Familial cortical myoclonic tremor with epilepsy (FCMTE) is a rare autosomal dominant epilepsy syndrome with genetic and clinical heterogeneity. It is also known as benign adult familial myoclonic epilepsy in Japan or autosomal-dominant cortical myoclonus and epilepsy or familial adult myoclonic epilepsy in Europe.1,2 Expanded intronic pentanucleotide (TTTCA)n insertion in the sterile alpha motif domain-containing 12 gene (SAMD12) is the genetic cause of FCMTE1 in Japanese,3 Chinese,4 Sri Lankan and Indian populations.5 Similar mutations have been identified in five other genes (STARD7, MARCH6, YEAST2, TNRC6A and RAPGEF2) in FCMTE2–4, 6 and 7, respectively. The two major clinical features of cortical tremor, which is characterized by tremulous involuntary movements in distal upper extremities, and infrequent epilepsy attack are well recognized. In addition to the two major symptoms, other symptoms, such as visual intolerance,6 night blindness, and migraine, are also reported in FCMTE patients.
Photic stimulation may play an important role in FCMTE. It has been wildly reported that photic stimulation can exaggerate cortical tremor and precipitate epileptic attack.1,7 Patients can also present visual intolerance, with patients unable to tolerate changes to ambient light or prolonged exposure to TV and computer screens or video games. Furthermore, intolerance to light always occurs in the second and third decades of life in patients already having cortical tremor and is considered a marker of disease progression. Photic stimulation-induced myoclonus has also been reported.8 On EEG, intermittent photic stimulation (IPS) can trigger a photoparoxysmal response (PPR), also known photosensitivity, with prevalence ranging from 24.5 to 95% in FCMTE.7,9,10 Photosensitivity is a hallmark of photosensitive epilepsy, including FCMTE, juvenile myoclonic epilepsy, idiopathic occipital photosensitive epilepsy, et al., and is strongly influenced by genetic factors.11,12 Therefore, study of the mechanism of photosensitivity can help reveal the pathogenesis of FCMTE and also of other photosensitivity epilepsies. Considering the prominent clinical and EEG features of FCMTE in response to photic stimulation, we hypothesized the existence of abnormal local neural activities in visual regions that probably involve visual-related networks in patients at resting state.
Resting-state functional magnetic resonance imaging (RS-fMRI) studies have provided some understanding of FCMTE. Previous MRI studies have shown structural, functional and metabolic changes in the cerebellum by diffuse tensor imaging,13 voxel-based morphometry of MRI images14 and proton magnetic resonance spectroscopy.15 MRI studies have also shown impaired brain activity in cortical areas16 and altered cerebellar-cerebral functional connectivity (FC).17 However, the above neuroimaging findings cannot explain the visual symptoms and photosensitivity. We recently conducted a RS-fMRI study in patients with genetically confirmed heterozygous FCMTE1 and observed an altered cerebello-motor network.18 We did not find abnormalities in visual-related regions, probably because of strict multiple testing correction and the high threshold we set for percent amplitude fluctuation.
Regional homogeneity (ReHo) and seed-based FC can assess synchronization of both local and distant brain activity.19 Degree centrality (DC) can determine the strength of the connectivity of one voxel compared with all other voxels in the brain.20 Independent component analysis (ICA), a data-driven approach, is widely used for the analysis of functional networks in fMRI data and can effectively determine the functional characteristics of mutually correlated brain components.21 The purpose of the current study was to investigate differences in intrinsic regional brain activity between genetically confirmed FCMTE1 patients and HCs using indices of ReHo and DC based on RS-fMRI, and to apply seed-based FC to evaluate aberrant distant networks. Furthermore, considering the prominent visual symptoms and photosensitivity in FCMTE, we measured the ICA-derived visual networks. Our results support our hypothesis and provide complementary insights into the established pathophysiological hypothesis of FCMTE.