A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients

Neshige, Shuichiro; Hitomi, Takefumi; Tojima, Maya; Oi, Kazuki; Kobayashi, Katsuya; Matsuhashi, Masao; Shimotake, Akihiro; Matsumoto, Riki; Kanda, Masutaro; Makino, Hírofumi; Ishiura, Hiroyuki; Tsuji, Shoji; Takahashi, Ryōsuke; Ikeda, Akio

doi:10.1002/mds.28718

Cited by 7 publications

(8 citation statements)

References 7 publications

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“…The latter finding is in line with our previous study 46 showing a gradual and progressive worsening of the myoclonus overtime, which was correlated with the duration of the disease and with patients’ age. Interestingly, Neshige et al 47 suggested that at least two mechanisms might be involved in time-dependent neuronal dysfunction, such as repeat expansion causing cellular toxicity in the long-term and continuous excessive hyperexcitability state or bombardment of epileptic discharges.…”

Section: Discussionmentioning

confidence: 99%

“…This finding seems to be in contrast with two previous cross-sectional studies that suggest a significant relationship between giant SEP and myoclonus severity 54 and aging. 47 A possible explanation may be the higher amount of ASMs that could reduce somatosensory cortex excitability in patients with more severe disease or possible concomitant cortical atrophy mechanisms in the later disease stage. However, only future longitudinal studies could address this important question.…”

Section: Discussionmentioning

confidence: 99%

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Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

Dubbioso

Striano

Tomasevic

et al. 2022

Brain Communications

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Familial Adult Myoclonic Epilepsy type 2 is a hereditary condition characterized by cortical tremor, myoclonus, and epilepsy. It belongs to the spectrum of cortical myoclonus and the sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying this condition. Besides pericentral cortical structures, the impairment of subcortical networks seems also to play a pathogenetic role, mainly via the thalamo-cortical pathway. However, the mechanisms underlying cortical-subcortical circuits dysfunction, as well as their impact on clinical manifestations, are still unknown. Therefore, the main aims of our study were to systematically study with an extensive electrophysiological battery the cortical sensorimotor as well as thalamo-cortical networks in genetically confirmed Familial Adult Myoclonic Epilepsy patients and to establish reliable neurophysiological biomarkers for the diagnosis. In 26 Familial Myoclonic Epilepsy subjects, harbouring the intronic ATTTC repeat expansion in the StAR-related lipid transfer domain-containing 7 gene, 17 Juvenile Myoclonic Epilepsy patients and 22 healthy controls, we evaluated the facilitatory and inhibitory circuits within the primary motor cortex using single and paired-pulse transcranial magnetic stimulation paradigms. We also probed the excitability of the somatosensory as well as the thalamo-somatosensory cortex connection by using ad hoc somatosensory evoked potential protocols. The sensitivity and specificity of transcranial magnetic stimulation and somatosensory evoked potential metrics were derived from receiver operating curve analysis. Familial Adult Myoclonic Epilepsy patients displayed increased facilitation and decreased inhibition within the sensorimotor cortex compared with Juvenile Myoclonic Epilepsy patients (all p< 0.05) and healthy controls (all p< 0.05). Somatosensory evoked potential protocols also displayed a significant reduction of early high-frequency oscillations and less inhibition at paired-pulse protocol, suggesting a concomitant failure of thalamo-somatosensory cortex circuits. Disease onset and duration, and myoclonus severity did not correlate either with sensorimotor hyperexcitability or thalamo-cortical measures (all p> 0.05). Patients with a longer disease duration had a more severe myoclonus (r= 0.467, p= 0.02) associated with a lower frequency (r= -0.607, p= 0.001) and higher power of tremor (r= 0.479, p= 0.02). Finally, Familial Adult Myoclonic Epilepsy was reliably diagnosed using transcranial magnetic stimulation, demonstrating its superiority as a diagnostic factor compared to somatosensory evoked potential measures. In conclusion, sensorimotor cortical and thalamo-cortical circuits are involved in the pathophysiology of Familial Adult Myoclonic Epilepsy even if these alterations are not associated with clinical severity. Transcranial magnetic stimulation-based measurements display an overall higher accuracy than somatosensory evoked potential parameters to reliably distinguish Familial Adult Myoclonic Epilepsy from Juvenile Myoclonic Epilepsy and healthy controls.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

Dubbioso

Striano

Tomasevic

et al. 2022

Brain Communications

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“…So far, neurophysiological studies have consistently demonstrated marked and diffuse hyperexcitability of cortical areas, such as somatosensory, motor, and visual areas, likely due to excessive facilitation along with decreased inhibition of cortical excitability only partially attenuated by current ASMs. However, such cortical hyperexcitability is not strictly associated with disease severity and the size of expanded repeats 39 . The lack of correlation among cortical hyperexcitability measures and phenotypes as well as genotype would point to the intrinsic heterogeneity in clinical (i.e., phenotypic variability due to different ethnic origins), genetic (i.e., the site of the intronic expansion), as well as neurophysiological features of the disease (i.e., complex pathophysiological interaction between cortical and subcortical structures) 2 …”

Section: Discussionmentioning

confidence: 99%

“…Somatosensory hyperexcitability, indexed by giant SEPs, seems to be associated with a more severe myoclonus 23 and older age 39 . However, such results were not entirely confirmed by the other two studies, 32,37 raising the question that not only cortical circuits but also subcortical networks might play a role in disease severity.…”

Section: Somatosensory Evoked Potentialsmentioning

confidence: 92%

“…However, such cortical hyperexcitability is not strictly associated with disease severity and the size of expanded repeats. 39 The lack of correlation among cortical hyperexcitability measures and phenotypes as well as genotype would point to the intrinsic heterogeneity in clinical (i.e., phenotypic variability due to different ethnic origins), genetic (i.e., the site of the intronic expansion), as well as neurophysiological features of the disease (i.e., complex pathophysiological interaction between cortical and subcortical structures). 2 We suggest that FAME/BAFME clinical features should arise from "an abnormal neuronal network" activity.…”

Section: Motor Evoked Potentialsmentioning

confidence: 99%

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Familial adult myoclonus epilepsy: Neurophysiological investigations

et al. 2023

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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.

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(TTTCA)exp Drives the Genotype–Phenotype Correlation and Genetic Anticipation in FCMTE1

Chen,

Wang,

Xia

et al. 2024

Movement Disorders

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BackgroundThe pentanucleotide (TTTCA) repeat expansion (exp) insertion, along with the accompanying (TTTTA)exp, causes familial cortical myoclonic tremor with epilepsy (FCMTE). The genotype–phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp are still unclear.ObjectiveThe aim was to investigate the genotype–phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp in FCMTE1.MethodsWe performed targeted long‐read sequencing on 77 FCMTE1 patients. After quality control, metrics such as total repeat count, respective (TTTTA)exp and (TTTCA)exp count, and interruptions were assessed in 73 patients. Correlations between metrics and the patients' clinical features, as well as repeat instability during parental transmission, were analyzed.ResultsAmong 73 alleles, the average total repeat counts were 848 ± 152 units, with (TTTTA)exp and (TTTCA)exp averaging 498 ± 196 units and 356 ± 110 units, respectively. (TTTCA)exp counts were inversely correlated with the age at onset for cortical tremor (Spearman's rho = −0.348, P = 0.005) and epilepsy (Spearman's rho = −0.424, P = 0.003). A negative correlation was found between (TTTCA)exp counts and relatively moderate seizure pattern with prodrome (odds ratio = 0.988, 95% confidence interval: 0.980–0.995, P = 0.002). During parental transmission, (TTTCA)exp counts increased significantly (P = 0.007), with maternal transmission showing a significantly larger increase compared to paternal transmission (P = 0.013).ConclusionThe (TTTCA)exp insertion serves as the length‐dependent pathogenic component within the two‐motif repeat expansion. Its differential expanding nature during parental transmissions is highly associated with the genetic anticipation in FCMTE1. © 2024 International Parkinson and Movement Disorder Society.

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A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients

Abstract: introduction, results, methods, comparison to the original assay, 2,5 and discussion are included as Appendix S1.

Cited by 7 publications

References 7 publications

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications

Familial adult myoclonus epilepsy: Neurophysiological investigations

(TTTCA)exp Drives the Genotype–Phenotype Correlation and Genetic Anticipation in FCMTE1

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