Objective: To present the preliminary results of an Italian multicentric study on inherited synaptopathies

Background: Inherited synaptopathies are rare genetic disorders characterized by complex and variable phenotypes including neurodevelopmental disorders, epilepsy, and movement disorders which are frequently reported, but often poorly characterized, limiting accurate genotype-phenotype correlations

Method: We enrolled 80 patients with 30 genetically confirmed synaptopathies (including individuals with ARHGEF9, CACNA1G, DHDDS, GABRB3, KCND3, NUS1, STXBP1 deficiencies) and collected clinical, genetic, and neurophysiological data. Among them, 12 patients with childhood-onset tremor or tremor-like movements underwent neurophysiological evaluation with EEG-EMG polygraphy. In selected cases, Jerk-Locked Back-Averaging (JLBA) and Cortico-Muscular Coherence (CMC) were applied to assess the cortical contribution to myoclonus

Results: All patients had neurodevelopmental disorders, including intellectual disability and/or autism spectrum disorder. Epilepsy and movement disorders were observed in the majority of cases; e.g., tremor or tremor-like movements were described since early childhood. Neurophysiological assessments were performed on 12 patients. In 6 of these patients, we observed either synchronous (n=4) or alternating (n=2) activation of agonist-antagonist muscles, with EMG burst durations ranging from 50-100 ms in 2 cases and >100 ms in 4 cases. Frequency analysis revealed narrow peaks in all 6 cases, consistent with tremor. In the remaining 8 patients, we observed strictly synchronous EMG bursts, with durations of less than 30 ms in 4 cases and between 30-50 ms in the others. A frequency peak was detected in only 3 of these cases. In 6 out of the 8 patients, advanced analyses (JLBA and/or CMC) suggested the presence of cortical myoclonus

Conclusion: Our study highlights the clinical complexity of inherited synaptopathies. Notably, myoclonus emerged as a common and likely underrecognized feature in these conditions. Neurophysiological characterization proved essential to support phenotyping and improving genotype-phenotype correlations in inherited synaptopathies

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MDS Abstracts - https://www.mdsabstracts.org/abstract/preliminary-results-from-an-italian-multicentric-study-on-inherited-synaptopathies-characterized-by-movement-disorders-and-epilepsy/