Benign Adult Familial Myoclonic Epilepsy Research Articles

Identification of a de novo CACNA1B variant and a start-loss ADRA2B variant in paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) represents the most prevalent form of paroxysmal dyskinesia, characterized by recurrent and transient attacks of involuntary movements triggered by a sudden voluntary action. In this study, whole-exome sequencing was conducted on a cohort of Chinese patients to identify causal mutations. In one young female case, a de novo CACNA1B variant (NM_000718.3:exon3:c.479C > T:p.S160F) was identified as the causative lesion. This finding may broaden the phenotypic spectrum of CACNA1B mutations and provide a prospective cause of primary PKD. Additionally, a novel start-loss variant (NM_000682.7:c.3G > A) within ADRA2B further denied its association with benign adult familial myoclonic epilepsy, and a KCNQ2 E515D variant that was reported as a genetic susceptibility factor for seizures had no damaging effect in this family. In sum, this study established a correlation between CACNA1B and primary PKD, and found valid evidence that further negates the pathogenic role of ADRA2B in benign adult familial myoclonic epilepsy.

Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disorder characterized by cortical tremors and seizures. Six types of BAFME, all caused by pentanucleotide repeat expansions in different genes, have been reported. However, several other BAFME cases remain with no molecular diagnosis. We aim to characterize clinical features and identify the mutation causing BAFME in a large Malian family with 10 affected members. Long-read whole genome sequencing, repeat-primed polymerase chain reaction and RNA studies were performed. We identified TTTTA repeat expansions and TTTCA repeat insertions in intron 4 of the RAI1 gene that co-segregated with disease status in this family. TTTCA repeats were absent in 200 Malian controls. In the affected individuals, we found a read with only nine TTTCA repeat units and somatic instability. The RAI1 repeat expansions cause the only BAFME type in which the disease-causing repeats are in a gene associated with a monogenic disorder in the haploinsufficiency state (ie, Smith-Magenis syndrome [SMS]). Nevertheless, none of the Malian patients exhibited symptoms related to SMS. Moreover, leukocyte RNA levels of RAI1 in six Malian BAFME patients were no different from controls. These findings establish a new type of BAFME, BAFME8, in an African family and suggest that haploinsufficiency is unlikely to be the main pathomechanism of BAFME. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Complete SAMD12 repeat expansion sequencing in a four-generation BAFME1 family with anticipation.

Benign adult familial myoclonic epilepsy type 1 (BAFME1) is an autosomal dominant, adult-onset neurological disease caused by SAMD12 repeat expansion. In BAFME1, anticipation, such as the earlier onset of tremor and/or seizures in the next generation, was reported. This could be explained by intergenerational repeat instability, leading to larger expansions in successive generations. We report a four-generation BAFME1-affected family with anticipation. Using Nanopore long-read sequencing, detailed information regarding the sizes, configurations, and compositions of the expanded SAMD12 repeats across generations was obtained. Unexpectedly, a grandmother-mother-daughter triad showed similar repeat structures but with slight repeat expansions, despite quite variable age of onset of seizures (range: 52-14 years old), implying a complex relationship between the SAMD12 repeat expansion sequence and anticipation. This study suggests that different factor(s) from repeat expansion could modify the anticipation in BAFME1.

Nine Hereditary Movement Disorders First Described in Asia: Their History and Evolution.

Clinical case studies and reporting are important to the discovery of new disorders and the advancement of medical sciences. Both clinicians and basic scientists play equally important roles leading to treatment discoveries for both cures and symptoms. In the field of movement disorders, exceptional observation of patients from clinicians is imperative, not just for phenomenology but also for the variable occurrences of these disorders, along with other signs and symptoms, throughout the day and the disease course. The Movement Disorders in Asia Task Force (TF) was formed to help enhance and promote collaboration and research on movement disorders within the region. As a start, the TF has reviewed the original studies of the movement disorders that were preliminarily described in the region. These include nine disorders that were first described in Asia - Segawa disease, PARK-Parkin, X-linked dystonia-parkinsonism (XDP), dentatorubral-pallidoluysian atrophy (DRPLA), Woodhouse-Sakati syndrome, benign adult familial myoclonic epilepsy (BAFME), Kufor-Rakeb disease, tremulous dystonia associated with mutation of the calmodulin-binding transcription activator 2 (CAMTA2) gene, and paroxysmal kinesigenic dyskinesia (PKD). We hope that the information provided will honor the original researchers and help us learn and understand how earlier neurologists and basic scientists together discovered new disorders and made advances in the field, which impact us all to this day.

Familial adult myoclonus epilepsy: Neurophysiological investigations.

Familial adult myoclonus epilepsy (FAME) also described as benign adult familial myoclonus epilepsy (BAFME) is a high-penetrant autosomal dominant condition featuring cortical myoclonus of varying frequency and occasional/rare convulsive seizures. In this update we provide a detailed overview of the main neurophysiological findings so far reported in patients with FAME/BAFME. After reviewing the diagnostic contribution of each neurophysiological technique, we discuss the possible mechanisms underlying cortical hyperexcitability and suggest the involvement of more complex circuits engaging cortical and subcortical structures, such as the cerebellum. We, thus, propose that FAME/BAFME clinical features should arise from an "abnormal neuronal network activity," where the cerebellum represents a possible common denominator. In the last part of the article, we suggest that future neurophysiological studies using more advanced transcranial magnetic stimulation (TMS) protocols could be used to evaluate the functional connectivity between the cerebellum and cortical structures. Finally,non-invasive brain stimulation techniques such as repetitive TMS or transcranial direct current stimulation could be assessed as potential therapeutic tools to ameliorate cortical excitability.

Clinical diagnostic criteria of benign adult familial myoclonus epilepsy type 1 are highly concordant with genetic testing

AbstractBackgroundThe clinical diagnostic criteria for benign adult familial myoclonus epilepsy (BAFME) originally included (1) cortical tremor and infrequent generalized seizures, (2) autosomal dominant inheritance, (3) lack of cognitive decline and other neurological symptoms, (4) electrophysiological findings of cortical reflex myoclonus, and (5) lack of clear clinical progression (BAFME criteria‐1). It was revised such that (1) included partial seizures, and (3) and (5) may develop among middle‐aged patients (Revised criteria‐2). The Japanese Ministry of Health, Labor and Welfare proposed their criteria, which included the EEG and MRI findings (MHLW criteria‐3). Recently, high‐frequency oscillations, superimposed on the giant somatosensory evoked potential P25 component (P25‐HFOs), have been found useful as a biomarker for BAFME diagnosis.AimWe examined the genetic diagnosis of BAFME type 1 and its consistency with the three diagnostic criteria and P25‐HFOs.MethodsTwenty‐four Japanese patients, who underwent BAFME genetic testing, were rated using three independent diagnostic criteria and P25‐HFOs.ResultsTwenty‐one patients were genetically diagnosed with BAFME type 1. Nineteen patients fulfilled BAFME‐1 (sensitivity 90%), and 21 fulfilled Revised‐2 and MHLW criteria‐3 (sensitivity 100%). We could evaluate P25‐HFOs in 19 of the 21 gene‐positive patients, and 17 of the 19 patients showed P25‐HFOs. Three patients with negative genetic testing did not meet any of the criteria and had no P25‐HFOs.ConclusionsThe three available clinical diagnostic criteria for BAFME were highly concordant with the positive result for genetic testing.

Recent advances in benign adult familial myoclonus epilepsy

AbstractBenign adult familial myoclonus epilepsy (BAFME), also called familial cortical myoclonic tremor and epilepsy (FCMTE), autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME), and familial adult myoclonic epilepsy (FAME) is a disorder characterized by infrequent generalized seizures and tremulous myoclonus with an autosomal dominant mode of inheritance. The diagnosis of BAFME was previously based on clinical features and electrophysiological findings, but genetic analysis is now increasingly becoming important in the diagnosis after identification of repeat expansions; BAFME is caused by expansions of TTTCA and TTTTA repeats in SAMD12 (BAFME1), STARD7 (BAFME2), MARCHF6 (BAFME3), YEATS2 (BAFME4), TNRC6A (BAFME6), or RAPGEF2 (BAFME7). The findings strongly support a concept of “repeat motif–phenotype correlation” which we have proposed previously. Pathologically, BAFME1 patients carrying heterozygous expansions of TTTCA and TTTTA repeats do not show any obvious abnormal neuropathological findings in the central nervous system. These pathological findings, in addition to electrophysiological studies, suggest a dysfunctional neuronal circuit that causes enhanced excitability of the sensorimotor cortex. Autopsied brains of BAFME1 patients showed RNA foci consisting of UUUCA repeats in cortical neurons and cerebellar Purkinje cells. These findings suggest that RNA toxicity caused by UUUCA repeat expansions is involved in the pathogenesis of BAFME. Since our discovery of the causative gene for BAFME1, progress has been made in genetic studies of each type of BAFME, as well as in pathogenetic mechanisms of BAFME caused by TTTCA and TTTTA expansions. Here, we present a comprehensive review on recent advances focusing on expanded TTTCA and TTTTA repeats in BAFME.

Altered cerebellar-motor loop in benign adult familial myoclonic epilepsy type 1: The structural basis of cortical tremor.

Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar-motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME. Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1-weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato-thalamo-(M1) (primary motor cortex) and globus pallidus internus (GPi)-thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted. Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato-thalamo-M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory-evoked potential P25-N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi-thalamic projection. Higher FA and lower RD in the right GPi-thalamic projection were also observed (FDR q < .05). The present findings support the hypothesis that the cerebello-thalamo-M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.

ATTCT and ATTCC repeat expansions in the ATXN10 gene affect disease penetrance of spinocerebellar ataxia type 10.

SummarySpinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850–4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.

Bilateral Representation of Sensorimotor Responses in Benign Adult Familial Myoclonus Epilepsy: An MEG Study.

Patients with cortical reflex myoclonus manifest typical neurophysiologic characteristics due to primary sensorimotor cortex (S1/M1) hyperexcitability, namely, contralateral giant somatosensory-evoked potentials/fields and a C-reflex (CR) in the stimulated arm. Some patients show a CR in both arms in response to unilateral stimulation, with about 10-ms delay in the non-stimulated compared with the stimulated arm. This bilateral C-reflex (BCR) may reflect strong involvement of bilateral S1/M1. However, the significance and exact pathophysiology of BCR within 50 ms are yet to be established because it is difficult to identify a true ipsilateral response in the presence of the giant component in the contralateral hemisphere. We hypothesized that in patients with BCR, bilateral S1/M1 activity will be detected using MEG source localization and interhemispheric connectivity will be stronger than in healthy controls (HCs) between S1/M1 cortices. We recruited five patients with cortical reflex myoclonus with BCR and 15 HCs. All patients had benign adult familial myoclonus epilepsy. The median nerve was electrically stimulated unilaterally. Ipsilateral activity was investigated in functional regions of interest that were determined by the N20m response to contralateral stimulation. Functional connectivity was investigated using weighted phase-lag index (wPLI) in the time-frequency window of 30–50 ms and 30–100 Hz. Among seven of the 10 arms of the patients who showed BCR, the average onset-to-onset delay between the stimulated and the non-stimulated arm was 8.4 ms. Ipsilateral S1/M1 activity was prominent in patients. The average time difference between bilateral cortical activities was 9.4 ms. The average wPLI was significantly higher in the patients compared with HCs in specific cortico-cortical connections. These connections included precentral-precentral, postcentral-precentral, inferior parietal (IP)-precentral, and IP-postcentral cortices interhemispherically (contralateral region-ipsilateral region), and precentral-IP and postcentral-IP intrahemispherically (contralateral region-contralateral region). The ipsilateral response in patients with BCR may be a pathologically enhanced motor response homologous to the giant component, which was too weak to be reliably detected in HCs. Bilateral representation of sensorimotor responses is associated with disinhibition of the transcallosal inhibitory pathway within homologous motor cortices, which is mediated by the IP. IP may play a role in suppressing the inappropriate movements seen in cortical myoclonus.

A new, sensitive biomarker for abnormal cortical excitability: Single trial based synchronization and desynchronization with cortical myoclonus

Giant somatosensory evoked potentials (SEPs), i.e., enlarged cortical components of SEPs, represent abnormal cortical excitability such as cortical myoclonus (CM). Recently, we reported high-frequency oscillations (HFOs) with a part of giant SEPs specifically observed in benign adult familial myoclonus epilepsy (Tojima et al., 2021). However, no clear HFOs after N33 were observed. We herein hypothesized, in CM patients, late cortical abnormal excitability may be poorly synchronized in average method and thus only detectable by single trial, event-related synchronization (ERS) and desynchronization (ERD). We also compared ERS/ERD between CM patients and healthy controls (HCs).

P-EP028. Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex

Introduction. Although low-dose perampanel (PER) is reportedly effective on cortical myoclonus in a limited number of patients, its underlying mechanisms remain unclear. We aimed to extract and elaborate the clinical effects of PER on refractory cortical myoclonus for dose, etiology and also somatosensory-evoked potential (SEP) findings. Method. We examined 18 epilepsy patients with seizure and cortical myoclonus (10 males; mean age, 48.4 ± 16.2 years; Unverricht-Lundborg disease = 7, benign adult familial myoclonus epilepsy = 6, dentatorubral-pallidoluysian atrophy = 2, Gaucher disease = 1, and Lance-Adams syndrome = 2). Based on data accumulated before and after PER treatment, activities of daily life [ADL]), short latency, cortical components of SEP, and PER blood concentration were analyzed. Results. PER (mean dose: 3.2 ± 2.1 mg/day) significantly improved seizure frequency, myoclonus and ADL scores. It also significantly decreased the amplitude of and prolonged correlate with clinical scores among all patients. In contrast, the degree of P25 prolongation ms) significantly correlated with improved ADL score (p = 0.019) and blood PER concentration (p = 0.011). The degree of N33 prolongation (32.1 ± 4.0 to 33.7 ± 3.4 ms) was positively correlated with ADL score and blood PER concentration (p = 0.025 and p = 0.025, respectively). Conclusion. Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. SEP, especially P25 latency, is a potentially good biomarker to assess the objective effects of PER on intractable cortical myoclonus. ( https://doi.org/10.1016/j.clinph.2019.07.006 ).

P-EV003. Origin of giant somatosensory evoked potentials (SEPS) in benign adult familial myoclonus epilepsy (BAFME) using principle component analysis

Introduction. Both benign adult familial myoclonus epilepsy (BAFME) and Unverricht- Lundborg disease (ULD) belong to progressive myoclonus epilepsy with giant somatosensory evoked potentials (SEPs), but their clinical courses are different from each other. We aimed to delineate the generator source of giant SEP P25 and their high frequency oscillations (HFOs) in patients with BAFME and ULD using principal component analysis (PCA). Methods. PCA was performed on giant SEPs and their HFOs obtained by multi-channel scalp recordings of five patients with BAFME and four patients with ULD. To identify HFOs, SEPs were digitally filtered using a 400–1000 Hz band-pass filter. From the peak latencies of the first or second principal component (PC), we identified the corresponding peaks of original P25 and HFOs near P25 (P25-HFOs). Then, from the polarity and distribution of first and second PCs, the P25 and P25-HFOs were estimated as tangential dipole with phase reversal between frontal and parieto-occipital electrodes or as radial dipole without phase reversal. Results. All five patients with BAFME had P25-HFOs, and both P25 and P25-HFOs were estimated as radial dipole, whereas in all four patients with ULD, P25-HFOs was not present and the estimated components of P25 varied among patients. Conclusion. The generator sources of both P25 and P25-HFOs in giant SEPs in patients with BAFME are radial dipole, which suggests crown origin, and P25-HFOs did not occur in patients with ULD. The generator mechanism of giant SEP P25 and P25-HFOs of BAFME may be different from that of ULD.

A Biomarker for Benign Adult Familial Myoclonus Epilepsy: High-Frequency Activities in Giant Somatosensory Evoked Potentials.

Benign adult familial myoclonus epilepsy (BAFME) is one of the diseases that cause cortical myoclonus (CM) with giant somatosensory evoked potentials (SEPs). There are no useful diagnostic biomarkers differentiating BAFME from other CM diseases. To establish reliable biomarkers including high-frequency oscillations (HFOs) with giant SEPs for the diagnosis of BAFME. This retrospective case study included 49 consecutive CM patients (16 BAFME and 33 other CM patients) who exhibited giant P25 or N35 SEPs. SEPs were processed by a band-pass filter of 400-1000 Hz to analyze HFOs. Clinical and SEP findings were compared between (1) BAFME and other CM groups and (2) patients with presence and absence of P25-HFOs (HFOs superimposed on giant P25). The diagnostic power of each factor for BAFME was calculated. All 16 BAFME patients showed SEP P25-HFOs with significantly higher occurrence (P < 0.0001) compared with that of other CM groups. The presence of P25-HFOs significantly correlated with a BAFME diagnosis (P < 0.0001) and high SEP P25 and N35 amplitudes (P=0.01 and P < 0.0001, respectively). BAFME was reliably diagnosed using P25-HFOs with high sensitivity (100%), specificity (87.9%), positive predictive value (80%), and negative predictive value (100%), demonstrating its superiority as a diagnostic factor compared to other factors. P25-HFOs with giant SEPs is a potential biomarker for BAFME diagnosis. P25-HFOs may reflect cortical hyperexcitability partly due to paroxysmal depolarizing shifts in epileptic neuronal activities and higher degrees of rhythmic tremulousness than those in ordinary CM. © 2021 International Parkinson and Movement Disorder Society.

Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment.

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype-phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype-phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.

DNA analysis of benign adult familial myoclonic epilepsy reveals associations between the pathogenic TTTCA repeat insertion in SAMD12 and the nonpathogenic TTTTA repeat expansion in TNRC6A.

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disease characterized by adult-onset tremulous hand movement, myoclonus, and infrequent epileptic seizures. Recently, intronic expansion of unstable TTTCA/TTTTA pentanucleotide repeats in SAMD12, TNRC6A, or RAPGEF2 was identified as pathological mutations in Japanese BAFME pedigrees. To confirm these mutations, we performed a genetic analysis on 12 Japanese BAFME pedigrees. A total of 143 participants, including 43 familial patients, 5 suspected patients, 3 sporadic nonfamilial patients, 22 unaffected familial members, and 70 unrelated controls, were screened for expanded abnormal pentanucleotide repeats in SAMD12, TNRC6A, RAPGEF2, YEAT2, MARCH6, and STARD7. DNA samples were analyzed using Southern blotting, long-range polymerase chain reaction (PCR), repeat-primed PCR, and long-range PCR followed by Southern blotting. Of the 51 individuals with clinically diagnosed or suspected BAFME, 49 carried a SAMD12 allele with an expanded TTTCA/TTTTA pentanucleotide repeat. Genetic and clinical anticipation was observed. As in previous reports, the one patient with homozygous mutant alleles showed more severe symptoms than the heterozygous carriers. In addition, screening for expanded pentanucleotide repeats in TNRC6A revealed that the frequency of expanded TTTTA repeat alleles in the BAFME group was significantly higher than in the control group. All patients who were clinically diagnosed with BAFME, including those in the original family reported by Yasuda, carried abnormally expanded TTTCA/TTTTA repeat alleles of SAMD12. Patients with BAFME also frequently carried a TTTTA repeat expansion in TNRC6A, suggesting that there may be unknown factors in the ancestry of patients with BAFME that make pentanucleotide repeats unstable.

Founder effect of the TTTCA repeat insertions in SAMD12 causing BAFME1.

Benign adult familial myoclonic epilepsy type 1 (BAFME1) in several Japanese and Chinese families has recently been found to be caused by pentanucleotide repeat expansions in SAMD12. We identified a Thai family with six members affected with BAFME. Microsatellite studies suggested a linkage to the BAFME1 region on chromosome 8q24. Subsequently, long-read whole-genome sequencing showed the (TTTTA)446(TTTCA)149 in intron 4 of SAMD12 in an affected member. Repeat-primed PCR and long-range PCR revealed that the pentanucleotide repeat expansions segregated with the disease status. Our Thai family is the first non-Japanese and non-Chinese family with BAFME1. SNP array showed that the aberrant repeats had the same haplotype as those previously determined in Japanese and Chinese patients suggesting a common ancestry. The variant is estimated to arise ~12,000 years ago.

O1-081 Pathophysiology of benign adult familial myoclonus epilepsy (BAFME) by means of principle component analysis of giant somatosensory evoked potentials (SEPs)

O1-081 Pathophysiology of benign adult familial myoclonus epilepsy (BAFME) by means of principle component analysis of giant somatosensory evoked potentials (SEPs)

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

Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical myoclonus with or without seizures. Recently, it was reported to be associated with intronic TTTTA/TTTCA expansions. To investigate whether these abnormal expansions are involved in our new pedigree from China, whole exome sequencing (WES) and repeat-primed polymerase chain reaction (RP-PCR) analysis were performed to detect potential mutation in pedigree members. Neither causal mutations cosegregated with the disease in the family nor any novel mutation was identified through WES, while an abnormal TTTCA expansion in SAMD12 was identified by RP-PCR and then proved to be cosegregated in the pedigree. All the 12 alive affected individuals (M/F = 4/8; average age = 46.7 years old, range from 27 to 66) showed typical characteristics of BAFME. In addition, maternal clinical anticipation was observed in six mother/child pairs. In conclusion, our study offered the evidence of intronic pentanucleotide expansions in SAMD12 from a new Chinese BAFME pedigree, which further confirmed the association between this expansion and the pathogenesis of BAFME.

TTTCA repeat insertions in an intron of YEATS2 in benign adult familial myoclonic epilepsy type 4.

Epilepsy is a common neurological disorder and identification of its causes is important for a better understanding of its pathogenesis. We previously studied a Thai family with a type of epilepsy, benign adult familial myoclonic epilepsy type 4 (BAFME4), and localized its gene to chromosome 3q26.32-q28. Here, we used single-molecule real-time sequencing and found expansions of TTTTA and insertions of TTTCA repeats in intron 1 of YEATS2 in one affected member of the family. Of all the available members in the family-comprising 13 affected and eight unaffected-repeat-primed PCR and long-range PCR revealed the co-segregation of the TTTCA repeat insertions with the TTTTA repeat expansions and the disease status. For 1116 Thai control subjects, none were found to harbour the TTTCA repeats while four had the TTTTA repeat expansions. Therefore, our findings suggest that BAFME4 is caused by the insertions of the intronic TTTCA repeats in YEATS2. Interestingly, all four types of BAFMEs for which underlying genes have been found (BAFMEs 1, 4, 6 and 7) are caused by the same molecular pathology, suggesting that the insertions of non-coding TTTCA repeats are involved in their pathogenesis.