Brain, Vol. 124, No. 12, 2459-2475,
December 2001
© 2001 Oxford University Press
Autosomal dominant cortical myoclonus and epilepsy (ADCME) with complex partial and generalized seizures
A newly recognized epilepsy syndrome with linkage to chromosome 2p11.1-q12.2
1 Neurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children and 2 Sobell Department of Neurophysiology, Institute of Neurology, London, UK, 3 Division of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, Pisa, 4 Stem Cells Research Institute (SCRI), Dibit—San Raffaele Hospital, Milan, 5 Telethon Institute of Genetics and Medicine, Naples, Italy, 6 Neurologische Klinik und Poliklinik, Charité, Campus Virchow-Klinikum, Berlin, Germany
Correspondence to:
Professor R. Guerrini, Neurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK E-mail: R.Guerrini{at}ich.ucl.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
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
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. autosomal dominant; cortical myoclonus; epilepsy; chromosome 2
ADCME = autosomal dominant cortical myoclonus and epilepsy; APB = abductor pollicis brevis; CMCT = central motor conduction time; DREAM = downstream regulatory element antagonist modulator; FAME = familial adult myoclonic epilepsy; GEFS = generalized epilepsy with febrile seizures; GTCS = generalized tonic–clonic seizure; MEP = motor evoked potential; NART = National Adult Reading Test; SEP = somatosensory evoked potential; TI = threshold stimulation intensity; TIB = Brief Intelligence Test; VEP = visual evoked potential; WAIS = Wechsler Adult Intelligence Scale
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
The study of genetic epilepsies with Mendelian inheritance has led to the identification of six genes that cause epilepsy (Steinlein et al., 1995
; Charlier et al., 1998; Singh et al., 1998; Wallace et al., 1998; De Fusco et al., 2000; Escayg et al., 2000a, b). Although epilepsies with simple inheritance represent only a minority of the genetically determined epilepsies (Berkovic and Scheffer, 1997), study of the segregation of the disease trait within families and cloning of responsible genes have improved our understanding of the pathophysiology of human epilepsy and have led to the formulation of new concepts defining the spectrum of idiopathic epilepsy syndromes (Scheffer et al., 1995; Scheffer and Berkovic, 1997). We now know that both voltage-gated and ion-gated ion channel dysfunction are causes of idiopathic epilepsy (Steinlein et al., 1995; Singh et al., 1998; Wallace et al., 1998), that the epilepsy-producing dysfunction may be specifically age- and localization-related and clinically heterogeneous and that epilepsy can co-segregate with other paroxysmal neurological disorders, namely paroxysmal dyskinesias (Szepetowsky et al., 1997; Guerrini et al., 1999).
Nosology of monogenic epilepsies has, until now, shown that the main subdivision of the idiopathic epilepsies into distinct focal and generalized forms is confirmed by clustering of either form in distinct families (Commission on Classification and Terminology of the International League Against Epilepsy, 1989), implying that epilepsy-producing genes are responsible for either focal or generalized epileptogenesis. Amongst the generalized epilepsies, a syndrome known as familial adult myoclonic epilepsy (FAME), has been described in several pedigrees from Japan (Mikami et al., 1999; Plaster et al., 1999). FAME is characterized by adult onset cortical tremor, i.e. a form of rhythmic distal cortical reflex myoclonus, generalized myoclonic jerks, rare generalized tonic–clonic seizures, generalized EEG abnormalities and normal IQ. A locus for this form of epilepsy has been mapped to chromosome 8q23.3-q24.1 through linkage analysis in Japanese families (Mikami et al., 1999; Plaster et al., 1999). Clinical and EEG characteristics suggest that FAME is a form of idiopathic generalized epilepsy akin to juvenile myoclonic epilepsy (Plaster et al., 1999).
Here, we describe an Italian pedigree in which, in addition to some clinical and neurophysiological characteristics similar to FAME and to frontotemporal and generalized EEG abnormalities present in all affected individuals, three of the eight living patients presented with complex partial seizures. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 on chromosome 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at 
0.0 for marker D2S2175. These findings indicate that the combination of rhythmic cortical myoclonus with generalized tonic–clonic seizures does not necessarily represent an expression confined to idiopathic generalized epilepsy. Furthermore, the exclusion of the FAME locus 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.
|
Patients and methods |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
Patients
The proband (IV-4, Fig. 1
) of a family from Tuscany, Italy, was referred for investigation of intractable seizures. A detailed family pedigree was constructed by collecting clinical histories on all putatively affected, as well as unaffected, individuals and spouses. There were 11 affected individuals (of whom eight are living) over five generations. We obtained genealogical information on 72 family members (including 10 spouses) and conducted a detailed evaluation of 19 individuals (Fig. 1 and Table 1). The inheritance pattern was autosomal dominant. Clinical characteristics in affected family members included: (i) adult onset of symptoms (all members); (ii) non-progressive course (all members); (iii) distal, fairly rhythmic myoclonus, enhanced during movement or posture maintenance (all members); (iv) generalized tonic–clonic seizures (all members); and (v) complex partial seizures (three patients: III-8, IV-2 and IV-4). Written informed consent was obtained from all patients included in the study. This study was fully approved by the Ethics Committee of the Institute for Medical Research, Stella Maris Foundation.
|
|
Clinical and video-electrophysiological studies
All but one of the affected individuals (III-13) were evaluated by video-EEG and simultaneous EMG monitoring while awake and asleep with bipolar and referential montages using silver–silver chloride surface cup electrodes. Long-term video-EEG monitoring was performed on two patients with refractory epilepsy. An EEG recording including sleep was also performed in five clinically unaffected individuals (III-9, III-10, III-12, IV-3 and V-1). Scalp electrode placement was performed according to the international 10–20 system. Recording included overbreathing and intermittent photic stimulation. EMG activity was recorded during movement and at rest using pairs of electrodes applied 3 cm apart over the masseter, orbicularis oris, deltoid, biceps, finger flexors and extensors, abductor pollicis brevis (APB) and tibialis anterior muscles. EEG–EMG activity was recorded on a computer for later analysis. Back-averaging of EEG activity data related to the EMG bursts was performed in all but one of the patients (III-13), using either APB or wrist extensor muscles as triggering muscles. The EEG signal was filtered using a bandpass of 1–100 Hz and digitized at the sampling rate of 1024 Hz. The average of 100–120 consecutive 500 ms artefact-free EEG epochs centred at the onset of the EMG burst (burst-locked EEG averages) was computed. At least two averages were generated for each patient to ensure reliability between trials. Consistency of the responses was verified using the coefficient of variation, in terms of the ratio between standard deviation of each sample of peak latency measurements and relative mean [coefficient of variation = (standard deviation/mean) x 100]. A threshold of 5% was set to define the measurements as statistically reproducible. Frequency analysis was also performed between EEG and rectified EMG in seven patients using previously described techniques (Brown et al., 1999
).
Visual and somatosensory evoked potentials and C-reflex
Visual (V) and somatosensory (S) evoked potentials (EPs) were recorded in all but one of the patients (III-13). For the flash VEPs, we measured amplitude and latency of the greatest positive peak. Control data were obtained from 10 age-matched healthy subjects.
SEPs were recorded from centroparietal (C3', C4' = 2 cm behind the International 10–20 system C3 and C4) regions, at the level of the seventh cervical spine, and from Erb's point, using several referential montages. Scalp electrodes were referred to the homologous contralateral area and contralateral mastoid, the seventh cervical spine to the anterior neck (thyroid cartilage) and Erb's point to the contralateral equivalent location. The C-reflex at rest was sought simultaneously by recording EMG activity from the following muscles: masseter, orbicularis oris, finger extensors and flexors, APB and tibialis anterior. The median nerve was electrically stimulated at the wrist, with a frequency of 1 Hz and a duration of 0.2 ms. The EEG signal was filtered with a bandpass of 1–2000 Hz. Blocks of 50–250 ms consecutive artefact-free responses were averaged. Trials were replicated to ensure reproducibility of the responses. Peak latency and amplitude were measured for each recognizable component at the C3', C4' electrodes. The amplitude was measured from the preceding peak of the opposite polarity. The nomenclature of each wave was the same as that used in other studies of cortical myoclonus (e.g. see Ikeda et al., 1995). SEPs were considered giant when the amplitude was >2.5 SD above the mean normal value (Shibasaki et al., 1985), established in 10 normal subjects aged 10–20 years (mean ± standard deviation, 16 ± 2.3 years). In selected patients, multiple channel SEPs were collected using average reference and displayed as topographic voltage maps. Taps to fingers were also employed to produce reflex myoclonic jerks. The C-reflex to both electrical and tapping stimulation was also studied in six unaffected individuals (III-9, III-10, III-11, III-12, IV-3 and V-1) using electrical stimuli at or just above motor threshold (Shibasaki et al., 1978).
Transcranial magnetic stimulation
A Cadwell magnetic device (Cadwell Laboratories, Kennewick, Wash., USA) was used to elicit motor evoked potentials (MEPs) in all but one of the patients (III-13), employing a flat, single round coil (outer diameter of 9.5 cm) placed on the vertex and C7 region. Threshold stimulation intensity (TI) and central motor conduction time (CMCT) were evaluated according to international guidelines (Rossini et al., 1994). In brief, the EMG electrodes were positioned bilaterally over the APB muscles. For each patient, TI (defined as the stimulus intensity required to produce a MEP of at least 50 µV amplitude in at least three out of five trials) was measured (Reutens et al., 1993). The intensity of transcranial magnetic stimulation was increased from sub-threshold levels by increments of 5% of maximum intensity. MEPs were then acquired for five stimuli at an intensity 10% above TI. In order to measure CMCT, peripheral latency was measured utilizing cervical stimulation at an intensity of 100% with the coil centred over the C7 spinous process. CMCT was calculated by subtracting the peripheral latency from total latency. We also evaluated the post-MEPs silent period following transcranial magnetic stimulation (Cantello et al., 1992) during rhythmic EMG bursting patterns of hand myoclonus accompanying voluntary movement. For this purpose, patients were instructed to exert a steady voluntary isometric contraction of target muscle at two-thirds of the maximum and the level of force was monitored with the EMG level. Stimulation intensity was set at 10% above TI.
Control data were obtained from 10 age-matched healthy subjects. Statistical comparisons were performed using Student's t-test for unpaired data. Intracortical inhibition and facilitation could not be tested using the paired pulse technique (Kujirai et al., 1993).
Neuropsychological testing
Seven patients (II-11, III-6, III-8, III-14, IV-2, IV-4 and V-2) were submitted to a battery of cognitive and memory tests which were performed in two sessions. In the first, general intellectual abilities were assessed with the Wechsler Adult Intelligence Scale (WAIS; Wechsler, 1955). One patient (III-6) could only be tested with the verbal subtests of the WAIS since she was visually impaired. For five patients, (III-8, III-14, IV-2, IV-4 and V-2) the pre-morbid level of verbal intellectual functioning was estimated with the Brief Intelligence Test (TIB; Sartori et al., 1995), the Italian version of the National Adult Reading Test (NART) (Nelson and O'Connell, 1978). TIB scores are highly correlated with WAIS verbal IQ, performance IQ and full-scale IQ in normal Italian adults. Patients II-11 and III-8 were not evaluated with the TIB because of non-compliance and presence of syllabic reading, respectively. In the second session, short-term and long-term verbal and non-verbal memory were evaluated as well as graphomotor abilities. The order of test presentation was the same for all patients, i.e. word-list learning (Mauri et al., 1997), Corsi's Block Tapping Span Test (Orsini et al., 1987), Supraspan learning of Corsi's block sequence (Splinnler and Tognogni, 1987), the Developmental Test of Visuo-Motor Integration—Revised (Beery, 1997), paired associate learning (Novelli et al., 1986) and Rey's Complex Figure (Rey, 1968). The patient's performance was compared with Italian normative data matched for chronological age, gender and years of education. No adult Italian norms were available for the Developmental Test of Visuo-Motor Integration—Revised, thus, only raw scores were considered. Five patients were submitted to the entire memory battery and graphomotor test, and two patients had limited assessment (Patient III-6 was unable to perform non-verbal memory and drawing tasks because of her poor vision, and Patient II-11 was not tested with the Rey's Complex Figure because of severe difficulties in the copying phase).
Neuroimaging
Six patients (II-11, III-6, III-14, IV-2, IV-4 and V-2) underwent brain MRI, using 1.5 T instrumentation. Single voxel 1H spectroscopy was performed to study the rolandic cortex using the short TE (echo time) stimulated echo acquisition mode technique [TR (repetition time) = 2010 ms, TE = 30 ms, TM (mixing time) = 13.7 ms, 256 scans accumulated for signal averaging, VOI (volume of interest) dimension = 3.4 cc]. Raw data were analysed off-line and compared with normal values obtained from the same VOI location in 20 age-matched healthy subjects.
Genetic linkage studies
A genome-wide linkage mapping was performed by using highly polymorphic fluorescence-labelled markers, spanning all the chromosomes at an average reciprocal distance of ~10 cM. These preliminary data were analysed by the MLINK programme of the LINKAGE software package (Lathrop et al., 1984; ftp://linkage.rockefeller.edu). Selected chromosomal regions were further investigated using additional markers which mapped telomeric and centromeric markers to the candidate loci. For linkage calculations, autosomal dominant cortical myoclonus and epilepsy (ADCME) was modelled as an autosomal dominant trait with 0.90 penetrance, mutation rate was assumed to be 10–4. Recombination frequencies for males and females were assumed to be equal. Markers' alleles were considered equally frequent in the preliminary screening, whereas published allelic frequencies were used for candidate loci calculations. Multi-point linkage analysis was performed using the LINKMAP program (Lathrop et al., 1984; at http://www.hgmp.mrc.ac.uk) moving the disease locus on subsets of four fixed markers.
|
Results |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
Clinical and neurophysiological data are summarized in Table 1
. |
Clinical data |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
The parents of Patients I-1 and I-2 originated in Italy. There was no known consanguinity in the family. All patients had suffered from apparently generalized tonic–clonic seizures (GTCSs) both while awake and asleep. These seizures appeared without warning (Table 1
), although in two patients (III-6 and III-14) some GTCSs were heralded by a cluster of generalized myoclonic jerks. The total number of GTCSs was variable but generally low (Table 1). Age at onset varied between 12 and 59 years (mean 25 years).
Three patients (III-8, IV-2 and IV-4) had also suffered from intractable complex partial seizures, which were often followed by secondary generalization. Ictal symptomatology of partial seizures was constant for each patient and varied slightly amongst patients. Patient IV-4 became suddenly unresponsive with a motionless stare, grimaced and nodded slowly, gradually recovering responsiveness after 20–30 s, without any language or motor deficit. She did not report any subjective symptoms. Several such seizures were recorded on video-EEG telemetry showing right temporal ictal activity (Fig. 2). Secondary generalization was very rare. Patient III-8 experienced an initial rising epigastric sensation, accompanied by sweating of the hands and followed by unresponsiveness with a motionless stare. Secondary generalization frequently ensued after ~15 s. Patient IV-2 reported an ill-defined unpleasant sensation accompanied by sweating of the hands, became unresponsive and slowly fell, without incurring any injury. In this patient too, secondary generalization also occurred frequently ~30 s after seizure onset.
|
All eight patients presented with rapid, fairly rhythmic myoclonic jerks of the hands of fluctuating amplitude, causing a tremor-like movement of variable severity. The patients with the most severe distal myoclonus were those who had suffered from intractable seizures (III-8, IV-2 and IV-4). Their hand jerking was obvious at rest, was exacerbated by posture maintenance and was accompanied by isolated arrhythmic multifocal jerks of the proximal arms, and eyelid twitching on some occasions. In the less severely affected individuals, only arm stretching or wrist extension uncovered the rhythmic jerking. Jerks disappeared during sleep. Age at onset of myoclonus ranged from 12 to 50 years (mean = 23 years) and, in most patients, slightly preceded or coincided with that at onset of the first seizure. The maximum severity of myoclonus was reached within the first year from its onset. Age at onset of both epilepsy and myoclonus did not show any systematic change across generations (see Table 1
), in particular, there was no evidence for anticipation. Patients II-11 and III-13 had only suffered one or two isolated GTCSs and were not treated with antiepileptic drugs. Patient III-14 had initially suffered three GTCSs followed by 20 years remission while treated with phenobarbital and phenytoin initially, and with valproate monotherapy subsequently. He refused to suspend his treatment. Patient V-2 had two initial GTCSs and was subsequently treated with valproate. In the following two years he suffered an additional similar episode after sleep deprivation. Patient III-8 had been seizure free over the last 20 years on phenobarbital and phenytoin, after having experienced several years of seizure intractability. She refused treatment simplification. Patient III-6 suffered from GTCSs, which had proven resistant to phenobarbital monotherapy and were only slightly improved after the addition of carbamazepine. The two remaining patients suffered intractable complex partial and generalized seizures in spite of polypharmacy (valproate + primidone + clonazepam in Patient IV-2 and primidone + levetiracetam + clonazepam in Patient IV-4). Both patients had previously undergone multiple antiepileptic drug trials.
In three patients (VI-2, VI-4 and V-2), myoclonus was considered to be severe or socially disabling enough to require treatment with clonazepam per se, with mild improvement. All three patients who had been treated with carbamazepine because of their seizures had experienced severe worsening of myoclonus (III-6, IV-2 and IV-4). While the drug was discontinued in two of them, the third patient (III-6) wanted to continue with carbamazepine treatment, which had improved her GTCSs.
Patients II-11 and III-14 reported that occasional intake of mild to moderate amounts of alcohol did not affect myoclonus.
Electrophysiological studies
EEGs showed normal background activity and interictal generalized epileptiform discharges in all seven patients studied and in two unaffected relatives (IV-3 and V-1). Six patients had focal temporal or frontotemporal spikes or spike and wave discharges as well as more diffuse abnormalities (Table 1 and Fig. 3). None of the patients showed more than one focus. The remaining patient (II-11), aged 81, had bilateral temporal predominant EEG abnormalities only. Transition from wakefulness to sleep produced an increase in interictal discharges. Intermittent photic stimulation at low rates (1–10 Hz) elicited a photoparoxysmal driving in which each flash triggered an occipital spike. There was neither clinical response to intermittent photic stimulation, nor a history of visually induced seizures.
|
EMG showed synchronous bursting of agonist and antagonist muscles with a mean frequency of 12 Hz (SEM ± 0.4; range 8–15 Hz) and a mean burst duration of 40 ms (SD ± 4). Each burst alternated with a period of EMG silence or near silence. On visual inspection of EEG-EMG traces, individual myoclonic potentials were not time-locked to any EEG transient (Fig. 4
). Back-averaging generated a series of waves, with a frequency that mirrored the frequency of EMG bursts. The biggest of these consisted of a reproducible positive–negative biphasic transient in the hemisphere contralateral to the jerking hand (Fig. 5). The positive component of this transient had a mean duration of 37 ms (SD ± 6) and its peak occurred 21 ms (SD ± 2) before the onset of the EMG bursts when these were recorded from the belly of the wrist extensors. This waveform could be identified in all patients and the averages were analysed. Nevertheless, as both myoclonus-related EMG and EEG activities were rhythmic, it was difficult to establish with absolute certainty from back-averages which of the various waves time-locked to the EMG discharge bore the most fixed temporal relationship to the EMG trigger. Conventionally it is assumed that the biggest in a train of waves is the most highly correlated with the EMG, but this is only true if all waves are of similar amplitude before averaging. We therefore complemented our back-averages with frequency analysis, and found significant peaks in coherence between EMGs and EEGs recorded over the contralateral rolandic area in five (II-11, III-6, III-8, III-14 and IV-2) out of the seven patients studied. The frequency of coherence was 8–25 Hz. More importantly, phase spectra confirmed that EEG activity preceded EMG activity (Fig. 6), although, as in other studies, the EMG lag (8–15 ms) tended to be shorter than that derived from back-averaging (see above) and brief for even the fastest corticomuscular pathways (discussed in Brown, 2000). Nevertheless, the frequency analysis results indicate that the apparent coupling of EEG with EMG was unlikely to arise through EMG or other contamination of the scalp EEG. Coherence was greatest over the rolandic area contralateral to the myoclonus, while EMG contamination would have been expected to be symmetrical and to cover a broader band of frequencies. Cortex precedes muscle, excluding volume conduction as an explanation of coupling, while artefact related to eye movement would have been expected to involve lower frequencies, to have been more symmetrical and not to exhibit any systematic phase coupling with myoclonic bursts. In two individuals (III-6 and IV-2), there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity during spontaneous and action-induced myoclonus. The latter was further supported by the finding of coherence between EMG bursts in the right and left forearms.
|
|
|
Visual and somatosensory evoked potentials and C-reflex
Flash VEP responses showed a significant increase in amplitude of the greatest positive peak compared with controls. For SEP responses recorded at Erb's point (N9), the seventh cervical spine (N13), N9–13 and N13–20 (expression of the central conduction time) interpeak times were within normal values. Mean baseline peak amplitude of the N20 component was within the normal range. In all patients, a significant increase was observed in interpeak amplitudes of the N20–P30 (16 µV; SD ± 5) and P30–N35 (23 µV; SD ± 10) complexes (+3 SD and +3 SD, respectively).
All patients presented hyper-excitable C-reflexes to electrical and mechanical stimulation at rest (Fig. 7). Their ipsilateral response had a latency of 43 ms (SD ± 3) and was followed by a contralateral response after ~8 ms. This inter-side latency is similar to that previously reported in cortical myoclonus, and is compatible with transcallosal spread (Brown et al., 1991). Spread of myoclonic activity was also evident within the stimulated limb (Fig. 8). Mapping of multi-channel SEPs (P30 wave) showed the same field distribution as that of the premyoclonic spike. None of the six clinically unaffected individuals in whom C-reflex was studied had an abnormal response.
|
|
Transcranial magnetic stimulation
MEPs showed total motor conduction time and CMCTs were within normal limits in all patients. The resting motor threshold intensity was significantly reduced (38%; SD = ±7; P = 0.01), despite the fact that five out of seven patients were tested while on antiepileptic drug treatment. When tested active, with an intensity of resting threshold of 120%, transcranial magnetic stimulation induced a post-MEP silent period lasting 101 ms (SEM = ±10). These values were markedly shortened compared with those obtained in controls (137 ms; SEM = ±18). The EMG activity following the silent period immediately resumed the rhythmic bursting pattern of the pre-stimulus period.
Neuropsychological testing
Three patients (III-6, III-8 and IV-4) had mild to moderate mental retardation and one (IV-2) had borderline intellectual functioning according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1994). In the remaining three patients tested, intelligence was in the low average range. Full scale IQ ranged from 49 to 94 in the six patients submitted to the entire scale. The verbal IQ score was higher than performance IQ score in four patients, but in all six, the worst performance was always found in the Performance Scale in Visuo-Constructive Subtests (Digit symbol and/or Object assembly). Estimated pre-morbid verbal intelligence ranged from 79 to 104. Estimated verbal IQ was higher than WAIS verbal IQ in the three patients with complex partial seizures (III-8, IV-2 and IV-4). Pre-morbid verbal intelligence was in line with verbal IQ in the other patients. Verbal memory was preserved and was in the average to above-average range in all patients except in the two patients with persistently intractable complex partial seizures (IV-2 and IV-4). These two patients displayed below average or impaired verbal memory performance. Non-verbal memory was generally less preserved than verbal memory and was in the below-average range in patients with generalized seizures only, and impaired or in the borderline range in the three patients who also suffered complex partial seizures. All five patients who were submitted to the Rey Complex Figure Test displayed marked difficulties in drawing the figure from memory. Myoclonus affected copying performance in four out of six patients. No patient displayed major spatial errors in copying performance in the Developmental Test of Visuo-Motor Integration—Revised.
Neuroimaging
Brain MRIs were normal. Spectra acquired on rolandic cortex exhibited no signal abnormalities when compared with our normal values.
Genetic linkage studies
Known loci previously reported to be associated with myoclonic epilepsy (EPM1, EPM2, EJM1, EJM2, FAME, EIM and CACNB4, the human orthologue of the mouse epilepsy lethargic gene) were excluded. We tested the probability of detecting significant linkage by simulation analysis of 400 replicate pedigrees by using SLINK (linkage simulation program, enclosed in the LINKAGE package) considering the phenotype with a frequency of 1 x 10–5. The maximum pairwise LOD (logarithm of the odds) score obtained from 400 simulated pedigrees was 3.4 at 0.0. In the genome-wide screening, only affected pedigree members were included. Selected loci suggestive of linkage (in 2cen and 3p26–25) were further characterized by locally increasing the marker density and by including all the available pedigree members. Chromosome 2 locus was significantly confirmed (Table 2) to be in linkage with ADCME linkage, reaching a LOD score value of 3.46 for D2S2175at 0.0. A common haplotype (1_3_1_2_1; Fig. 1) shared by all the affected individuals was identified with markers D2S388, D2S2216, D2S2175, D2S113 and D2S2264. A wide multi-point linkage analysis was performed with markers D2S139, D2S161, D2S388, D2S2216, D2S2175, D2S113, D2S2264, D2S1897 and D2S293. The graph (Fig. 9) shows a multi-point LOD score value of 3.74 around D2S2175, thus placing the localization of the ADCME gene in the centromeric region of chromosome 2.
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
Affected members of this family presented with a homogeneous syndromic core including an association of non-progressive cortical reflex myoclonus, expressed with semi-continuous rhythmic distal jerking (cortical tremor), GTCSs (preceded in two patients by generalized myoclonic jerks) and generalized EEG abnormalities. The age at onset of cortical tremor and of GTCSs overlapped in a given individual but varied between individuals, ranging from 12 to 50 years. This clinical picture shares some features with FAME (Mikami et al., 1999
; Plaster et al., 1999), identified as a form of autosomal dominant generalized epilepsy. However, all our patients had in addition focal frontotemporal EEG abnormalities, and three individuals also presented with complex partial seizures starting around the same age as the other manifestations, which were either intractable or, alternatively, went into remission after several years. In addition, myoclonic seizures were not a prominent feature in the family described here. We therefore decided to use the acronym ADCME, as clinical features are not consistent with a form of myoclonic epilepsy.
The distal jerking observed in all patients of this family had the characteristics of cortical tremor (Ikeda et al., 1990; Toro et al., 1993). A stereotyped pattern of rhythmic involuntary hand movements was evident during isometric muscle contraction, with rhythmic EMG bursts at 8–15 Hz synchronously involving agonist and antagonist muscles of the forearms. Involvement of more proximal as well as facial muscles, especially the eyelids, was noticed in some patients. Back-averaging and frequency analysis indicated that EEG activity was coherent with EMG at the frequency of the myoclonus and that EEG preceded EMG bursts. The C-reflex at rest was enhanced, SEPs were of high amplitude, motor threshold was reduced and the post-MEP silent period was shortened. Clinical and neurophysiological characteristics suggested a high propensity for intra-hemispheric and inter-hemispheric cortical spread as well as rhythmicity of myoclonic activity. In addition, intermittent photic stimulation at low rates evoked single occipital spikes in response to each flash, and flash VEPs were of very high amplitude. All these findings suggest widespread cortical hyperexcitability with deficits in inhibitory cortical mechanisms (Brown et al., 1991, 1996; Uozumi et al., 1992; Guerrini et al., 1996; Cicinelli et al., 2000). Rhythmic motor cortex excitation can originate from rhythmic generators within cortical layers IV and V (Connors and Amitai, 1997) or, alternatively, cortical neurones could be driven by a subcortical generator (Toro et al., 1993).
Cortical tremor may be observed in different clinical settings, as a consequence of multiple aetiological factors enhancing motor cortex excitability. In addition to FAME (Ikeda et al., 1990; Yasuda et al., 1991; Terada et al., 1997; Mikami et al., 1999; Plaster et al., 2000), it may also be observed in other genetic disorders including a form of familial mental retardation and generalized epilepsy (Elia et al., 1998), Angelman syndrome (Guerrini et al., 1996) and progressive myoclonus epilepsies (Toro et al., 1993), in which it may be accompanied by generalized as well as focal seizures. Sporadically, patients with a clinical picture identical to FAME have also been described (Ikeda et al., 1990). In addition, cortical tremor has been observed in association with focal motor seizures after ischaemic brain lesions involving the sensorimotor cortex (Schulze-Bonhage et al., 1998; Wang et al., 1999), or, as an isolated symptom, after surgical removal of a frontal lobe meningioma (Botzel and Werhahn, 1999) and in patients with no other neurological abnormality (Toro et al., 1993). A condition that can probably be included within the spectrum of cortical tremor is mini polymyoclonus (Wilkins et al., 1985). This phenomenon is characterized by quasi-rhythmic tiny finger movements due to synchronous jerks in both hands, preceded by a cortical potential. Although the original description indicated that mini polymyoclonus was related to primary generalized epileptic myoclonus (Wilkins et al., 1985), current classification concepts indicate that some of the patients described had generalized symptomatic, non-genetic epilepsies (Commission on Classification and Terminology of the International League Against Epilepsy, 1989). All these observations indicate that cortical tremor is a common neurological manifestation and is often associated with epilepsy of either symptomatic or genetic aetiology.
All patients had rare GTCSs without any warning. Patients with focal seizures also had generalized seizures preceded by a focal onset, although the propensity to generalization was variable. Complex partial seizures were similar in the three patients, being mainly characterized by a motionless stare with unresponsiveness for ~20–30 s, without any automatism, preceded in one by an epigastric aura and another by a non-specific warning. These seizure patterns cannot be attributed with certainty to any specific lobar origin. A frontotemporal origin is most likely and is, in part, supported by the presence of frontal and anterior temporal interictal EEG spikes in all three patients, and by the recording of partial seizures accompanied by ictal EEG activity in the right temporal lobe in one patient. Definition of the site of onset of focal seizures can be very difficult based on clinical and surface EEG findings alone when neuroimaging is normal. Attribution to a definite lobar origin may be misleading in the absence of a highly characteristic clustering of symptoms, and the epileptogenic area may not respect the anatomical limits of the cerebral lobes. A large study including 19 families with dominant partial epilepsies showed that there may be no clear boundary between the different genetic syndromes of focal epilepsy and that reliable lobar classification of the epilepsy can be difficult (Picard et al., 2000). In addition, seizure spread from clinically silent areas may be rapid, producing unresponsiveness before subjective symptoms can be reported or memorized (Munari et al., 1980). Certainly, electrophysiology indicated very rapid transcallosal spread between the two sensorimotor hemispheres during myoclonic jerks in some patients. Since frontotemporal interictal EEG abnormalities were present in all affected family members, it is also possible that pronounced cortical hyperexcitability and propensity to spread may facilitate rapid seizure generalization, which obscures the focal nature of epilepsy in most patients.
As patients in this family had variable clinical severity and different drug treatments, it is very difficult to establish which antiepileptic drugs were more effective. The severity of the disorder seemed to be scarcely influenced by drugs, as demonstrated by the benign seizure outcome in the two patients who were never treated and by the drug resistance in others. In general, drugs combining antiepileptic and antimyoclonic properties such as valproate, phenobarbital and benzodiazepines produced the most benefit, while carbamazepine had paradoxical effects, causing seizure improvement and worsening of myoclonus.
Patients with well-controlled seizures displayed low average intelligence, had normal verbal memory and difficulties in some non-verbal memory tasks. Estimated pre-morbid verbal intelligence was generally in line with WAIS verbal IQ. Less preserved non-verbal memory in these patients, as well as the lower performance abilities on the WAIS, both requiring visuomotor integration, may be tied to continuous myoclonus. Patients with complex partial seizures had borderline intelligence to moderate mental retardation and global memory deficits, the latter occurring when seizures were intractable. Pre-morbid estimation of verbal intelligence indicated cognitive deterioration over time in the two patients with persistently intractable complex partial seizures, possibly as a consequence of the detrimental effect of uncontrolled seizures on cognition. This result should, however, be interpreted with caution since there is evidence that the NART overestimates intelligence at the lower end of the IQ range (Ryan and Paolo, 1992). On the whole, neuropsychological evidence indicates that low IQ may not be primarily genetically determined, but may result as a consequence of long-lasting severe epilepsy. Furthermore, the data suggest that the memory impairment observed in patients with complex partial seizures may not be tied directly to selective temporal lobe dysfunction, as performance was not impaired across all long-term memory tasks, and in some tasks, memory performance was not compromised more than general intelligence.
Two distinct phenotypes coexisted in the family reported here: a core clinical syndrome with generalized seizures and rhythmic myoclonus sharing common features with FAME, and a more severe phenotype also including complex partial seizures. This combination of symptoms in a unigenic model of epilepsy can be interpreted in different ways. One possibility is that this family has a FAME plus syndrome analogous to generalized epilepsy with febrile seizures (GEFS) plus syndrome, in which all affected individuals present febrile seizures early in life and later in life most of them develop different types of generalized seizures or, rarely, focal seizures (Singh et al., 1998; Baulac et al., 1999). In this hypothesis, the same gene would be expressed with generalized as well as focal epileptogenesis, and focal seizures would just represent a non-specific expression of diffuse cortical hyperexcitability that is manifested in some patients. However, with diffuse cortical hyperexcitability we would expect multiple cortical areas to be able to generate different seizure types, while, in our patients, focal seizures were stereotyped and not polymorphous. A more likely alternative is that the responsible gene causes cortical hyperexcitability that is widespread, but particularly involves frontotemporal circuits as evidenced by the focal seizure activity in some patients, and the frontotemporal EEG abnormalities and myoclonic tremor due to involvement of the motor cortex in all patients. The implication is that the genetic defect can result in a relatively focal disturbance of cortical rhythmicity and excitability, and that generalized seizures originate from spread of regional epileptogenesis. In the case of the cortical tremor, this may involve disinhibition of the motor cortex physiological tendency to oscillatory discharge in the mu frequency range. The mu rhythm is present when a healthy subject is at rest and is attenuated (desynchronized) on tactile stimulation or voluntary muscle contraction (Tiihonen et al., 1989). Nevertheless, a component of cortical activity persists in the same frequency band during isometric contraction and is coherent with EMG (Conway et al., 1995; Salenius et al., 1997). It is this component that we hypothesize was exaggerated in our patients with cortical tremor, as abnormal corticomuscular rhythmicity occurred in the same frequency band and under similar circumstances of isometric contraction, such as holding the arms outstretched. Interestingly, those physiological motor circuits leading to rhythmicities in the gamma band (Brown et al., 1998) seem essentially spared by this condition, unlike many other myoclonic syndromes (Brown et al., 1999).
Co-occurrence of focal and apparently generalized seizures has been reported in the same family on several occasions (Singh et al., 1998; Baulac et al., 1999; Picard et al., 2000). Patients with generalized seizures have sometimes been excluded from studies aimed at characterizing focal epilepsy phenotypes for the purpose of genotype analysis (Picard et al., 2000). However, studies on genetic epilepsies indicate that the same gene may be expressed to a different degree and with different regional predominance in different individuals. For example, patients with GEFS plus may have carrier relatives with temporal lobe epilepsy (Singh et al., 1998). Some individuals with GEFS plus may also present with both primary generalized and focal electroclinical features (Baulac et al., 1999). In partial epilepsy with variable foci different brain areas are involved in the same family (Scheffer et al., 1998).
Considering the putative function of the genes mapping within the 12 cM critical region of this form of epilepsy, we identified the following candidates: downstream regulatory element antagonist modulator (DREAM) (Carrion et al., 1999); calsenilin-KchIP3, a calcium binding protein that regulates voltage-gated potassium currents, and hence neuronal excitability, in response to changes in intracellular calcium (An et al., 2000) (DREAM and calsenilin are highly homologous and are predominantly expressed in brain); NPAS2 (neuronal PAS domain protein 2) (Zhou, et al., 1997), a neuronal transcription factor; and GPCR45 (G protein-coupled receptor 45) (Marchese et al., 1999), an integral membrane protein expressed in basal forebrain, caudate and frontal cortex. In addition, several partial transcripts encoding for potential candidate genes map to the ADCME locus. However, the large chromosomal area identified by the ADCME locus renders a positional cloning strategy quite unfeasible, while new ADCME pedigrees will contribute new recombination events to narrow the candidate region.
In our opinion, the manifestations of epilepsy and distal cortical myoclonus clustering in this family could be much more frequent than so far recognized. Since we started this study, we have identified several sporadic patients with similar clinical features. These patients may easily be misdiagnosed as having juvenile myoclonic epilepsy (Panayiotopoulos et al., 1994), with generalized tonic–clonic seizures and proximal jerks being typical of both conditions. Complex partial seizures without automatisms seen in some of our patients are easily confused with absence seizures, and cortical tremor is interpreted as simple tremor, a relatively frequent side-effect of valproate treatment (Karas et al., 1982).
|
Acknowledgements |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
This study was partially supported by Grant MMNTDQR from Fund for Epilepsy, UK and Italian National Institute of Health research funding (Ministero della Sanità RF3/00 and RC2/01).
|
References |
|---|
|
TopAbstractIntroductionPatients and methodsResultsClinical dataDiscussionAcknowledgementsReferences |
|---|
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. DSM-IV. 4th ed. Washington (DC): American Psychiatric Association; 1994.
An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 2000; 403: 553–6.[Medline]
Baulac S, Gourfinkel-An I, Picard F, Rosenberg-Bourgin M, Prudhomme JF, Baulac M, et al. A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33. Am J Hum Genet 1999; 65: 1078–85.[Web of Science][Medline]
Beery KE. Developmental Test of Visuo-Motor Integration (VMI). 4th ed. New Jersey: Modern Curriculum Press; 1997.
Berkovic SF, Scheffer IE. Epilepsies with single gene inheritance. [Review]. Brain Dev 1997; 19: 13–18.[Web of Science][Medline]
Botzel K, Werhahn KJ. A case of myoclonic cortical tremor after extirpation of a parietal meningioma. Mov Disord 1999; 14: 1033–5.[Web of Science][Medline]
Brown P. Cortical drives to human muscle: the Piper rhythm and related rhythms. [Review]. Prog Neurobiol 2000; 60: 97–108.[Web of Science][Medline]
Brown P, Day BL, Rothwell JC, Thompson PD, Marsden CD. Intrahemispheric and interhemispheric spread of cerebral cortical myoclonic activity and its relevance to epilepsy. Brain 1991; 114: 2333–51.
Brown P, Ridding MC, Werhahn KJ, Rothwell JC, Marsden CD. Abnormalities of the balance between inhibition and excitation in the motor cortex of patients with cortical myoclonus. Brain 1996; 119: 309–17.
Brown P, Salenius S, Rothwell JC, Hari R. Cortical correlate of the Piper rhythm in humans. J Neurophysiol 1998; 80: 2911–17.
Brown P, Farmer SF, Halliday DM, Marsden J, Rosenberg JR. Coherent cortical and muscle discharge in cortical myoclonus. Brain 1999; 122: 461–72.
Cantello R, Gianelli M, Civardi C, Mutani R. Magnetic brain stimulation: the silent period after the motor evoked potential. Neurology 1992; 42: 1951–9.
Carrion AM, Link WA, Ledo F, Mellstrom B, Naranjo JR. DREAM is a Ca2+-regulated transcriptional repressor. Nature 1999; 398: 80–4.[Medline]
Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998; 18: 53–5.[Web of Science][Medline]
Cicinelli P, Mattia D, Spanedda F, Traversa R, Marciani MG, Pasqualetti P, et al. Transcranial magnetic stimulation reveals an interhemispheric asymmetry of cortical inhibition in focal epilepsy. Neuroreport 2000; 11: 701–7.[Web of Science][Medline]
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–99.[Web of Science][Medline]
Connors BW and Amitai Y. Making waves in the neocortex. [Review]. Neuron 1997; 18: 347–9.[Web of Science][Medline]
Conway BA, Halliday DM, Farmer SF, Shahani U, Maas P, Weir AI, et al. Synchronization between motor cortex and spinal motoneuronal pool during the performance of a maintained motor task in man. J Physiol (Lond) 1995; 489: 917–24.
De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, et al. The nicotinic receptor beta2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 2000; 26: 275–6.[Web of Science][Medline]
Elia M, Musumeci SA, Ferri R, Scuderi C, Del Gracco S, Bottitta M, et al. Familial cortical tremor, epilepsy, and mental retardation: a distinct clinical entity? Arch Neurol 1998; 55: 1569–73.
Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, et al. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 2000a; 24: 343–5.[Web of Science][Medline]
Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, et al. Coding and noncoding variation of the human calcium-channel beta(4)-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 2000b; 66: 1531–9.[Web of Science][Medline]
Guerrini R, De Lorey TM, Bonanni P, Moncla A, Dravet C, Suisse G, et al. Cortical myoclonus in Angelman syndrome. Ann Neurol 1996; 40: 39–48.[Web of Science][Medline]
Guerrini R, Bonanni P, Nardocci N, Parmeggiani L, Piccirilli M, De Fusco M, et al. Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12–11.2. Ann Neurol 1999; 45: 344–52.[Web of Science][Medline]
Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 1990; 40: 1561–5.
Ikeda A, Shibasaki H, Nagamine T, Xu X, Terada K, Mima T, et al. Peri-rolandic and fronto-parietal components of scalp-recorded giant SEPs in cortical myoclonus. Electroencephalogr Clin Neurophysiol 1995; 96: 300–9.[Medline]
Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Valproate tremors. Neurology 1982; 32: 428–32.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Cortico-cortical inhibition in human motor cortex. J Physiol (Lond) 1993; 471: 501–19.
Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 1984, 36: 460–5.[Web of Science][Medline]
Marchese A, Sawzdargo M, Nguyen T, Cheng R, Heng HH, Nowak T, et al. Discovery of three novel orphan G-protein-coupled receptors. Genomics 1999; 56: 12–21.[Web of Science][Medline]
Mauri M, Carlesimo GA, Graceffa AMS, Loasses A, Lorusso S, Sinforiani S, et al. Standardizzazione di due nuovi test di memoria: apprendimento di liste di parole correlate e non correlate semanticamente. [Standardization of two new memory tests: learning lists of semantically and non-semantically related words]. Arch Psicol Neurol Psich 1997; 58: 621–54.
Mikami M, Yasuda T, Terao A, Nakamura M, Ueno S, Tanabe H, et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am J Hum Genet 1999; 65: 745–51.[Web of Science][Medline]
Munari C, Bancaud J, Bonis A, Stoeffels C, Szikla G, Talaivach J. Impairment of consciousness in temporal lobe seizures: a stereoelectroencephalographic study. In: Canger R, Angeleri F, Penry JK, editors. Advances in epileptology: XIth Epilepsy International Symposium. New York: Raven Press; 1980. p. 111–14.
Nelson HE, O'Connell A. Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex 1978; 14: 234–44.[Web of Science][Medline]
Novelli G, Papagno C, Capitani E, Laiacona M, Cappa SF, Vallar G. Tre test clinici di memoria verbale a lungo termine: taratura su soggetti normali. [Three verbal long-term memory tests for clinical use: normative data]. Arch Psicol, Neurol Psich 1986; 34: 278–96.
Orsini A, Grossi D, Capitani E, Laiacona M, Papagno C, Vallar G. Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci 1987; 8: 539–48.[Web of Science][Medline]
Panayiotopoulos CP, Obeid T, Tahan AR. Juvenile myoclonic epilepsy: a 5-year prospective study. Epilepsia 1994; 35: 285–96.[Web of Science][Medline]
Picard F, Baulac S, Kahane P, Hirsch E, Sebastianelli R, Thomas P, et al. Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families. Brain 2000; 123: 1247–62.
Plaster NM, Uyama E, Uchino M, Ikeda T, Flanigan KM, Kondo I, et al. Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 1999; 53: 1180–3.
Reutens CD, Puce A, Berkovic SF. Cortical hyperexcitability in progressive myoclonus epilepsy: a study with transcranial magnetic stimulation. Neurology 1993; 43: 186–92.
Rey A. Reattivo della figura complessa di Rey—Manuale [Rey Complex Figure—Manual]. Firenze: Organizzazioni Speciali; 1968.
Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RO, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee. Electroencephalogr Clin Neurophysiol 1994; 91: 79–92.[Web of Science][Medline]
Ryan JJ, Paolo AM. A screening procedure for estimating premorbid intelligence in the elderly. Clin Neuropsychol 1992; 6: 53–62.
Salenius S, Portin K, Kajola M, Salmelin R, Hari R. Cortical control of human motoneuron firing during isometric contraction. J Neurophysiol 1997; 77: 3401–5.
Sartori G, Colombo L, Vallar G, Rusconi ML, Pinarello A. TIB-Test di Intelligenza Breve per la valutazione del quoziente intellettivo attuale e pre-morboso. [TIB-Brief Test of Intelligence for assessing present and pre-morbid intelligence]. Professione di Psicologo. Giornale dell'Ordine degli Psicologi 1995; 4: 1–24.
Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 1997; 120: 479–90.
Scheffer IE, Jones L, Pozzebon M, Howell RA, Saling MM, Berkovic SF. Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation. Ann Neurol 1995; 38: 633–42.[Web of Science][Medline]
Scheffer IE, Phillips HA, O'Brien CE, Saling MM, Wrennall JA, Wallace RH, et al. Familial partial epilepsy with variable foci: a new partial epilepsy syndrome with suggestion of linkage to chromosome 2. Ann Neurol 1998; 44: 890–9.[Web of Science][Medline]
Schulze-Bonhage A, Ferbert A. Cortical action tremor and focal motor seizures after parietal infarction. Mov Disord 1998; 13: 356–8.[Web of Science][Medline]
Shibasaki H, Yamashita Y, Kuroiwa Y. Electroencephalographic studies of myoclonus. Brain 1978; 101: 447–60.
Shibasaki H, Yamashita Y, Neshige R, Tobimatsu S, Fukui R. Pathogenesis of giant somatosensory evoked potentials in progressive myoclonic epilepsy. Brain 1985; 108: 225–40.
Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998; 18: 25–9.[Web of Science][Medline]
Spinnler H, Tognoni G, editors. Standardizzazione e taratura italiana di test neuropsicologici. [Italian standardization and normative data of neuropsychological tests]. Ital J Neurol Sci 1987; Suppl 8.
Steinlein OK, Mulley JC, Propping P, Wallace RH, Phillips HA, Sutherland GR, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11: 201–3.[Web of Science][Medline]
Szepetowski P, Rochette J, Berquin J, Piussan C, Lathrop GM, Monaco AP. Familial infantile convulsions and paroxysmal choreoathetosis: a new neurological syndrome linked to the pericentromeric region of human chromosome 16. Am J Hum Genet 1997; 61: 889–98.[Web of Science][Medline]
Terada K, Ikeda A, Mima T, Kimura K, Nagahama Y, Kamioka Y, et al. Familial cortical myoclonic tremor as a unique form of cortical reflex myoclonus. Mov Disord 1997; 12: 370–7.[Web of Science][Medline]
Tiihonen J, Kajola M, Hari R. Magnetic mu rhythm in man. Neuroscience 1989; 32: 793–800.[Web of Science][Medline]
Toro C, Pascual-Leone A, Deuschl G, Tate E, Pranzatelli MR, Hallett M. Cortical tremor: a common manifestation of cortical myoclonus. Neurology 1993; 43: 2346–53.
Uozumi T, Ito Y, Tsuji S, Murai Y. Inhibitory period following motor potentials evoked by magnetic cortical stimulation. Electroencephalogr Clin Neurophysiol 1992; 85: 273–9.[Web of Science][Medline]
Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr, Phillips HA, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet 1998; 19: 366–70.[Web of Science][Medline]
Wang HC, Hsu WC, Brown P. Cortical tremor secondary to a frontal cortical lesion. Mov Disord 1999; 14: 370–4.[Web of Science][Medline]
Wechsler D. Wechsler Adult Intelligence Scale. Manual. New York: Psychological Corporation; 1955. [Italian Edition, Scala di Intelligenza Wechsler per adulti. Firenze: Organizzazioni Speciali, 1974].
Wilkins DE, Hallett M, Erba G. Primary generalised epileptic myoclonus: a frequent manifestation of minipolymyoclonus of central origin. J Neurol Neurosurg Psychiatry 1985; 48: 506–16.
Yasuda T. Benign adult familial myoclonus epilepsy (BAFME). Kawasaki Med J 1991; 17: 1–13.
Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, et al. Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system. Proc Natl Acad Sci USA 1997; 94: 713–18.
Received February 5, 2001. Revised June 20, 2001. Accepted July 25, 2001.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Striano, S. Striano, F. Zara, and J. A. Carr FAME 3: A NOVEL FORM OF PROGRESSIVE MYOCLONUS AND EPILEPSY Neurology, January 1, 2008; 70(1): 85 - 86. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Carr, P. E. van der Walt, J. Nakayama, Y. -H. Fu, V. Corfield, P. Brink, and L. Ptacek FAME 3: A novel form of progressive myoclonus and epilepsy Neurology, April 24, 2007; 68(17): 1382 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Brown Action myoclonus-renal failure syndrome: the definitive clinico-pathological description Brain, October 1, 2004; 127(10): 2151 - 2152. [Full Text] [PDF]
|
|
|
|
|
|
F.A. de Falco, P. Striano, A. de Falco, S. Striano, R. Santangelo, A. Perretti, P. Balbi, M. Cecconi, and F. Zara Benign adult familial myoclonic epilepsy: Genetic heterogeneity and allelism with ADCME Neurology, April 22, 2003; 60(8): 1381 - 1385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Grosse, R. Guerrini, L. Parmeggiani, P. Bonanni, A. Pogosyan, and P. Brown Abnormal corticomuscular and intermuscular coupling in high-frequency rhythmic myoclonus Brain, February 1, 2003; 126(2): 326 - 342. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||