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

Pan, Sipei; Li, Xuying; Li, Liping; Hua, Lin; Wang, Dequan; Zhang, Xiating; Zhao, Xin; Ye, Jing; Huang, Zhaoyang; Lin, Yicong; Duan, Yiran; Ma, Rui; Gao, Lehong; Wang, Chaodong; Wang, Yuping

doi:10.1016/j.seizure.2021.02.026

Cited by 11 publications

(13 citation statements)

References 26 publications

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“…These included NM_173851.3:c.206A > T:p.(Tyr69Phe) in SLC30A8 (FAME1), 7 NM_000682.7:c.675_686delinsGTTTGGCAG in ADRA2B (FAME2), 23 and NM_001332.4:c.3130G > A:p.(Glu1044Lys) in CTNND2 (FAME3) 21 . Isolated variants, all of which fell outside known FAME linkage intervals, were also identified: NM_015902.6:c.5720G > A:p.(Arg1907His) in UBR5 in a Chinese family, 24 NM_003560.4:c.475G > A, p.Ala159Thr in PLA2G6 in a Chinese family (who now have a confirmed SAMD12 repeat expansion), 25,26 NM_138326.3:c.77G > A:p(Trp26*) in ACMSD in a Spanish family, 27 and NM_003946.7:c.61G > C:p.(Glu21Gln) in NOL3 in a Canadian family with familial cortical myoclonus without epilepsy 28 . Finally, a homozygous variant, NM_005076.5:c.504del (p.Trp168fs) in CNTN2 , segregated with autosomal recessive FAME (OMIM, FAME5: 615400) in an Egyptian family 29 .…”

Section: The Hunt For the Genetic Cause Of Famementioning

confidence: 99%

“…Mizuguchi et al 43 identified a huge degree of variability in the numbers of copies of TTTTA and TTTCA pentamers in FAME1 repeats between different individuals from different families, including in one individual where only 14 copies of the TTTCA motif were observed. To date, there is no evidence that TTTTA expansions alone are pathogenic 26 …”

Section: Genotype To Phenotype Relationships In Famementioning

confidence: 99%

“…Anticipation occurs in FAME families; however, correlation of anticipation with an increase in repeat length between parent and child remains uncertain due to the low numbers of relationships where this has been studied at the molecular level 31,39,46 . Paternal or maternal inheritance and maternal age have been investigated as potential risk factors; however, these have not shown significant correlation with germline repeat instability to date 4,26,39 . There are no known genetic modifiers for susceptibility to germline or somatic repeat instability of FAME repeat expansions.…”

Section: Genotype To Phenotype Relationships In Famementioning

confidence: 99%

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Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions

Corbett

Depienne²,

Veneziano

et al. 2023

Epilepsia

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Familial adult myoclonus epilepsy (FAME) is a genetic epilepsy syndrome that for many years has resisted understanding of its underlying molecular cause. This review covers the history of FAME genetic studies worldwide, starting with linkage and culminating in the discovery of noncoding TTTTA and inserted TTTCA pentanucleotide repeat expansions within six different genes to date (SAMD12, STARD7, MARCHF6, YEATS2, TNRC6A, and RAPGEF2). FAME occurs worldwide; however, repeat expansions in particular genes have regional geographical distributions. FAME repeat expansions are dynamic in nature, changing in length and structure within germline and somatic tissues. This variation poses challenges for molecular diagnosis such that molecular methods used to identify FAME repeat expansions typically require a trade‐off between cost and efficiency. A rigorous evaluation of the sensitivity and specificity of each molecular approach remains to be performed. The origin of FAME repeat expansions and the genetic and environmental factors that modulate repeat variability are not well defined. Longer repeats and particular arrangements of the TTTTA and TTTCA motifs within an expansion are correlated with earlier onset and increased severity of disease. Other factors such as maternal or paternal inheritance, parental age, and repeat length alone have been suggested to influence repeat variation; however, further research is required to confirm this. The history of FAME genetics to the present is a chronicle of perseverance and predominantly collaborative efforts that yielded a successful outcome. The discovery of FAME repeats will spark progress toward a deeper understanding of the molecular pathogenesis of FAME, discovery of new loci, and development of cell and animal models.

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Section: The Hunt For the Genetic Cause Of Famementioning

confidence: 99%

Section: Genotype To Phenotype Relationships In Famementioning

confidence: 99%

Section: Genotype To Phenotype Relationships In Famementioning

confidence: 99%

See 1 more Smart Citation

Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions

Corbett

Depienne²,

Veneziano

et al. 2023

Epilepsia

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“…- Nucleotide repeat expansions: increment of the number of adjacent repetitions of a determined nucleotide (e.g., triplets) in a given DNA region, leading to different functional results depending on the number of repetitions and other factors. These variants are related to particular syndromes, such as familial cortical myoclonus ( 12 ) or Fragile X syndromes ( 13 ) and cannot be detected with conventional methods such as gene-panel sequencing or microarrays ( 14 ).…”

Section: Basic Concepts About Types Of Genetic Variantsmentioning

confidence: 99%

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Beltrán‐Corbellini

Aledo‐Serrano

Møller³

et al. 2022

Front. Neurol.

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This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.

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“…These larger cohorts lead to a much better genotype–phenotype characterization of these syndromes. In the past 2 years, several single-center and multicentric studies have generated new insights into the electrographic and phenotypic spectrum of the following genetic epilepsies: PIGS-associated early-onset developmental and epileptic encephalopathy [6], Angelman syndrome [7], LAMA-2 -related muscular dystrophy [8], Mowat–Wilson syndrome [9], neurofibromatosis type 1 [10], CLCN4 -related epilepsy [11], Poirier–Bienvenu syndrome [12], and familial cortical myoclonic tremor with epilepsy type 1 [13].…”

Section: Genotype–phenotype Correlationmentioning

confidence: 99%

Updates on the diagnostic evaluation, genotype–phenotype correlation, and treatments of genetic epilepsies

Zimmern

Korff

2022

Current Opinion in Pediatrics

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Purpose of reviewThis article reviews the latest publications in genetic epilepsies, with an eye on publications that have had a translational impact. This review is both timely and relevant as translational discoveries in genetic epilepsies are becoming so frequent that it is difficult for the general pediatrician and even the general child neurologist to keep up.Recent findingsWe divide these publications from 2021 and 2022 into three categories: diagnostic testing, genotype–phenotype correlation, and therapies. We also summarize ongoing and upcoming clinical trials.SummaryTwo meta-analyses and systematic reviews suggest that exome and genome sequencing offer higher diagnostic yield than gene panels. Genotype–phenotype correlation studies continue to increase our knowledge of the clinical evolution of genetic epilepsy syndromes, particularly with regards to sudden death, auditory dysfunction, neonatal presentation, and magnetoencephalographic manifestations. Pyridoxine supplementation may be helpful in seizure management for various genetic epilepsies. There has been interest in using the neurosteroid ganaxolone for various genetic epilepsy syndromes, with clear efficacy in certain trials. Triheptanoin for epilepsy secondary to glucose transporter 1 (GLUT1) deficiency syndrome is not clearly effective but further studies will be needed.

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

Cited by 11 publications

References 26 publications

Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions

Genetics of familial adult myoclonus epilepsy: From linkage studies to noncoding repeat expansions

Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies

Updates on the diagnostic evaluation, genotype–phenotype correlation, and treatments of genetic epilepsies

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