Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant (AD) condition characterized by cortical tremor, myoclonic jerks, and generalized seizures with nonprogressive course. This association was first described in Japan (1–3) and mapped on chromosome 8q24 (4). Subsequently, the same phenotype was reported outside Japan (5), and linkage to 8q24 excluded in two large European pedigrees (6,7). Autosomal dominant cortical myoclonus and epilepsy (ADCME) shared many clinical and electrophysiologic features with BAFME, but some affected members showed intractable partial epilepsy and mental retardation (8). ADCME maps to chromosome 2p11.1-q12.2. Recently we described two BAFME families showing linkage to the same chromosomal region and suggested allelism with ADCME (9). Here we report a new BAFME pedigree in which linkage analysis once again suggests linkage to 2p11.1-q12.2.
The family pedigree indicated AD inheritance without consanguineous marriages (Fig. 1). Clinical and neurophysiologic data are summarized in Table 1. Seven members (six living, five investigated) had cortical tremor. Generalized seizures occurred in six. Cortical tremor was the initial symptom in all cases, appearing at age 13 to 18 years (mean, 14.6 years). It consisted of continuous, distal, fine twitches at the hands, resembling essential tremor, and enhanced by emotion or fatigue without significant progression over time, as first described by Ikeda et al. (10). Tremor was not responsive to β-blockers, piracetam, levetiracetam (LEV), and 5-OH-tryptophan, but improved with valproate (VPA) and clonazepam (CZP). In addition to tremor, patients also had distal arrhythmic myoclonic jerks of the upper limbs. All affected individuals but one experienced rare (from one to four) generalized seizures; precipitant factors, such as sleep deprivation, emotional stress, and photic stimulation were often reported. Four patients had normal cognitive level except from one who had an IQ of 79. Affected individuals underwent EEG-electromyogram (EMG) polygraphic study, jerk-locked back-averaging (JLA), somatosensory evoked potentials (SEPs), and long-latency reflex I (LLRI). Methods used are described in detail elsewhere; SEPs were judged as “giant” when the components N20-P25 and P25-N33 were larger than 8.6 μV and 8.4 μV, respectively (9).
|Patient ID Number||Sex, age (yr)||Onset (age)||EEG, PPR||Giant SEPs||LLRI||AEDs||Brain MRI|
|Cortical tremor||Generalized seizures|
|II:2||F, 72||18||−||GPA, −||−||+||VPA||ND|
|II:4||M, 65||14||46||GPA, −||+||+||PHT||ND|
|III:4||M, 39||13||18||GPA, ++||+||+||VPA, PB||Normal|
|III:6||M, 38||13||25||GPA, +||−||+||VPA, CZP||Normal|
|III:8||M, 37||15||30||GPA, −||+||+||VPA, CZP||Normal|
Generalized paroxysmal abnormalities were found in all cases, whereas a photoparoxysmal response was observed in two. JLA showed a positive–negative spike or a series of wavelets related to myoclonus on the contralateral sensorimotor regions. Three patients showed giant SEPs. LLRI was recognized in all, at a latency of 38.2 to 44.5 ms after stimulation.
Two-point linkage analysis was performed with 10 microsatellite markers to investigate candidate loci on chromosomes 8q24 (D8S1784, D8S555, D8S514, D8S1804, D8S284) and 2p11.2-12.2 (D2S2333, D2S2216, D2S2264, D2S1897, D2S160). Although the power of this small family does not achieve statistical significance, we could clearly exclude the chromosome 8 locus. However, the lod score value of 1.55 for D2S2333 at no recombination, which closely approaches the maximal value obtained by linkage simulations, suggests that this family is likely to be associated with the ADCME locus (condition was modeled as an AD trait with 0.90 penetrance).
This new pedigree closely resembles Japanese families as well as those previously reported by some of us (9). It shows a homogeneous syndrome core including the association of cortical tremor, myoclonus, and generalized seizures with benign course and a characterizing electrophysiologic pattern. If we consider the occurrence of partial seizures and mental retardation possibly related to additional individual factors, including intractable seizures, ADCME and BAFME could be included within the same spectrum; it would be supported by the allelism between these two conditions. Thus we think this is a worldwide but genetically heterogeneous condition, with Japanese families linked to 8q24 and European ones to 2p11.1-q12.2; this report further supports this concept. Pathogenesis remains only speculative, as a causative gene has not been identified. Ion channels have been considered for candidate genes (4,7); however, Sano et al. (11) recently excluded mutations of voltage-gated potassium channel on chromosome 8q (11). Understanding of the genetic background of this spectrum of disorders could provide new interesting insights into the field of idiopathic epilepsies.