Abstracts

Rationale: Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE) is an autosomal dominant disorder characterized by cortical myoclonic tremor and infrequent seizures with a benign clinical course. Similar phenotypes have been described under various names, including benign adult familial myoclonic epilepsy (BAFME) et al. To date, more than sixty families have been reported since the first description of FCMTE. Here we describe the electro-clinical and genetic characteristics of a large family from China. Methods: We have followed this family since 1996 when the proband first presented. Clinical assessment, electroencephalogram (EEG), and imaging studies have been done since on affected family members. Whole exome sequencing (WES) was performed on eight affected and three unaffected individuals to identify the disease causing variants. WES data were analyzed using Varsifter. Repeat-primed fluorescent PCR (RP-PCR) using primer sets for TTTTA and TTTCA repeats in intron 4 of SAMD12 was performed as described recently (Ishiura et al., 2018).  Results: There are 21 clinically affected individuals in six generations in this extended family of over 130 members, with an inheritance pattern suggesting an autosomal dominant disease. All affected individuals manifested adult onset seizures, and age- dependent cortical myoclonic postural tremors starting after the third or fourth decade of life. The proband has had worsening cortical tremor and ataxia over 22 years of follow-up. Their EEG showed generalized spikes or multi spikes and slow wave complexes. In comparison with other progressive myoclonus epilepsies, the course and prognosis were apparently benign. Disorders similar to these we describe herein have been shown to map to different loci, indicating genetic heterogeneity. All the Japanese families and most Chinese families examined to date show linkage to the 8q24 region. Analysis of WES data on our family also showed segregation of several variants from 8q22 to 8q24 region with the disease phenotype. A recent study (Ishiura et al., 2018) reported that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12, which lies in the 8q24 region, cause BAFME in several Japanese families. This led us to examine our family for the presence of these intronic repeat expansions using RP-PCR. Our data showed that the pentanucleotide repeat expansions in intron 4 of SAMD12 segregate with the disease phenotype in our family too, thus identifying this novel mechanism of intronic repeat expansions as the underlying cause of FCMTE. Our future plans include long-range PCR and sequencing to determine the exact size and sequence of repeats in our family.  Conclusions: We describe a family of several generations with seizures and tremors whose underlying genetic defect we have identified. Because of associated ataxia and tremor, it is possible that the mutation influences Purkinje cells in the cerebellum leading to decreased inhibition in cortical and other motor networks. Funding: National Natural Science Foundation of China; Intramural Research Program of the National Human Genome Research Institute, NIH