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Recently repeat expansions have been found in more than 10 diseases in the past two years. Because the same repeat motifs are found in similar disease (as exemplified by benign adult familial myoclonic epilepsy) or in diseases with overlapping phenotype (as exemplified by fragile X tremor/ataxia syndrome, neuronal intranuclear inclusion disease, oculopharyngeal myopathy with leukoencephalopathy, and oculopharyngodistal myopathy), we propose a new concept of 'repeat motif-phenotype correlation', which argue for toxic gain-of-function mechanism caused by expanded repeats, rather than altered functions of genes harboring expanded repeats. The concept is expected to help identify repeat expansions taking the similar or overlapping clinical presentations as the clues. Although repeat expansions have been identified predominantly in autosomal dominant diseases, recent progresses have demonstrated that they are also observed in autosomal recessive diseases. Furthermore, repeat expansions are not infrequently observed in patients without family histories, which urges us to pay attention to sporadic diseases. We should expand our views toward repeat expansion diseases to accelerate discovery of diseases caused by repeat expansions, better understanding the disease mechanisms, and development of therapeutic measures.

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.

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.

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.

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.

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.

Noncoding expanded repeats have been implicated in a wide range of diseases. A new report uncovers expanded TTTCA and TTTTA repeats in an intronic region of SAMD12, and at least two other genes, in individuals with benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures. We investigated a Thai BAFME family. Clinical and electrophysiological studies revealed that 13 were affected with BAFME. There were a total of 24 individuals studied. Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23.3-q24.1, and 2p11.1-q12.2. GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26.32-3q28. This locus represents the fourth chromosomal region for BAFME.

Benign adult familial myoclonic epilepsy (BAFME) is a non-progressive monogenic epilepsy syndrome. So far, the structural and functional brain reorganizations in BAFME remain uncharacterized. This study aims to investigate gray matter atrophy and related functional connectivity alterations in patients with BAFME using magnetic resonance imaging (MRI). Eleven BAFME patients from a Chinese pedigree and 15 matched healthy controls were enrolled in the study. Optimized voxel-based morphometric and resting-state functional MRI approaches were performed to measure gray matter atrophy and related functional connectivity, respectively. The Trail-Making Test-part A and part B, Digit Symbol Test (DST), and Verbal Fluency Test (VFT) were carried out to evaluate attention and executive functions. The BAFME patients exhibited significant gray matter loss in the right hippocampus, right temporal pole, left orbitofrontal cortex, and left dorsolateral prefrontal cortex. With these regions selected as seeds, the voxel-wise functional connectivity analysis revealed that the right hippocampus showed significantly enhanced connectivity with the right inferior parietal lobule, bilateral middle cingulate cortex, left precuneus, and left precentral gyrus. Moreover, the BAFME patients showed significant lower scores in DST and VFT tests compared with the healthy controls. The gray matter densities of the right hippocampus, right temporal pole, and left orbitofrontal cortex were significantly positively correlated with the DST scores. In addition, the gray matter density of the right temporal pole was significantly positively correlated with the VFT scores, and the gray matter density of the right hippocampus was significantly negatively correlated with the duration of illness in the patients. The current study demonstrates gray matter loss and related functional connectivity alterations in the BAFME patients, perhaps underlying deficits in attention and executive functions in the BAFME.

Lili Long,1 Yanmin Song,1 Linlin Zhang,2 Chongyu Hu,3 Jian Gong,2 Lin Xu,1 Hongyu Long,1 Luo Zhou,1 Yunci Zhang,2 Yong Zhang,2 Bo Xiao1 1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 2The People’s Hospital of Fuyang, Anhui Province, People’s Republic of China; 3Department of Neurology, Hunan Provincial People’s Hospital, People’sRepublic of China Background: Benign adult familial myoclonic epilepsy (BAFME) is a rare form of epilepsy syndrome. The pathogenesis of BAFME remains unclear, though it seems to involve dysfunction of the cerebellum. Objectives: The purpose of this study was to use proton magnetic resonance spectroscopy (1H-MRS) to investigate whether neurochemical changes underlie abnormal brain function in BAFME. Methods: Twelve BAFME patients from one family and 12 age- and sex-matched healthy controls were enrolled in this study. The ratios of NAA/Cr, NAA/Cho, Cho/Cr, and NAA/(Cr+Cho) were analyzed. Results: The BAFME patients exhibited a decreased N-acetylaspartate (NAA)/choline (Cho) ratio in the cerebellar cortex, whereas there were no significant differences in the NAA/creatine (Cr), Cho/Cr, and NAA/(Cr+Cho) ratios compared with healthy controls. There were no significant differences in 1H-MRS values in the frontal cortex or thalamus between the BAFME patients and controls. No correlation was detected between the NAA/Cho ratio in the cerebellar cortex and disease duration, myoclonus severity, or tremor severity. Conclusion: Our results indicate clear cerebellar dysfunction in BAFME. 1H-MRS is a useful tool for the diagnosis of BAFME in combination with family history and electrophysiological examination. Keywords: benign adult familial myoclonic epilepsy (BAFME), proton magnetic resonance spectroscopy (1H-MRS), cerebellum, cortical tremor, myoclonus

The association of cortical tremor, myoclonus and epileptic seizures has been reported in many Japanese and European families with different acronyms. We reviewed the familial cases presenting the clinical picture of autosomal dominant cortical tremor, myoclonus and epilepsy and analysed the phenotypic differences between the pedigrees, according to the recent genetic acquisitions. We concluded that BAFME, FAME, FEME, FCTE and ADCME are the same clinical entity even if genetically heterogeneous, with Japanese families linked to 8q24 and Italian ones to 2p11.1-q12. A third locus could also be involved. Further studies should better clarify the electrophysiological features of this condition and identify the underlying molecular defects.

Summary: Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course, recognized in Japanese families. We recently assigned the gene locus to chromosome 8q23.3-q24.11 by linkage analysis. In this study, we identified the sequence of human cDNA encoding Kv8.1, a neuronal modulatory α-subunit of the voltage-gated potassium channel, mapped to human chromosome 8q22.3-8q24.1. Human Kv8.1 cDNA had a 1,500-nucleotide open reading frame encoding a polypeptide of 500 amino acids, in which six hydrophobic transmembrane segments were well conserved, and its overall amino acids homology as compared with those of rat and golden hamster was 95.0% and 95.0%. Tissue-distribution analysis by reverse transcription–polymerase chain reaction (RT-PCR) showed the presence of the Kv 8.1 transcript exclusively in the brain. The analysis of the genomic organization of the human gene revealed consistency of three exons interrupted by two introns each of 1.2 and 3.5 kb. We analyzed the genomic sequence of the patients with BAFME and found no change in the pathogenesis of the disease.

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1).

application/pdf, Epilepsy is a neurological disorder characterized by recurring seizures. It is physiologically characterized by abnormal, excessive and self-terminating discharges from neurons. Epilepsy affects more than 0.5 % of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the identity of the susceptibility genes is largely unknown. This article reviews recent progress made in molecular genetics of epilepsy, including our own discovery of two novel mutations in the genes of autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions, and our mapping of the genetic locus of benign adult familial myoclonic epilepsy. Pathogenesis of epilepsy as a channelopathy and perspectives of molecular genetic study of epilepsy are also discussed., 弘前医学. 51(Suppl.), 1999, p.S99-105

application/pdf, てんかんの原因遺伝子解明を目標に,1993年｢てんかん･熱性けいれん遺伝(千)解 析に関する共同研究グループ｣が設立され,家系収集とサンプリングおよび連鎖解析が進行 している｡家系調査の対象は,特発性てんかんbenignadultfamilialmyoclonicepilepsy, severemyoclonicepilepsyininfancy,benigninfantilefamilialconvulsions, 熱性けいれんである｡特に,特発性てんかんのうち,childhoodabsenceepilepsy,epi･ lepsywithgeneralizedtonic-clonicseizures,benignchildhoodepilepsywithcen･ trotemporalspikeについては,発端者の親子よりも同胞にてんかん罷患者が多く,その てんかん類型は発端者と同じである傾向が大きいことが明瞭であった｡熱性けいれんの家系 は22,benignadultfamilialmy∝lonicepilepsy(BAFME)の家系は17収集されて いる｡BAFMEの連鎖解析により,現時点でその原因遺伝子は,6p,8p,12p,21qには 存在しないことが判明した., てんかん･熱性けいれん遺伝(子)解析に関する共同研究グループ 兼子直ほか37名, てんかん治療研究振興財団研究年報. 8, 1996, p.80-90

Several names (“Cortical Tremor” = Crt Tr, Familial Adult Myoclonic Epilepsy = FAME, Benign Adult Familial Myoclonic Epilepsy = BAFME, Autosomal Dominant Cortical Myoclonus and Epilepsy = ADCME, Familial Cortical Myoclonic Tremor = FCMT, Familial Cortical Tremor with Epilepsy = FCTE, Familial Essential Myoclonus and Epilepsy = FEME, Familial Benign Myoclonus Epilepsy of Adult onset = FMEA, Heredofamilial Tremor and Epilepsy = THE) have been used to define a unique entity, Familial Myoclonic Cortical Tremor with Epilepsy (FCMTE), as proposed by van Rootselaar et al. (2005). All patients with FCMTE criteria share clinical and electrophysiological features. In contrast, Familial Infantile Myoclonic Epilepsy (FIME) and Adult-onset Myoclonic Epilepsy (AME) cannot yet be considered as FMCTE (Striano et al. 2009a).

This is the first report of benign adult familial myoclonic epilepsy (BAFME) with night blindness. Our cases of BAFME (mother, son, and daughter) demonstrated night blindness with a reduced b-wave response on electroretinography (ERG) suggesting an alteration in calcium-mediated neurotransmitter release from photoreceptors in response to light. Several familial epilepsies have been shown to be due to a channelopathy. On the other hand, the mutation of a calcium-channel gene in Xp11.23 was recently reported in incomplete X-linked congenital stationary night blindness (CSNB). Although the gene locus of BAFME was recently assigned to 8q23.3-q24.1, the causative gene has yet to be identified. The present familial case suggests that BAFME may also be a disease of the calcium channel that is present in the retina and the central nervous system (CNS).

Benign adult familial myoclonic epilepsy (BAFME), alternatively named familial adult myoclonic epilepsy 1/familial cortical myoclonic tremor with epilepsy 1 (FAME1/FCMTE1), is a hereditary epileptic syndrome characterized by autosomal dominant inheritance, adult-onset tremulous hand movement, myoclonus, infrequent epileptic seizure and non-progressive course without cerebellar ataxia and dementia. We previously reported evidence for linkage of BAFME to the region between D8S1784 and D8S1694 on chromosome 8q. Subsequently, other research groups reported mapping of the same clinical syndrome to different chromosomal loci, 2p and 5p, in Italian (FAME2/FCMTE2) and French (FAME3/FCMTE3) families, respectively. In this study, we performed a genome-wide linkage analysis using 10K single-nucleotide polymorphism arrays and additional microsatellite markers to reconfirm the BAFME-linked region. The BAFME-linked region was mapped to 7.16 Mb spanned by rs1898287 and rs2891799 on chromosomes 8q23.3-8q24.13 with a maximum two-point logarithm of odds score of 6.0 for the marker rs1021897. Sequence analysis and copy-number variant analysis of all 38 genes localized in the candidate region were performed, but no pathogenic mutation was identified. We conclude that the etiology of BAFME remains to be solved, and further genetic studies, which may require analysis in non-coding regions of a gene, introns or intergenic spacer regions, are necessary to reveal its unknown mutations.

There were several reports in Japan on cases that had characteristic features of what is now called benign adult familial myoclonic epilepsy (BAFME). Patients with BAFME often had irregular fine dysrhythmic involuntary movement, which became evident on outstretched extended arms. One of the characteristics of BAFME was giant somatosensory evoked potential (G-SEP) with enhanced long-loop cortical reflexes and premovement cortical spikes by the jerk-locked averaging method, suggesting hyperexcitability of cerebral cortex. Differential diagnosis includes a variety of progressive myoclonus epilepsy, hereditary tremor, and idiopathic epilepsies such as juvenile myoclonic epilepsy (JME) and grand mal on awaking. Careful history-taking reveals that the BAFME family history had a dominant hereditary pattern of almost complete penetrance, which is unusual for idiopathic generalized epilepsy (IGE). The presence of involuntary hand tremor with seizure strongly suggests the diagnosis of BAFME.

International audience; BACKGROUND: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by autosomal dominant adult-onset cortical myoclonus (CM) and seizures in 40% of patients. Two loci, 8q23.3-q24.11 (FAME1/FCMTE1) and 2p11.1-q12.2 (FAME2/FCMTE2), were previously reported without an identified gene. Unlinked families argue for a third mutated gene. METHODS: A genome-wide scan was performed in a large FCMTE family using Linkage-12 microarrays (Illumina). Refinement of the locus on 5p was performed by genotyping 13 polymorphic microsatellite markers in the 45 available family members. RESULTS: This large French FCMTE family included 16 affected relatives. The first symptoms were CM in 5 patients (31.2%), seizures in 5 patients (31.2%), and both at the same time in 6 patients (37.5%). A total of 12.5% (2/16) had only CM without seizures. The genome-wide scan identified a single region on 5p15.31-p15, with a multipoint lod score of 3.66. Further genotyping of all family members confirmed that the region spans 9.31 Mb between D5S580 and D5S2096, 2-point lod scores reaching 6.3 at theta = 0 for D5S486. Sequencing of the SEMA5A and CTNND2 genes failed to detect mutations. CONCLUSIONS: We report the clinical and genetic characteristics of a large familial cortical myoclonic tremor with epilepsy family. The third gene maps to 5p15.31-p15. Identification of the mutated gene is ongoing.

Work on the classification of epileptic syndromes is ongoing, and many syndromes are still under discussion. In particular, special difficulty still persists in correctly classifying epilepsies with myoclonic seizures. The existence of special familial epileptic syndromes primarily showing myoclonic features has been recently suggested on the basis of a clear pattern of inheritance or on the identification of new chromosomal genetic loci linked to the disease. These forms in development include familial infantile myoclonic epilepsy (FIME), benign adult familial myoclonic epilepsy (BAFME), or autosomal dominant cortical myoclonus and epilepsy (ADCME), and, maybe, adult-onset myoclonic epilepsy (AME). In the future, the identification of responsible genes and the protein products will contribute to our understanding of the molecular pathways of epileptogenesis and provide neurobiologic criteria for the classification of epilepsies, beyond the different phenotypic expression.

Summary Purpose: To investigate the neurochemical pattern in patients with benign adult familial myoclonic epilepsy (BAFME/FAME), an inherited form of myoclonic epilepsy, by proton magnetic resonance (MR) spectroscopy (1H-MRS). Methods: Eleven BAFME patients from three families showing linkage to 2p11.1-q12.2 were compared with 11 age-matched healthy control subjects. Results: MR imaging of all the patients and healthy subjects exhibited no structural abnormalities on detailed visual assessment. However, compared with healthy subjects, patients with BAFME displayed elevated choline/creatine ratio in the cerebellar cortex (p = 0.01), whereas there was no significant difference for the other ratios. No 1H-MRS values in the frontal and occipital cortex differed significantly in the patients compared with the healthy controls. No correlation was detected between 1H-MRS values and disease duration (p = −0.35) as well as myoclonus severity (p = −0.48). Conclusions: Our findings suggest that the cerebellum is a prominent site of dysfunction in BAFME. The abnormal choline concentrations could reflect changes in the chemical and functional nature of cell membranes. 1H-MRS was able to detect brain changes also in patients with recent disease onset and may be a useful tool supporting the diagnosis based on familial and electrophysiologic data. The relationship between cortical tremor and the cerebellum is also discussed.

Benign adult familial myoclonic epilepsy (BAFME or FAME) is an autosomal dominant condition, characterized by shivering-like tremors of cortical origin, myoclonus, and epilepsy. Linkage to chromosomes 2p11.1-q12.2 and 8q23.1-q24.11 has been reported in Japanese and Italian families, respectively. We aimed to determine whether a common founder haplotype was shared by five BAFME families from southern Italy and attempted preliminary genotype-phenotype correlation analyses. Five Italian BAFME families were identified. One family has not been previously reported. DNA from 53 affected individuals was genotyped with highly polymorphic microsatellite markers spanning chromosomes 2p11.1-q12.2 and 8q23.1-q24.11. Multipoint linkage analysis was performed using LINKMAP 5.1 software assuming an autosomal dominant trait with 0.99 penetrance and frequency of 0.001. Significant linkage was found on chromosome 2p11.1-q12.2 and a maximum cumulative lod score of 18.5 was found for markers D2S2161 and D2S388. The haplotype "5332" of adjacent markers D2S388, D2S2216, D2S113, and D2S2175 segregates with the disease in all families indicating that the same mutation inherited from a common ancestor segregates in these families. Preliminary genotype-phenotype showed that patients carrying the disease haplotype show minor clinical differences, suggesting that expressivity of the founder mutation is not markedly influenced by other factors. The identification of causative mutations in BAFME requires an extensive and collaborative screening effort.

Benign adult familial myoclonic epilepsy (BAFME) were mapped on chromosome 8q24 and 8q23.3-q24.1 in Japanese pedigrees and mapped on 2p11.1-2q12.2 in European pedigrees, respectively. Recently, we recruited a large BAFME pedigree in China. After genotyping 11 microsatellite markers covering the two previously identified chromosome regions, we performed linkage analyses. However, evidence of negative linkage was found in the two previously reported candidate regions (LOD score-3.0 at no recombination). Our data suggest that the causative gene responsible for BAFME in the Chinese pedigree may be located on a new region other than 8q23.3-q24.1 and 2p11.1-q12.2, indicating the presence of a third locus for BAFME.

Summary: Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant condition characterized by cortical tremor and generalized seizures, mapped on chromosome 8q24 by Japanese authors. Recently the same phenotype also was reported in European families, with linkage on chromosome 2. We present a new family with suggestion of linkage to chromosome 2p11.1-2q12.2 (lod score value, 1.55). This observation would confirm that BAFME is a worldwide, genetically heterogeneous condition, probably with Japanese families linked to 8q24 and European families to 2p11.1-q12.2.

Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q24; however, genetic heterogeneity has been recently suggested. The authors report a clinical and electrophysiologic study of two Italian BAFME families showing linkage to chromosome 2p11.1-q12.2. Their report supports the evidence of non-Japanese families with BAFME and suggests a possible allelism with the recently described autosomal dominant cortical myoclonus and epilepsy syndrome.

Epilepsy affects >0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance, and the identity of the susceptibility genes is largely unknown despite recent advances in molecular biology. However, genetic identifiers of certain types of epilepsy with neurodegenerative characteristics and of a small number of familial idiopathic epilepsies have been uncovered to date. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy together with our own discovery of novel mutations in the genes of autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions (BFNCs), and the genetic locus of benign adult familial myoclonic epilepsy. Pathogenesis of epilepsy as a channelopathy and of BFNC also is discussed.

Epilepsy affects more than 0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy, and those of two K(+) channel genes were identified to be responsible for underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na(+) -channel (alpha1,2 and beta1 subunit), and GABA receptor (gamma2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe myoclonic epilepsy in infancy. Mutations of Ca(2+)-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of epilepsy are discussed.

Objective : To describe electrophysiological findings in a patient with Creutzfeldt–Jakob disease (CJD) showing negative myoclonus. Methods and results : We studied this CJD patient electrophysiologically, in comparison with two patients with cortical reflex positive myoclonus due to benign adult familial myoclonic epilepsy (BAFME). Spontaneous negative myoclonus was associated with periodic synchronous discharges (PSDs) on the electroencephalogram, but negative myoclonus could also be induced by electrical stimulation of the median nerve in the CJD patient. This patient showed giant somatosensory evoked potentials (SEPs) and enhanced C reflexes, and the duration of the induced EMG silences was found to be significantly correlated with the amplitude of cortical SEPs. The duration of silent periods (SPs) produced by magnetic stimulation of the motor cortex was extremely long. The study of recovery function of SEPs suggested that the excitability of the somatosensory cortex was decreased during a long post-stimulus period. These findings were clearly different from those of patients with BAFME. Conclusions : This CJD patient had two types of negative myoclonus; one was associated with PSDs and the other was cortical reflex negative myoclonus. The long-lasting decrease in excitability of the sensorimotor cortices after stimulation could be related to the occurrence of both types of negative myoclonus.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Objective: To identify the genetic locus for the familial adult myoclonic epilepsy ( FAME ) gene. Background: Idiopathic generalized epilepsy (IGE) represents a collection of disorders in which affected individuals present with recurring seizures that have diffuse onset on EEG. These individuals have no known structural cerebral lesions or other identifiable etiology. IGE accounts for approximately 40% of all epilepsies. FAME is a type of IGE characterized by autosomal dominant inheritance, adult onset, varying degrees of myoclonus in the limbs, rare tonic-clonic seizures, and a benign course. Methods: We investigated four previously reported Japanese kindreds and performed a genome-wide screen with genetic linkage analysis. Results: Clinical characterization and sampling of 30 individuals in four families revealed that 21 had the FAME phenotype. We defined a 4.6-cM region on chromosome 8q24 (maximum lod score of 4.86 at θ = 0) that contains the FAME gene. Conclusions: The identification and characterization of the FAME gene allows us to better understand the molecular basis of FAME. Such knowledge may provide clues to understanding the molecular basis of the clinically similar, and more common, juvenile myoclonic epilepsies, and other generalized seizure disorders that have thus far eluded genetic approaches.

Objective To describe a European family with cortical tremor, epilepsy, and mental retardation, the pedigree of which indicates an autosomal dominant inheritance of the disease. Design Clinical, laboratory, neurophysiological, and neuroimaging data were studied. Setting Institute for research on mental retardation. Patients Two siblings (aged 25 and 28 years) and their 49-year-old mother had postural and action tremor, seizures, and mental retardation. Only tremor was present in the maternal grandmother (aged 68 years). The electroencephalogram showed diffuse spike-and-wave complexes and/or posterior spikes, and a photoparoxysmal response in the 4 subjects. The typical electrophysiologic features of cortical reflex myoclonus, such as giant somatosensory evoked potentials, enhancement of the C-reflex, and jerk-locked premyoclonus spikes, were found in all patients. Conclusion This syndrome may represent a specific form of familial cortical tremor with a benign form of epilepsy and a new genetic model of cortical hyperexcitability inherited with an autosomal dominant mechanism.

We describe a pedigree in which eight individuals presented with a non-progressive disorder with onset between the ages of 12 and 50 years. It was characterized by predominantly distal, semi-continuous rhythmic myoclonus (all patients), generalized tonic-clonic seizures (all patients) and complex partial seizures (three patients). Most individuals had rarely suffered seizures and had a normal cognitive level, but three individuals with intractable seizures had mild mental retardation. The pattern of inheritance was autosomal dominant with high penetrance. We defined this disorder as autosomal dominant cortical myoclonus and epilepsy (ADCME). All patients had frontotemporal as well as generalized interictal EEG abnormalities. A neurophysiological study of the myoclonus suggested a cortical origin. Back-averaging of the data generated a series of waves with a frequency that mirrored the frequency of EMG bursts. Frequency analysis identified significant peaks with coherence between EMG and EEG, which were recorded over the contralateral rolandic area in five patients. The frequency of coherence was 8-25 Hz and phase spectra confirmed that EEG activity preceded EMG activity by 8-15 ms. In two individuals there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity. The C-reflex at rest was enhanced and somatosensory and visual evoked potentials were of high amplitude. The resting motor threshold intensity to transcranial magnetic stimulation was significantly reduced (38%; SD +/- 7; P = 0.01) and the post-motor evoked potential silent period (101 ms; SEM +/- 10) was significantly shortened compared with the controls (137 ms; SEM +/- 18). These clinical and neuro- physiological characteristics suggest diffuse cortical hyperexcitability and high propensity for intra-hemispheric and inter-hemispheric cortical spread, as well as rhythmic myoclonic activity. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 in 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at Theta 0.0 for marker D2S2175. Multipoint LOD score values, reaching 3.74 around D2S2175, localize the ADCME gene to the centromeric region of chromosome 2. The exclusion of the locus for familial adult myoclonic epilepsy on chromosome 8q23.3-q24 from linkage to our family and the new localization of the responsible gene to chromosome 2cen, together with the different phenotype, define a new epilepsy syndrome. We hypothesize that the responsible gene causes cortical hyperexcitability that is widespread but particularly involves the frontotemporal circuits.