Clinical, Electrophysiological, and Genetic Analysis in a Family with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Sung Il Sohn, M.D., Yong Won Cho, M.D.*, Sang Doe Yi, M.D.*, Dae Kwang Kim, M.D., Du Kyo Jung, M.D.*, Hyung Lee, M.D.*, Jung Gun Lim, M.D.*, Ju Hwa Lee, M.D.* Department of Neurology, Eulji University School of Medicine Department of Neurology* and Anatomy, Keimyung University School of Medicine Background : Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct epilepsy syndrome and a genetically heterogeneous disorder linked to chromosomes 20q13.2, 15q24, and 1p21. Missense and insertion mutations in neuronal nicotine acetylcholine receptor 4 (CHRNA4) and 2 (CHRNB2) genes have been found in families with ADNFLE. Methods : Clinical, EEG-Video monitoring, and neuropsychologic study in a family with ADNFLE were tested. For detect of mutation gene, polymerase chain reaction for CHRNA4 gene and CHRNB2 gene, single strand conformational polymorphism (SSCP) analysis and DNA sequencing were done. R e s u l t s : Among 15 living family members in three generations, nine had seizures. EEG-Video monitoring showed ictal epileptiform discharges genetically or regionally in frontal, frontocentral, frontotemporal, or temporal areas and less frequently no epileptiform discharges or non-specific generalized slowing. Two affected individuals demonstrated interictal temporal spikes, whereas the others were normal. Neuropsychological study showed mental retardation and decreased frontal executive function in five affected individuals. A cytosine to thymine exchange (755C>T; S252L) in exon 5 of the CHRNA4 gene was found on all affected individuals except in an individual who wasn t tested, but this change was absent in those without epilepsy. Conclusions : This is the first study of genetically confirmed ADNFLE in a Korean family, who had mental retardation and various EEG abnormalities, ictally and interictally. J Korean Neurol Assoc 20(6):600~611, 2002 Key Words : Epilepsy, Frontal lobe, Autosomal dominant, ADNFLE, CHRNA4 gene, Mental retardation Sung Il Sohn, M.D. 600 Copyright 2002 by the Korean Neurological Association
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µ µ µ Figure 1. Pedigree of a Korean family with autosonal dominant nocturnal frontal lobe epilepsy. The solid symbols represent affected status, and open symbols represent unaffected status. Arrow indicates a proband. Table 1. PCR primer pairs for amplification of CHRNB2 and CHRNA4 genes µ µ µ µ µ µ µ Exon Forward primer Reverse primer CHRNB2 1 GAGGCAGCGAGCTATGCCCG GCGGCGACTCTTGGGCCGT 2 GAGCTGGGTGGGCTCTCCT GCAGAGAGCCTGGGACCTCT 3 GGAGGTGTGAGAGGGACCCT CCAGGGGTGTGGGTGGAAG 4 CTCTAGTTCGTTTCCTTAAC CCTCCCTGAGCCCTCCAATG 5a AGGGCTGACTGTGCCCATC GTCCACGCTGGCCACCTCA 5b CACAGAGATCGACTTGGTGCT GAAGACAAGGATGGCTAGCG 5c CACCATCAACCTCATCATCC AGCAGCGCGGGCAGCTTC 5d CCTGCCCTCCGAGTGTGGC GGTCCCACCGTGCGGCACT 6 CGTTTGTCTCCCATCCTGC TGGCTGGGTGAAAGAGCATG CHRNA4 1 GGTGCGTGCGCCATGGAGC GCAGTCAGCAGCCTGCCTC 2 ACCTGAGCCACTGGCCTGCC CGACCTCAGTCACAGCGCAC 3 CCCGTCCACCATATCTTGC GGCAGTGCCCTCCCACTC 4 CATCCAGGAGTGGCACGACTA ACCAAGGCCCTGTAGAGGAC 5a ACCCTTCGCTCTCTTCCTGC CCACGATGACCCACTCGCC 5b CGGCTCCTGGACCTACGAC CAGGCAGGGGATGATGAGG 5c GGCGAGTGGGTCATCGTGG GATGACCAGTGAGGTGGACG 5d CCTGCCCTCCGAGTGTGGC GGGCATGGTGTGCGTGCGTG 5e ACGCACGCACACCATGCCC GCGGCAGGGTCCAGGCGAG 5f CCTTCCTGCAAGTCACCCTCC GTGCTTTGGTGCTGCGGGTC 5g AAGGAGCCCTCTTCGGTGTC CCCAAAGCGAAGCAGCCTGA 6 GGCCGTGCTGGAGTGACG GCCCCACAGAGTCCAGGG J Korean Neurol Assoc / Volume 20 / November, 2002 602
Table 2. Clinical and neuroimaging findings in the family members with autosomal dominant nocturnal frontal lobe epilepsy Patient II-1 II-6 III-2 III-3 III-8 III-9 III-10 III-11 Age/Sex 53/M 46/F 24/F 22/F 23/F 22/F 20/M 18/F History of febrile convulsion No No No No No No No No Age at onset (years) Childhood 6 8 14 17 13 12 13 Time of seizure Night Day & night Night Night Night Night Night Night Relation to sleep Falling Sleep Through Through Within Falling Falling Falling asleep aggravates all night all night 2hr asleep asleep or asleep or episodes after sleep waking up waking up Brain MRI ND Normal ND ND Normal Normal Arachnoid Normal cyst on left temporal pole Current medication None CBZ CBZ TPM Stop CBZ CBZ VBG VPA TBM LTG since VPA OCBZ CBZ VGB 19-year-old PRM VPA TPM OCBZ LTG ZNS Seizure frequency 1-4/year 3-4/day 3-4/month Seizure 3-4/month 2-5/month 1-4/year after medication free CBZ; carbamazepine, OCBZ; oxcarbazepine, VPA; sodium valproate, LTG; lamotrigine, VGB; vigabatrin, TPM; topiramate, ZNS; zonisamide, PRM; primidone, PHT; phenytoin, PB; phenobarbital, ND; not done. J Korean Neurol Assoc / Volume 20 / November, 2002 603
Figure 2. Interictal EEG recording in III-8 case with poorly controlled seizure. The EEG shows isolated repetitive spike-and-wave complexes with phase reversals on the right frontotemporal area. Figure 3. Ictal EEG recording of brief attack arising from stage 2 non-rapid eye movement sleep in a 46-year-old woman (II-6). Ictal EEG shows rhythmic epileptiform discharges over bilateral frontal, central, and temporal areas. 604 J Korean Neurol Assoc / Volume 20 / November, 2002
Table 3. Video-EEG monitoring findings in the family members with autosomal dominant nocturnal frontal lobe epilepsy Patient II-6 III-2 III-3 III-9 III-10 III-11 No of seizure 7 19 35 4 6 7 during a night Seizure 19-75 10-70 13-51 23-53 20-54 31-62 duration (sec) 36.1±26.6 43.3±17.9 29.2±12.2 32.3±14 38.3±12.0 52±11.2 (mean±sd) No of secondary 2 0 0 0 1 0 generalization Postictal confusion Yes No No No Yes Yes Seizure clusters Yes No No Yes Yes Yes Interictal EEG Normal Intermittent Intermittent Normal Intermittent Normal bifrontal bifrontal generalized theta waves theta waves theta waves Ictal semiology Shouting Ah, Moaning, Mumbling, Moaning, Moaning, lip Moaning, moaning, eye blinking, head neck smacking, head nodding, drooling, hand shaking, shaking or extension, both arm neck eye blinking, both arm nodding, both arm tonic flexion, extension both arm tonic flexion tonic flexion tonic flexion neck tonic tonic flexion, of right arm, extension neck tonic neck tonic extension extension Ictal onset areas Right Bilateral Bilateral Generalized, Generalized Bilateral temporal, frontal areas frontocentral central, or or bilateral frontocentral right areas bilateral frontal areas areas fontotemporal, frontal areas or bilateral frontal areas Ictal onset patterns Low voltage Rhythmic Rhythmic Rhythmic Semirhythmic Rhythmic rhythmic theta waves beta waves delta or spike/sharp alpha theta, superimposed alpha waves waves waves, nonspecific with beta nonspecific theta slowing waves theta slowing No; number, Rt; right. J Korean Neurol Assoc / Volume 20 / November, 2002 605
Table 4. Results of neuropsychological tests in the family members with autosomal dominant nocturnal frontal lobe epilepsy Patient II-6 III-2 III-3 III-9 III-10 III-11 K-WAIS Verbal IQ 72 54 65 60 71 46 Performance IQ 67 61 80 51 89 52 Full IQ 68* 54* 69* 53* 76 <45 K-MAS Short-term M (%ile) 112 (93) 69 (2) 58 (<1) 91 (28) 118 (89) 72 (3) Verbal M (%ile) 61 (<1) 58 (<1) 110 (75) 99 (47) 96 (40) 86 (18) Visual M (%ile) 53 (<1) 74 (4) 72 (4) 83 (13) 110 (75) 63 (1) Total M (%ile) 53 (<1) 62 (1) 89 (23) 84 (14) 104 (61) 72 (3) Rey-CFT Copy 15.5 30 33 33 34 NA Immediate recall 0 2 1.5 10 15 NA 20min delayed recall 0 2.5 2 10 14.5 NA Trailmaking test Part A (%ile) 115 (<10) 52 (<10) 55 (<10) 78 (<10) 80 (<10) 78 (<10) Part B (%ile) 43 (<10) Refuse 135 (<10) 126 (<10) 159 (<10) 195 (<10) Pegboard test Refuse Right 105 60 65.5 72.5 90 (Mean±SD) (66.5±7.0) (67.6±20.9) (60.4±6.4) (62.1±20.8) (60.4±6.4) Left 93 75.5 79 78.5 94 (Mean±SD) (71.1±8.5) (62.2±11.8) (64.1±9.2) (67.6±20.9) (64.1±9.2) WCST Refuse Refuse Total errors (%ile) 102 (<1) 101 (<1) 17 (68) 56 (5) % Errors (%ile) 80 (<1) 79 (<1) 14 (84) 44 (6) PR (%ile) 102 (<1) 14 (39) 8 (77) 24 (14) PE (%ile) 81 (<1) 14 (37) 8 (73) 24 (9) NCC (%ile) 0 (<1) 0 (<1) 6 (>16) 5 (>16) TCFC (%ile) 65 (2-5) 65 (2-5) 10 (>16) 12 (>16) FMS (%ile) 0 (>16) 0 (>16) 4 (6-10) 1 (>16) * mild mental retardation by American Association on Mental Deficiency, moderate mental reterdation by AAMD, age and sex matched normative data, K-WAIS; Korean-Wechsler Adult Intelligence Scale, K-MAS; Korean-Memory Assessment Scale, IQ; Intelligence Quotient, Rey-CFT; Rey-Osterrieth Complex Figure Test, %ile; percentile, WCST; Wisconsin Card Sorting Test, PR; perseverative responses, PE; perseverative errors, NCC; number of categories completed, TCFC; trials to complete first category, FMS; failure to maintain set. 606 J Korean Neurol Assoc / Volume 20 / November, 2002
Figure 4. Single-strand conformational polymorphism (SSCP) mutation analysis of exon 5 of CHRNA4 gene in a Korean family with autosomal dominant nocturnal frontal lobe epilepsy. The migration differences of the bands () in affected patients (lane 1-4 and 6-9) are clearly evident and indicate that shift bands contain a putatively mutated allele. Figure 5. Nuleotide sequence of the relevant region of exon 5 of CHRNA4 gene. Arrow indicates the position of the mutat- ed 755 nucleotide. A C to transition (: 755 C>T) resulting in a S252L missense mutation is found in exon 5. Nucleotied numbers are based on the nomenclature for the Torpedo a- subunit of an acetylcholine receptor. J Korean Neurol Assoc / Volume 20 / November, 2002 607
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