The Neurophysiological Features of Myoclonus-Dystonia and Differentiation From Other Dystonias

Abstract

IMPORTANCE Myoclonus-dystonia (M-D) is a clinical syndrome characterized by a combination of myoclonic jerks and mild to moderate dystonia. The syndrome is related to ε-sarcoglycan (SGCE) gene mutations in about half the typical cases. Whether the M-D phenotype reflects a primary dysfunction of the cerebellothalamocortical pathway or of the striatopallidothalamocortical pathway is unclear. The exact role of an additional cortical dysfunction in the pathogenesis of M-D is also unknown. OBJECTIVE To clarify the neurophysiological features of M-D and discuss whether M-D due to SGCE deficiency differs from other primary dystonias. DESIGN, SETTING, AND PARTICIPANTS We studied a referred sample of 12 patients with M-D (mean [SD] age, 28.8 [6.2] years; age range, 19-38 years; 5 women) belonging to 11 unrelated families with a proven mutation or deletion of the SGCE gene and a group of 12 age-and sex-matched healthy control individuals. Every participant underwent 3 sessions exploring the excitability of the primary motor cortex, the response of the primary motor cortex to a plasticity-inducing protocol, and the cerebellar-dependent eye-blink classic conditioning (EBCC). The clinical evaluation of patients included the Unified Myoclonus Rating Scale and Burke-Fahn-Marsden Dystonia Rating Scale. EXPOSURE Myoclonus-dystonia with a proven SGCE mutation. MAIN OUTCOMES AND MEASURES We measured resting and active motor thresholds, and short-interval intracortical inhibition and facilitation. The plasticity of the motor cortex was evaluated before and for 30 minutes after 600 pulses of rapid paired associative stimulation. The cerebellar functioning was evaluated with the number of conditioned responses during the 6 blocks of EBCC and 1 extinction block. All data were compared between the 2 groups. For patients, correlations were explored between electrophysiological data and clinical scores. RESULTS We found lower membrane excitability of the corticocortical axons and normal intracortical γ-aminobutyric acid inhibition in contrast with what has been described in other forms of primary dystonia. Myoclonus-dystonia patients also shared some common pathophysiological features of dystonia, including enhanced responsiveness of the motor cortex to plasticity induction and abnormal response to cerebellar conditioning as tested by EBCC. CONCLUSIONS AND RELEVANCE Specific underlying dysfunctions are associated with the very particular clinical phenotype of M-D and make it a unique entity that stands apart from other primary dystonias.

Cerebellum: An explanation for dystonia?

“…FHD and CD [97, 98]. The response to cerebellar conditioning, as assessed by the EBCC, has also been shown to be abnormal in myoclonus-dystonia patients [99]. It is, however, unclear whether the impaired EBCC observed in patients with primary dystonia is due to actual cerebellar pathology or reflects functional cerebellar disruption.…”

Delineating cerebellar mechanisms in DYT11 myoclonus‐dystonia

“…The most frequent genetic cause of myoclonus‐dystonia, DYT11, is the result of loss of function mutations in the ɛ‐sarcoglycan gene and is inherited in an autosomal dominant manner with incomplete penetrance . With no overt neurodegeneration, the disease is thought to represent a functional neural disturbance across a predominantly subcortical network . Recently there has been much attention on the role of the cerebellum within pathophysiological models for DYT11, with cerebellar involvement suggested by both animal models and human studies …”

Long‐term GPi‐DBS improves motor features in myoclonus‐dystonia and enhances social adjustment

“…The brain‐specific function of the gene is not completely elucidated, but it is a part of the dystrophin‐associated membrane complex . Histopathological, neurophysiological, and imaging studies point to a crucial role of the cerebellothalamic pathways in the generation of these motor symptoms, as well as objective improvement after alcohol intake …”