Comprehensive genetic, clinical and electrophysiological studies of familial cortical myoclonic tremor with epilepsy 1 highlight the role of gene configurations.

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.