TTTCA repeat expansion causes familial cortical myoclonic tremor with epilepsy

Abstract

Background and purpose The aim was to investigate whether abnormal TTTTA and TTTCA repeat expansions in introns of SAMD12, TNRC6A and RAPGEF2 are involved in the pathogenesis of familial cortical myoclonic tremor with epilepsy (FCMTE). Methods Five families diagnosed with FCMTE were included in the current genetic analysis. Whole‐exome sequencing was performed in selected patients of each family. TTTTA and TTTCA expansions were examined by repeat‐primed polymerase chain reaction. The clinical features of FCMTE were elicited as defined by the common genetic mechanism of 14 patients. Results Abnormal TTTCA expansion was identified and co‐segregated in all five FCMTE families, four inserted in SAMD12 and one in RAPGEF2. The insertion of expanded TTTCA was not found in 116 control alleles. TTTTA expansion in SAMD12 was detected in 90.9% (10/11) of patients or mutation carriers; TTTTA expansion in RAPGEF2 was not found. The onset age of myoclonic tremor was 27.4 ± 5.9 (19–37) and epilepsy usually presented around age 34. Focal and generalized seizures were witnessed with various origins recorded by electroencephalogram. Cognitive deficits were not common within the first 3 years after epilepsy onset. Emotional instability was reported by most patients. No patients showed any cerebellar deficits. Valproate added with clonazepam is effective in controlling seizures but cannot guarantee a complete remission of tremor. Repeat length showed intergenerational instability and was inversely correlated with age at onset of myoclonic tremor and epilepsy. Conclusions TTTCA expansion insertion is associated with FCMTE in Chinese families. The homogenous genetic mechanism allowed for a higher precision of FCMTE description.

TTTCA Repeat Expansion of SAMD12 in a New Benign Adult Familial Myoclonic Epilepsy Pedigree

“…A recent report of BAFME pedigree identified interindividual instability of the pentanucleotide repeats and inversely correlated with age at onset of myoclonic tremor and seizure (11). Our study confirmed the interindividual instability, but minimum repeat size estimated by RP-PCR shows no relation to the age of onset in this BAFME family.…”

“…Recently, pentanucleotide expansions of intronic TTTCA and TTTTA were found to be involved in the pathogenesis of BAFME 1 in Japanese pedigrees regardless of the gene location (4). Three more recent reports also confirmed TTTCA pentanucleotide expansions in BAFME 1 families of another ethic background (9)(10)(11). Subsequently, TTTCA repeat insertions in an intron of YEATS2 in BAFME 4 was confirmed in a Thailand pedigree (7).…”

Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms

“…Thus, the associations of the expanded dodecamer repeat from the cystatin B (CSTB) gene promoter with progressive myoclonus epilepsy (EPM1) [16][17][18] were identified. For instance, length polymorphisms of 5-HTTLPR and 5-HTTVNTR (VNTR-2, STin2) of the serotonin transporter gene (5-HTT) with susceptibility to temporal lobe epilepsy (TLE) [19,20], the monoamine oxidase A promoter variable number of tandem repeat (MAOA-uVNTR) with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) [21], and expansion of intronic pentanucleotide repeats of SAMD12, STARD7, YEATS2 and MARCH 6 genes with adult benign familial myoclonic epilepsy (BAFME) [22]. Those associations of tandem repeats with diseases may be explained by their participation in the regulation of gene expression [23][24][25].…”

Clinical and genomic analysis of a large Chinese family with familial cortical myoclonic tremor with epilepsy and SAMD12 intronic repeat expansion

“…Of these, the repeat expansion in intron four of SAMD12 was the most frequent and was observed in 48 out of 51 FCMTE families 9 . These findings were subsequently validated in additional Japanese and Chinese families with FCMTE 10–13 . Here, we present a large multigenerational Chinese family with more than twenty individuals with FCMTE symptoms from five generations that we have been studying for 23 years.…”

“…9 These findings were subsequently validated in additional Japanese and Chinese families with FCMTE. [10][11][12][13] Here, we present a large multigenerational Chinese family with more than twenty individuals with FCMTE symptoms from five generations that we have been studying for 23 years. Using a combination of the repeatprimed PCR, long-range PCR, and PacBio sequencing, we identified a 4.2-4.7 kb repeat with 549-603 copies of TTTTA and 287-343 copies of TTTCA repeat motifs in intron four of SAMD12 in affected individuals.…”