 years) representing the parental generation of the affected individuals. These data were compared to scan data from age-matched healthy control subjects using voxel-based whole brain searches and group differences were considered significant at p < 0.05 (corrected, statistical parametric mapping). As a secondary analysis, overlapping abnormalities were identified by comparisons to hereditary dystonias (DYT1, DYT6, dopa-responsive dystonia) and to posthypoxic myoclonus.

Results: We found significant DYT11 genotype-specific metabolic increases in the inferior pons and in the posterior thalamus as well as reductions in the ventromedial prefrontal cortex. Significant phenotype-related increases were present in the parasagittal cerebellum. This latter abnormality was shared with posthypoxic myoclonus, but not with other forms of dystonia. By contrast, all dystonia cohorts exhibited significant metabolic increases in the superior parietal lobule.

Conclusions: The findings are consistent with a subcortical myoclonus generator in DYT11-MD, likely involving the cerebellum. By contrast, subtle increases in the superior parietal cortex relate to the additional presence of dystonic symptoms. Although reduced penetrance in DYT11-MD has been attributed to the maternal imprinting epsilon-sarcoglycan mutations, NM-DYT11 carriers showed significant metabolic abnormalities that are not explained by this genetic model.

Figure 1. Metabolic abnormalities in DYT11 mutation carriers regardless of symptoms

Statistical parametric maps (SPM) comparing [¹⁸F]-fluorodeoxyglucose PET scans from DYT11 mutation carriers to control subjects (table 2). (A) Increased regional metabolism was found in the inferior pons and posterior thalamus (table 2Aiii). (B) Decreased regional metabolism was found in the ventromedial prefrontal cortex (table 2Biii). (SPM{t} maps were superimposed on a single-subject MRI T1 template. Coordinates indicate the position of the slice in Montreal Neurological Institute standard space. The color scales represent t scores thresholded at t = 3.5, SPM corrected p < 0.05.)

Figure 2. Metabolic abnormalities in symptomatic DYT11 mutation carriers

(A) Metabolic increases in DYT11 myoclonus-dystonia (MD) relative to nonmanifesting DYT11 mutation carriers and to age-matched controls were present in the parasagittal cerebellum bilaterally (see table 3). (B) Metabolic increases of parasagittal cerebellar nuclei were a shared characteristic of DYT11-MD and posthypoxic myoclonus. (Statistical parametric maps [SPM{t}] were superimposed as in figure 1 [with identical slice positions of figure 2, A and B]. The color scales represent t scores thresholded at t = 3.0, SPM corrected p < 0.001.)