Developmental variability in paediatric SGCE-related myoclonus dystonia syndrome

Abstract

Myoclonus dystonia syndrome due to a SGCE pathogenic variant is a rare condition that typically manifests early in childhood.¹ It is characterized by a motor phenotype combining dystonia and myoclonus of subcortical origin, associated with a high prevalence of psychiatric disorders, particularly anxiety disorders, depression, and obsessive-compulsive disorder.¹ This condition is generally considered minimally progressive in adults,¹ but its natural course in children and adolescents remained largely unknown.

De Francesch et al.² offer a longitudinal study over an average follow-up period of 4 years involving 38 patients with myoclonus dystonia from Spanish and Dutch cohorts. The primary finding of this study is the clear progression of motor symptoms over time, affecting both action myoclonus and dystonia.

This study highlights a striking contrast between the progression observed during childhood and adolescence, and the overall stability typically reported in adult patients. It represents an important initial step in characterizing the progressive nature of the disease across the neurodevelopmental trajectory. Notably, the very early onset of motor symptoms (mean age 2–3 years) and their progression, confined to this critical developmental period support the classification of myoclonus dystonia as a neurodevelopmental disorder, although this categorization remains debated. Furthermore, beyond its impact on motor circuit development, the study also suggests dysfunction in the maturation of non-motor circuits. This is supported by a high prevalence of specific learning disorders and the frequent occurrence of psychiatric conditions in young patients — affecting up to 74% of them — including anxiety disorders, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder.

Longitudinal evaluations of these non-motor symptoms, which has not been thoroughly conducted in this study, would be highly valuable for future research, despite the complexity of execution. Interestingly, this perspective aligns with neuronal-level findings, where several distinctive variations such as larger dendritic spines, more complex morphology, and a higher number of excitatory synapses with greater functional secondary to SGCE mutation are shared with other monogenic neurodevelopmental disorders linked to developmental delays or autism spectrum disorders (e.g. SYNGAP1, FMR1) and schizophrenia (e.g. SETD1A), although their significance remains elusive.^{3, 4} Altogether, we propose that myoclonus dystonia may be considered a neurodevelopmental disorder with mixed neuropsychiatric expression.

The article also raises the point that the neurodevelopmental trajectory of these patients appears heterogeneous. While the general trend points to worsening motor symptoms, it is noteworthy that some young patients experience symptom improvement. These differences in developmental profiles influence therapeutic decisions for each patient, particularly regarding the indication for deep brain stimulation, which remains the most effective treatment for myoclonus dystonia symptoms.¹ The article by De Francesch et al. stresses the importance of identifying biomarkers to predict each patient's developmental trajectory early, paving the way for increasingly personalized medicine. The authors propose that this variability in developmental outcomes may stem from intrinsic factors, such as multiple mutations within SGCE, leading to diverse protein dysfunctions, as well as modifiable factors, including epigenetic and environmental influences.

Additionally, compensatory mechanisms that emerge during neurodevelopment (with varying effectiveness across patients) may also contribute to these differences, as suggested by microarchitectural reorganization of the motor cortex and its afferent pathways, which are associated with the severity of motor symptoms.⁵ Identifying and addressing modifiable factors, gaining a deeper understanding of the compensatory mechanisms, and developing strategies to enhance them represent significant challenges for the future. Achieving this goal will require multicenter longitudinal studies with larger cohorts and multimodal investigative approaches.