Sipei Pan1, Xuying Li2, Liping Li2, Hua Lin2, Dequan Wang2, Xiating Zhang2, Xin Zhao2, Jing Ye2, Zhaoyang Huang1, Yicong Lin1, Yiran Duan1, Rui Ma1, Lehong Gao3, Chaodong Wang4, Yuping Wang5. 1. Department of Neurology, Xuanwu Hosptial, Captial Medical University, Beijing, 100053, China; Beijing Key Laboratory of Neuromodulation, Beijing, 100053, China. 2. Department of Neurology, Xuanwu Hosptial, Captial Medical University, Beijing, 100053, China. 3. Department of Neurology, Xuanwu Hosptial, Captial Medical University, Beijing, 100053, China; Beijing Key Laboratory of Neuromodulation, Beijing, 100053, China. Electronic address: gaolehong@sina.com. 4. Department of Neurology, Xuanwu Hosptial, Captial Medical University, Beijing, 100053, China; National Clinical Research Center for Geriatric Diseases, Beijing, 100053, China. Electronic address: cdongwang01@xwhosp.org. 5. Department of Neurology, Xuanwu Hosptial, Captial Medical University, Beijing, 100053, China; Beijing Key Laboratory of Neuromodulation, Beijing, 100053, China. Electronic address: mdwangyp@sina.cn.
Abstract
OBJECTIVES: Two configurations of TTTTA/TTTCA expansion in SAMD12 have been identified in familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1). This study investigated the clinical and neurophysiological features of FCMTE1 and their association with TTTTA/TTTCA expansion patterns. METHODS: In total, 76 patients from 20 Chinese pedigrees were enrolled. Genetic (TTTTA/TTTCA configuration), clinical (e.g., onset, medication, prognosis, and anticipation) and neurophysiological examination (e.g., electroencephalogram and magnetoencephalography) data were evaluated, and associations between these parameters were analyzed. RESULTS: All patients carried the TTTTA/TTTCA expansion mutation, 19 displayed the (TTTTA)exp(TTTCA)exp (type I) configuration and 1 displayed the (TTTTA)exp (TTTCA)exp(TTTTA)exp (type II) configuration. All patients manifested as progressive tremor, but symptoms of patients carrying type II expansion were more severe. The onset of tremor but not generalized tonic and clonic seizures displayed clinical anticipation between generations of 7 pedigrees, but the pedigree carrying the type II mutation did not show anticipation. Nanopore sequencing showed that the repeats expanded during maternal/offspring transmission (pedigree #7) but shrank during paternal/offspring transmission (pedigree #9). Magnetoencephalographic dipoles were localized in the right frontal lobe near the central sulcus in 4 patients carrying the type I mutation and on the left side in one patient carrying the type II mutation. SIGNIFICANCE: We confirmed the causative roles played by TTTTA/TTTCA repeat expansion in the SAMD12 gene in FCTME1. Both the length and the configuration of the repeats contribute to the clinical and neurophysiological characteristics of the disease.
OBJECTIVES: Two configurations of TTTTA/TTTCA expansion in SAMD12 have been identified in familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1). This study investigated the clinical and neurophysiological features of FCMTE1 and their association with TTTTA/TTTCA expansion patterns. METHODS: In total, 76 patients from 20 Chinese pedigrees were enrolled. Genetic (TTTTA/TTTCA configuration), clinical (e.g., onset, medication, prognosis, and anticipation) and neurophysiological examination (e.g., electroencephalogram and magnetoencephalography) data were evaluated, and associations between these parameters were analyzed. RESULTS: All patients carried the TTTTA/TTTCA expansion mutation, 19 displayed the (TTTTA)exp(TTTCA)exp (type I) configuration and 1 displayed the (TTTTA)exp (TTTCA)exp(TTTTA)exp (type II) configuration. All patients manifested as progressive tremor, but symptoms of patients carrying type II expansion were more severe. The onset of tremor but not generalized tonic and clonic seizures displayed clinical anticipation between generations of 7 pedigrees, but the pedigree carrying the type II mutation did not show anticipation. Nanopore sequencing showed that the repeats expanded during maternal/offspring transmission (pedigree #7) but shrank during paternal/offspring transmission (pedigree #9). Magnetoencephalographic dipoles were localized in the right frontal lobe near the central sulcus in 4 patients carrying the type I mutation and on the left side in one patient carrying the type II mutation. SIGNIFICANCE: We confirmed the causative roles played by TTTTA/TTTCA repeat expansion in the SAMD12 gene in FCTME1. Both the length and the configuration of the repeats contribute to the clinical and neurophysiological characteristics of the disease.