Objective: To characterize brain network abnormalities and gene-imaging associations in genetically confirmed FCMTE1 (SAMD12) patients using multimodal MRI.

Background: Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by intronic pentanucleotide repeat expansion in SAMD12. Beyond cortical hyperexcitability, the network mechanism underlying tremor and photosensitivity remains poorly defined.

Method: Thirty-seven genetically confirmed FCMTE1 patients and 50 matched healthy controls underwent 3T multimodal MRI (T1-weighted, resting-state fMRI, diffusion tensor imaging). Surface-based morphometry quantified cortical thickness. Fractional amplitude of low-frequency fluctuations (fALFF) assessed regional activity. Thalamic seed-based functional connectivity (FC) and network-based statistic (NBS) analysis examined circuit and whole-brain network alterations. SAMD12 total repeat expansion length was determined via long-range PCR and PacBio long-read sequencing.

Results: Patients showed significant cortical thinning in left precentral gyrus, negatively correlated with tremor duration (r=-0.31, p=0.048)[figure1]. fALFF was increased in left thalamus and calcarine cortex[figure2]. Thalamic seed-based FC revealed a characteristic input-output decoupling pattern: enhanced connectivity with cerebellum Crus I and occipital pole, but reduced connectivity with bilateral precentral gyri[figure2]. NBS identified two hyperconnected subnetworks: Network 1 (cerebellum-thalamus-cortical network) correlated with tremor severity (r=0.42, p=0.004); Network 2 (visual-cerebellar-sensorimotor) correlated with photoparoxysmal response grade (r=0.38, p=0.011)[figure 3]. Critically, SAMD12 total repeat expansion length was negatively correlated with thalamo-precentral FC strength (r=-0.45, p=0.006).

Conclusion: These findings support FCMTE1 as a thalamus-centered network disorder rather than a purely cortical hyperexcitability syndrome. The dose-dependent association between SAMD12 repeat length and thalamo-motor connectivity provides the first direct link between genetic burden and circuit dysfunction in FCMTE1.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/thalamic-hub-dysregulation-in-fcmte1-multimodal-mri-and-gene-imaging-evidence/