Medical management of myoclonus-dystonia and implications for underlying pathophysiology

Abstract

Myoclonus-dystonia is an early onset genetic disorder characterised by subcortical myoclonus and less prominent dystonia. Its primary causative gene is the epsilonsarcoglycan gene but the syndrome of "myoclonic dystonia" has been shown to be a heterogeneous group of genetic disorders. The underlying pathophysiology of myoclonus-dystonia is incompletely understood, although it may relate to dysfunction of striatal monoamine neurotransmission or disruption of cerebellothalamic networks (possibly via a GABAergic deficit of Purkinje cells). A broad range of oral medical therapies have been used in the treatment of myoclonus-dystonia with a varying response, and limited data relating to efficacy and tolerability, yet this condition responds dramatically to alcohol. Few well conducted randomized controlled trials have been undertaken leading to an empirical ad hoc approach for many patients. We review the current evidence for pharmacological therapies in myoclonus-dystonia, discuss implications for underlying pathogenesis of the condition and propose a treatment algorithm for these patients.

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons

“…However, the expression of the genes encoding GABA A receptor subunits and GABAergic calcium signaling were comparable in SGCE and control MSNs. The reduced neuronal GABAergic synaptic density in striatal MSNs seen in our study could be one pathophysiological cause for the improvement of symptoms after ingestion of alcohol [ 28 , 29 , 45 ] or likewise benzodiazepines [ 1 , 42 , 45 ], which both enhance GABAergic transmission. Even earlier, it was suggested that the striatum plays an important pathophysiological role in DYT-SGCE but other brain regions seem to be also involved in the pathogenesis [ 27 , 33 , 34 ].…”

“…These results may suggest an increased signaling via the muscarinic acetylcholine receptor in DYT-SGCE MSNs compared to healthy controls, which could be accompanied by a reduced transmission via the nicotinic acetylcholine receptor. In line with this, a medication with anticholinergic drugs such as trihexyphenidyl that is a muscarinic acetylcholine receptor blocker, could improve motor symptoms in DYT-SGCE [ 42 , 43 , 44 , 45 ]. So it could be hypothesized that cholinergic signaling, especially via muscarinic acetylcholine receptors, plays an important role in DYT-SGCE.…”

“…In accordance with the assumption that the striatum as part of the basal ganglia could be important for the pathogenesis of DYT- SGCE, deep-brain stimulation of the internal globus pallidus and the ventral intermediate thalamic nucleus improved symptoms of DYT-SGCE patients [ 54 , 55 , 56 ]. A dysfunction of the cerebello-thalamico-cortical and striato-pallido-thalamo-cortical pathway, potentially due to a GABAergic deficit, is assumed to be one of the main causes of DYT-SGCE [ 5 , 23 , 45 ].…”

Efficacy and Safety of Zolpidem for Focal Dystonia After Neurosurgical Treatments: A Retrospective Cohort Study

“…The basal ganglia and thalamus have a high density of GABA-A receptors, which is the binding site of zolpidem ( 24 , 25 ). In the basal ganglia, the ventral pallidum, substantia nigra pars reticulata, and subthalamic nucleus have the highest density of zolpidem-binding GABA-A receptors, suggesting that zolpidem may help restore the influence of basal ganglia output on the thalamus and motor cortex ( 26 , 27 ). Badillo et al suggested that the effects of zolpidem result from the facilitation of inhibitory pathways in the basal ganglia-thalamo-cortical circuit, which leads to the improvement of dystonia ( 13 ).…”

Approach to the Treatment of Pediatric Dystonia

“…Clonazepam was also reported to be beneficial in the treatment of myoclonusdystonia in the pediatric population (39,40). The majority of the data regarding the treatment of myoclonus-dystonia comes from the adult literature and includes drugs such as zonisamide, tetrabenazine, and levodopa (41).…”