Cell Biochem Biophys DOI 10.1007/s12013-014-9843-5
ORIGINAL PAPER
A Chinese Benign Adult Familial Myoclonic Epilepsy Pedigree Suggesting Linkage to Chromosome 5p15.31–p15.1 Jia Li • Xinyu Hu • Qiuhui Chen • Yizhi Zhang Ying Zhang • Guohua Hu
•
Ó Springer Science+Business Media New York 2014
Abstract Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q23.3–q24.1, 2p11.1–q12.1, 5p15.31–p15.1, and 3q26.32–3q28, in Japanese, Italian, Thai, and French pedigrees, respectively. Recently, we investigated a Chinese BAFME family. Clinical and electrophysiological studies revealed that nine individuals were affected with BAFME. We aimed to establish the causative gene for this pedigree. We genotyped 17 microsatellite markers covering the four previously identified chromosome regions and performed linkage analyses. The linkage analysis data showed that the LOD score was 2.80 for D5S486 at no recombination. This suggested linkage to 5p15.31–p15.1 and excluded linkage to the other three loci (LOD score\0 at no recombination). Our study suggests that the causative gene responsible for BAFME in the Chinese pedigree may be located on chromosome 5p15.31–p15.1. Keywords Benign adult familial myoclonic epilepsy BAFME Linkage analysis Genetic heterogeneity
Introduction Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant, idiopathic epileptic syndrome,
J. Li Q. Chen Y. Zhang Y. Zhang G. Hu (&) Department of Neurology, the Second Hospital of Jilin University, 218 Ziqiang Road, Changchun 130041, Jinlin, China e-mail: [email protected] X. Hu Department of Neurology, the First Hospital of Jilin University, Changchun, China
characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course [1]. The typical features can be accompanied by mental retardation, migraine, and night blindness [2–4]. BAFME is also known as familial cortical myoclonic tremor with epilepsy. BAFME diagnosis is based on clinical and electrophysiological criteria. It consists of features favoring cortical reflex myoclonus and a good response to antiepileptic drugs [5]. Electrophysiological studies that confirm the cortical origin of myoclonus show enhanced long latency reflexes at rest, giant cortical somatosensory evoked potentials (SEPs), and premyoclonus cortical spikes detected by the jerk-locked back averaging (JLA) method. In 1990, Ikeda et al. [6] first reported electrophysiological studies in two Japanese patients who had adultonset finger tremor, seizure, and a family history of the same condition without a progressive course. They demonstrated involuntary movement as a form of cortical reflex myoclonus. In 1991, Yasuda [7] reported electrophysiological studies in two similar large Japanese families and proposed the syndrome name of BAFME. Since then, a few similar clinical cases have been reported, mainly in Japan. Previous studies have revealed that BAFME is mapped to four chromosomal regions on 8q23.3–q24.1, 2p11.1–q12.1, 5p15.31–p15.1, and 3q26.32–3q28 in Japanese, Italian, Thai, and French pedigrees, respectively [8–11]. Thus, BAFME shows genetic heterogeneity among pedigrees. However, the causative genes of BAFME are still unidentified. Recently, we investigated a Chinese BAFME family consisting of nine affected members. The linkage analysis suggests that the causative gene responsible for this pedigree may be located on chromosome 5p15.31– p15.1.
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Materials and Methods Clinical Study We identified a BAFME family in China (Fig. 1) that comprises 43 individuals through four generations. Nine of the family members were affected, with males and females affected equally. This was consistent with autosomal dominant inheritance. We collected information about age, sex, age of onset of cortical tremor, and generalized seizures, frequency of seizures, severity of tremors, family history, and medical history (Table 1). The affected members all had cortical tremor. This manifested as continuous, distal, rhythmic involuntary movements, enhanced by fatigue and anger. Eight of the affected family members had generalized seizures, and only one did not have seizures. The patients had hand tremor before the onset of seizures. The average age of
onset was 34 years for tremor and 41 years for seizure. Treatment with antiepileptic drugs resulted in symptom relief. Electroencephalography (EEG), SEP studies, and neurological examinations were performed for further diagnosis. Genetic study Samples Collection and DNA Extraction We collected 18 blood samples from the pedigree, including: II 1, 2, 4, 5, and 7–12; III 1–4, 7, and 16; and IV 6 and 12. Informed consent was given by all the recruited individuals before study entry. Genomic DNA was extracted using the phenol–chloroform method. DNA concentration was determined by DNA/Protein Analyzer (Beckman Instruments, Fullerton, CA, USA), and the DNA samples were stored below –80 °C.
Fig. 1 Pedigree of a Chinese family with BAFME
Table 1 Clinical and neurophysiological findings in eight patients with BAFME Patient
Gender
Age at follow-up (years)
Age of onset (years) Cortical tremor
Generalized seizures
EEG
SEPs
Medication
Seizure frequency (in past year)
II 1
M
66
35
43
Normal
?
VPA
GTCS twice a year
II 4
F
63
31
40
N/A
N/A
None
None
II 9
F
59
35
45
N/A
N/A
None
None
II 11
F
58
34
42
Multifocal PSW
?
VPA
None
III 2
M
42
36
41
Multifocal PSW
?
None
GTCS Once a year
III 3
F
39
33
38
N/A
N/A
None
GTCS Once a year
III 7
F
40
34
38
Normal
N/A
None
None
III 16
F
35
34
None
N/A
?
None
None
EEG electroencephalographic, SEPs somatosensory evoked potentials, N/A not available, GTCS generalized tonic–clonic convulsion seizures, PSW polyspikes and wave, VPA valproic acid, 1 presence
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Genotyping Genetic Markers We selected four microsatellite markers (D2S388, D2S1897, D2S2216, and D2S2264) covering chromosome 2p11.1–q12.2; five (D8S1784, D8S1779, D8S1694, D8S514, and D8S1804) covering chromosome 8q23.3– q24.1; four (D5S2096, D5S1380, D5S580, and D5S486) covering chromosome 5p15.31-p15.1; and four (D3S3609, D3S1602, D3S1571, and D3S1262) covering chromosome 3q26.32-3q28. These markers were selected from those used by others to define the four chromosome regions, and the primer sequences of these markers came from Genethon Microsatallite Map (http://www.genlink.wustl.edu/ genethonframe/). PCR-PAGE was used to genotype the markers. The PCRs were run on PE 9700 Thermal Cyclers (Perkin Elmer, Norwalk, CT, USA). The annealing temperature was reduced from 63 to 55 °C. PAGE was run on a PE 3730 Sequencer (ABI, Foster City, CA, USA). GeneScan v3.1, Genotyper v2.1, and GenoDB v1.0 were used to determine the fragment length of the genetic markers’ alleles, as described previously [12]. Before linkage analysis, Mendelian heredity was also examined, and the ineligible genotypic data that did not follow Mendelian inheritance were excluded.
linkage between the potential causative locus and the analyzed genetic markers. The LOD is defined as the common logarithm of the likelihood ratio by comparing the likelihood of linkage (i.e., at a certain recombination rate between a genetic marker and disease locus) with the likelihood under the assumption of no linkage. A LOD score [3.0 indicates positive linkage and \-2.0 indicates negative linkage.
Results EEG, SEP Studies, and Neurological Examinations Two of the four patients available for EEG had polyspike and wave discharges, and the other two had no EEG abnormalities. Four patients had increased cortical SEP amplitudes in the study of median nerve SEPs (Figs. 2, 3). We demonstrated the cortical origin of myoclonus and tremors. Neurological abnormalities such as ataxia and dementia were not found in any patient. Clinical and neurophysiological studies are summarized in Table 1. Linkage to 5p15.31–p15.1 and Absence of Linkage to the Other Three Loci
Linkage Analysis The MLINK program was used to run the two-point linkage analysis with the following model: autosomal dominant inheritance, frequency of the dominant allele of the causative gene 0.0001, and penetrance 0.9. The LOD likelihood method was used to evaluate the possibility of
Two-point linkage analysis showed a LOD score of 2.80 for D5S486 at no recombination, suggesting linkage to 5p15.31–p15.1. We excluded linkage to the three chromosome regions 8q23.3–q24.1, 2p11.1–q12.1, and 3q26.32–3q28 (LOD score \0 at no recombination) (Table 2).
Fig. 2 EEG from Patient II-11 showed generalized polyspikes and wave
123
Cell Biochem Biophys Fig. 3 SEP of right tibial and left median nerve showed giant cortical potential in Patient II-1
Table 2 LOD scores of MLINK analysis Marker
LOD score at h= 0.0
0.1
0.2
0.3
0.4
0.5
D8S1804
-2.09
-0.78
-0.29
-0.09
-0.02
0.00
D8S1784
-1.71
-0.26
-0.08
-0.06
-0.05
0.00
D8S1779
-3.53
-1.00
-0.46
-0.22
-0.09
0.00
D8S1694
-5.50
-1.06
-0.47
-0.19
-0.05
0.00
D8S514
-2.66
-0.76
-0.35
-0.14
-0.03
0.00
D2S388
-1.75
-0.42
-0.16
-0.06
-0.02
0.00
D2S1897 D2S2216
-5.06 -3.49
-1.14 -1.03
-0.49 -0.39
-0.20 -0.10
-0.05 -0.01
0.00 0.00
D2S2264
-3.07
-0.34
-0.18
-0.09
-0.04
0.00
D5S2096
0.21
0.24
0.20
0.14
0.07
0.00
D5S1380
0.28
0.23
0.17
0.12
0.07
0.00
-0.03
0.03
0.04
0.03
0.01
0.00
D5S580 D5S486 D3S3609
2.80
2.40
1.32
0.53
0.48
0.00
-4.00
-1.76
-0.79
-0.32
-0.09
0.00
D3S1602
-3.32
-1.39
-0.44
-0.19
-0.08
0.00
D3S1571
-2.85
-1.18
-0.61
-0.29
-0.11
0.00
D3S1262
-3.14
-0.46
-0.25
-0.15
-0.07
0.00
Discussion The clinical and electrophysiological features of our patients confirmed the diagnosis of BAFME and excluded the diagnosis of familial myoclonus epilepsy, progressive myoclonus epilepsy, juvenile myoclonus epilepsy, and essential tremor. SEPs revealed cortical hyperexcitability with cortical origin of tremor. Our patients had a nonprogressive clinical course. Myoclonic tremor and seizure
123
responded well to antiepileptic drugs, such as valproic acid, clonazepam, or levetiracetam. Electrophysiological studies such as EEG, SEPs, long-loop reflexes, and JLA EEG need to be performed on more patients to confirm the diagnosis. All nine affected family members had tremor, and eight of them developed generalized tonic–clonic seizure. We did not find anyone affected in the fourth generation. This may have been because they had not reached the onset age. Our study suggests that the causative gene for BAFME in our Chinese pedigree may be located on chromosome 5p15.31–p15.1. This excludes linkage to the three chromosome regions 8q23.3–q24.1, 2p11.1–q12.1, and 3q26.32–3q28. Genetic heterogeneity is not uncommon in human diseases including neurological disorders. A striking example is spinocerebellar ataxia, which has at least 33 underlying genes [13]. A previous study of epilepsy suggested that ion channel or ion-channel-related genes are the candidate causative genes [14]. Additional studies to elucidate the role of these genes on disease etiology are warranted. Such studies will provide further understanding of the molecular basis of epilepsy. This will enable us to find more effective treatment for the disease. Acknowledgments in this study.
We thank the family members for participating
References 1. Striano, P., de Falco, F. A., Minetti, C., & Zara, F. (2009). Familial benign nonprogressive myoclonic epilepsies. Epilepsia, 50(Suppl 5), 37–40. 2. Elia, M., Musumeci, S. A., Ferri, R., Scuderi, C., Del Gracco, S., & Bottitta, M. (1998). Familial cortical tremor, epilepsy, and
Cell Biochem Biophys
3. 4.
5.
6.
7. 8.
9.
mental retardation: a distinct clinical entity. Archives of Neurology, 55, 1569–1573. Saka, E., & Saygi, S. (2000). Familial adult onset myoclonic epilepsy associated with migraine. Seizure, 9, 344–346. Manabe, Y., Narai, H., Warita, H., Hayashi, T., Shiro, Y., & Sakai, K. (2002). Benign adult familial myoclonic epilepsy (BAFME) with night blindness. Seizure, 11, 266–268. Regragui, W., Gerdelat-Mas, A., & Simonetta-Moreau, M. (2006). Cortical tremor (FCMTE: familial cortical myoclonic tremor with epilepsy). Neurophysiologie Clinique, 36, 345–349. Ikeda, A., Kakigi, R., Funai, N., Neshige, R., Kuroda, Y., & Shibasaki, H. (1990). Cortical tremor: a variant of cortical reflex myoclonus. Neurology, 40, 1561–1565. Yasuda, T. (1991). Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Medical Journal, 17, 1–13. Mikami, M., Yasuda, T., Terao, A., et al. (1999). Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3–q24.1. American Journal of Human Genetics, 65(3), 745–751. Striano, P., Chifari, R., Strino, S., et al. (2004). A new benign adult familial myoclonic epilepsy (BAFME) pedigree suggesting linkage to chromosome 2p11.1-q12.2. Epilepsia, 45, 190–192.
10. Depienne, C., Magnin, E., Bouteiller, D., et al. (2010). Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p. Neurology, 74(24), 2000–2003. 11. Yeetong, P., Ausavarat, S., Bhidayasiri, R., et al. (2013). A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26.32–3q28. European Journal of Human Genetics, 21(2), 225–228. 12. Li, J. L., Deng, H., Lai, D. B., Xu, F., Chen, J., & Gao, G. (2001). Toward high-through put genotyping: dynamic and automatic software for manipulating large-scalegenotype data using fluorescently labeled dinucleotide markers. Genome Research, 11, 1304–1314. 13. Teive, H. A. (2009). Spinocerebellar ataxias. Arquivos de NeuroPsiquiatria, 67, 1133–1142. 14. Singh, N. A., Charlier, C., Stauffer, D., et al. (1998). A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of new borns. Nature Genetics, 18, 25–29.
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ORIGINAL PAPER
A Chinese Benign Adult Familial Myoclonic Epilepsy Pedigree Suggesting Linkage to Chromosome 5p15.31–p15.1 Jia Li • Xinyu Hu • Qiuhui Chen • Yizhi Zhang Ying Zhang • Guohua Hu
•
Ó Springer Science+Business Media New York 2014
Abstract Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q23.3–q24.1, 2p11.1–q12.1, 5p15.31–p15.1, and 3q26.32–3q28, in Japanese, Italian, Thai, and French pedigrees, respectively. Recently, we investigated a Chinese BAFME family. Clinical and electrophysiological studies revealed that nine individuals were affected with BAFME. We aimed to establish the causative gene for this pedigree. We genotyped 17 microsatellite markers covering the four previously identified chromosome regions and performed linkage analyses. The linkage analysis data showed that the LOD score was 2.80 for D5S486 at no recombination. This suggested linkage to 5p15.31–p15.1 and excluded linkage to the other three loci (LOD score\0 at no recombination). Our study suggests that the causative gene responsible for BAFME in the Chinese pedigree may be located on chromosome 5p15.31–p15.1. Keywords Benign adult familial myoclonic epilepsy BAFME Linkage analysis Genetic heterogeneity
Introduction Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant, idiopathic epileptic syndrome,
J. Li Q. Chen Y. Zhang Y. Zhang G. Hu (&) Department of Neurology, the Second Hospital of Jilin University, 218 Ziqiang Road, Changchun 130041, Jinlin, China e-mail: [email protected] X. Hu Department of Neurology, the First Hospital of Jilin University, Changchun, China
characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course [1]. The typical features can be accompanied by mental retardation, migraine, and night blindness [2–4]. BAFME is also known as familial cortical myoclonic tremor with epilepsy. BAFME diagnosis is based on clinical and electrophysiological criteria. It consists of features favoring cortical reflex myoclonus and a good response to antiepileptic drugs [5]. Electrophysiological studies that confirm the cortical origin of myoclonus show enhanced long latency reflexes at rest, giant cortical somatosensory evoked potentials (SEPs), and premyoclonus cortical spikes detected by the jerk-locked back averaging (JLA) method. In 1990, Ikeda et al. [6] first reported electrophysiological studies in two Japanese patients who had adultonset finger tremor, seizure, and a family history of the same condition without a progressive course. They demonstrated involuntary movement as a form of cortical reflex myoclonus. In 1991, Yasuda [7] reported electrophysiological studies in two similar large Japanese families and proposed the syndrome name of BAFME. Since then, a few similar clinical cases have been reported, mainly in Japan. Previous studies have revealed that BAFME is mapped to four chromosomal regions on 8q23.3–q24.1, 2p11.1–q12.1, 5p15.31–p15.1, and 3q26.32–3q28 in Japanese, Italian, Thai, and French pedigrees, respectively [8–11]. Thus, BAFME shows genetic heterogeneity among pedigrees. However, the causative genes of BAFME are still unidentified. Recently, we investigated a Chinese BAFME family consisting of nine affected members. The linkage analysis suggests that the causative gene responsible for this pedigree may be located on chromosome 5p15.31– p15.1.
123
Cell Biochem Biophys
Materials and Methods Clinical Study We identified a BAFME family in China (Fig. 1) that comprises 43 individuals through four generations. Nine of the family members were affected, with males and females affected equally. This was consistent with autosomal dominant inheritance. We collected information about age, sex, age of onset of cortical tremor, and generalized seizures, frequency of seizures, severity of tremors, family history, and medical history (Table 1). The affected members all had cortical tremor. This manifested as continuous, distal, rhythmic involuntary movements, enhanced by fatigue and anger. Eight of the affected family members had generalized seizures, and only one did not have seizures. The patients had hand tremor before the onset of seizures. The average age of
onset was 34 years for tremor and 41 years for seizure. Treatment with antiepileptic drugs resulted in symptom relief. Electroencephalography (EEG), SEP studies, and neurological examinations were performed for further diagnosis. Genetic study Samples Collection and DNA Extraction We collected 18 blood samples from the pedigree, including: II 1, 2, 4, 5, and 7–12; III 1–4, 7, and 16; and IV 6 and 12. Informed consent was given by all the recruited individuals before study entry. Genomic DNA was extracted using the phenol–chloroform method. DNA concentration was determined by DNA/Protein Analyzer (Beckman Instruments, Fullerton, CA, USA), and the DNA samples were stored below –80 °C.
Fig. 1 Pedigree of a Chinese family with BAFME
Table 1 Clinical and neurophysiological findings in eight patients with BAFME Patient
Gender
Age at follow-up (years)
Age of onset (years) Cortical tremor
Generalized seizures
EEG
SEPs
Medication
Seizure frequency (in past year)
II 1
M
66
35
43
Normal
?
VPA
GTCS twice a year
II 4
F
63
31
40
N/A
N/A
None
None
II 9
F
59
35
45
N/A
N/A
None
None
II 11
F
58
34
42
Multifocal PSW
?
VPA
None
III 2
M
42
36
41
Multifocal PSW
?
None
GTCS Once a year
III 3
F
39
33
38
N/A
N/A
None
GTCS Once a year
III 7
F
40
34
38
Normal
N/A
None
None
III 16
F
35
34
None
N/A
?
None
None
EEG electroencephalographic, SEPs somatosensory evoked potentials, N/A not available, GTCS generalized tonic–clonic convulsion seizures, PSW polyspikes and wave, VPA valproic acid, 1 presence
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Cell Biochem Biophys
Genotyping Genetic Markers We selected four microsatellite markers (D2S388, D2S1897, D2S2216, and D2S2264) covering chromosome 2p11.1–q12.2; five (D8S1784, D8S1779, D8S1694, D8S514, and D8S1804) covering chromosome 8q23.3– q24.1; four (D5S2096, D5S1380, D5S580, and D5S486) covering chromosome 5p15.31-p15.1; and four (D3S3609, D3S1602, D3S1571, and D3S1262) covering chromosome 3q26.32-3q28. These markers were selected from those used by others to define the four chromosome regions, and the primer sequences of these markers came from Genethon Microsatallite Map (http://www.genlink.wustl.edu/ genethonframe/). PCR-PAGE was used to genotype the markers. The PCRs were run on PE 9700 Thermal Cyclers (Perkin Elmer, Norwalk, CT, USA). The annealing temperature was reduced from 63 to 55 °C. PAGE was run on a PE 3730 Sequencer (ABI, Foster City, CA, USA). GeneScan v3.1, Genotyper v2.1, and GenoDB v1.0 were used to determine the fragment length of the genetic markers’ alleles, as described previously [12]. Before linkage analysis, Mendelian heredity was also examined, and the ineligible genotypic data that did not follow Mendelian inheritance were excluded.
linkage between the potential causative locus and the analyzed genetic markers. The LOD is defined as the common logarithm of the likelihood ratio by comparing the likelihood of linkage (i.e., at a certain recombination rate between a genetic marker and disease locus) with the likelihood under the assumption of no linkage. A LOD score [3.0 indicates positive linkage and \-2.0 indicates negative linkage.
Results EEG, SEP Studies, and Neurological Examinations Two of the four patients available for EEG had polyspike and wave discharges, and the other two had no EEG abnormalities. Four patients had increased cortical SEP amplitudes in the study of median nerve SEPs (Figs. 2, 3). We demonstrated the cortical origin of myoclonus and tremors. Neurological abnormalities such as ataxia and dementia were not found in any patient. Clinical and neurophysiological studies are summarized in Table 1. Linkage to 5p15.31–p15.1 and Absence of Linkage to the Other Three Loci
Linkage Analysis The MLINK program was used to run the two-point linkage analysis with the following model: autosomal dominant inheritance, frequency of the dominant allele of the causative gene 0.0001, and penetrance 0.9. The LOD likelihood method was used to evaluate the possibility of
Two-point linkage analysis showed a LOD score of 2.80 for D5S486 at no recombination, suggesting linkage to 5p15.31–p15.1. We excluded linkage to the three chromosome regions 8q23.3–q24.1, 2p11.1–q12.1, and 3q26.32–3q28 (LOD score \0 at no recombination) (Table 2).
Fig. 2 EEG from Patient II-11 showed generalized polyspikes and wave
123
Cell Biochem Biophys Fig. 3 SEP of right tibial and left median nerve showed giant cortical potential in Patient II-1
Table 2 LOD scores of MLINK analysis Marker
LOD score at h= 0.0
0.1
0.2
0.3
0.4
0.5
D8S1804
-2.09
-0.78
-0.29
-0.09
-0.02
0.00
D8S1784
-1.71
-0.26
-0.08
-0.06
-0.05
0.00
D8S1779
-3.53
-1.00
-0.46
-0.22
-0.09
0.00
D8S1694
-5.50
-1.06
-0.47
-0.19
-0.05
0.00
D8S514
-2.66
-0.76
-0.35
-0.14
-0.03
0.00
D2S388
-1.75
-0.42
-0.16
-0.06
-0.02
0.00
D2S1897 D2S2216
-5.06 -3.49
-1.14 -1.03
-0.49 -0.39
-0.20 -0.10
-0.05 -0.01
0.00 0.00
D2S2264
-3.07
-0.34
-0.18
-0.09
-0.04
0.00
D5S2096
0.21
0.24
0.20
0.14
0.07
0.00
D5S1380
0.28
0.23
0.17
0.12
0.07
0.00
-0.03
0.03
0.04
0.03
0.01
0.00
D5S580 D5S486 D3S3609
2.80
2.40
1.32
0.53
0.48
0.00
-4.00
-1.76
-0.79
-0.32
-0.09
0.00
D3S1602
-3.32
-1.39
-0.44
-0.19
-0.08
0.00
D3S1571
-2.85
-1.18
-0.61
-0.29
-0.11
0.00
D3S1262
-3.14
-0.46
-0.25
-0.15
-0.07
0.00
Discussion The clinical and electrophysiological features of our patients confirmed the diagnosis of BAFME and excluded the diagnosis of familial myoclonus epilepsy, progressive myoclonus epilepsy, juvenile myoclonus epilepsy, and essential tremor. SEPs revealed cortical hyperexcitability with cortical origin of tremor. Our patients had a nonprogressive clinical course. Myoclonic tremor and seizure
123
responded well to antiepileptic drugs, such as valproic acid, clonazepam, or levetiracetam. Electrophysiological studies such as EEG, SEPs, long-loop reflexes, and JLA EEG need to be performed on more patients to confirm the diagnosis. All nine affected family members had tremor, and eight of them developed generalized tonic–clonic seizure. We did not find anyone affected in the fourth generation. This may have been because they had not reached the onset age. Our study suggests that the causative gene for BAFME in our Chinese pedigree may be located on chromosome 5p15.31–p15.1. This excludes linkage to the three chromosome regions 8q23.3–q24.1, 2p11.1–q12.1, and 3q26.32–3q28. Genetic heterogeneity is not uncommon in human diseases including neurological disorders. A striking example is spinocerebellar ataxia, which has at least 33 underlying genes [13]. A previous study of epilepsy suggested that ion channel or ion-channel-related genes are the candidate causative genes [14]. Additional studies to elucidate the role of these genes on disease etiology are warranted. Such studies will provide further understanding of the molecular basis of epilepsy. This will enable us to find more effective treatment for the disease. Acknowledgments in this study.
We thank the family members for participating
References 1. Striano, P., de Falco, F. A., Minetti, C., & Zara, F. (2009). Familial benign nonprogressive myoclonic epilepsies. Epilepsia, 50(Suppl 5), 37–40. 2. Elia, M., Musumeci, S. A., Ferri, R., Scuderi, C., Del Gracco, S., & Bottitta, M. (1998). Familial cortical tremor, epilepsy, and
Cell Biochem Biophys
3. 4.
5.
6.
7. 8.
9.
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