Address correspondence to Prof. A. Berardelli, Department of Neurological Sciences, Sapienza University of Rome, Viale dell’Università, 30, 00185 Rome, Italy. E-mail: email@example.com
We studied the clinical, neuropsychological, neurophysiologic, and genetic features of an Italian family with familial cortical myoclonic tremor with epilepsy (FCMTE). Clinically affected members of the family had limb and voice tremor, seizures, and myoclonus involving the eyelids during blinking. Neuropsychological testing disclosed visuospatial impairment, possibly due to temporal lobe dysfunction. Neurophysiologic findings suggested increased primary motor cortex excitability with normal sensorimotor integration. Linkage analysis excluded the 8q24 locus, where patients shared a common haplotype spanning 14.5 Mb in the pericentromeric region of chromosome 2.
This report describes the clinical, neuropsychological, neurophysiologic, and genetic features of a new Italian family with FCMTE.
Materials and Methods
We studied seven members of a three-generation family (four males and three females) (age at the time of the study for subject I:2 = 83 years; II:1 = 52 years; II:2 = 49 years; II:3 = 57 years; II:4 = 58 years; III:1 = 28 years; and III:2 = 28 years; mean age ± SD = 50.7 ± 19 years) (Fig. 1). There was no consanguinity between parents and grandparents. The proband (III:1) was referred to us for investigation of seizures. Members of the family with the main FCMTE clinical features were considered clinically affected (II:2, II:3, III:1, and III:2), whereas those without were considered clinically unaffected (I:2, II:1, and II:4).
Written informed consent was obtained from all patients, and the study was approved by the local ethical committee.
Clinical and magnetic resonance imaging examination
All family members underwent neurologic examination and a magnetic resonance imaging (MRI) brain scan.
All the clinically affected members underwent a neuropsychological assessment. When necessary, scores were adjusted for age, gender, and education using demographically corrected normative data (Table 1).
Table 1. Neuropsychological evaluation: Wechsler Adult Intelligence Scale (WAIS) Revised (verbal IQ, performance IQ, full scale IQ, and index of cognitive deterioration) and the Mini Mental State Examination (MMSE) or general cognitive status; Digit Span, Rey’s 15 Words Immediate Recall (IR) and Delayed Recall (DR) for verbal memory; Corsi’s Block Tapping Test, Rey’s Complex Figure IR and DR for visual memory; Frontal Assessment Battery (FAB), Digit Span, and Corsi’s Block Tapping Test backward, Phonological Verbal Fluency Test, Trail Making Test A and B for executive functions; Raven’s Progressive Matrices for abstract reasoning; Attentive Matrices for attention; Copy of Rey’s Complex Figure, Benton’s Judgement of Line Orientation Test (JLOT) and Street’s Completion Test for visuospatial processing; Token Test and the oral denomination part of the Aachener Aphasie Test (AAT) for language
Bold values indicate pathologic values. The cutoff scores for the four subjects tested are reported.
Rey’s 15 Words-IR
Rey’s 15 Words-DR
Rey’s Complex Figure IR
II:3: ≥9.9; II:2: ≥15.7; III:1-III:2: ≥17
Rey’s Complex Figure DR
II:3: ≥9; II:2: ≥15.9; III:1-III:2: ≥17
Corsi’s Block Tapping test
Digit Span backward
Phonological Verbal Fluency
Trail Making Test A
Trail Making Test B
Raven’s Progressive Matrices
Rey’s Complex Figure copy
ll:3: ≥28.9.; ll:2: ≥33; 111:1-111:2: ≥34
Judgement of Line Orientation Test (JLOT)
Street’s Completion Test
II:3: ≥5.7; II:2-III:1-III:2: ≥6.1
The clinically affected family members underwent a neurophysiologic examination at least one week after discontinuing therapy with valproate and clonazepam. Postural tremor was recorded through pairs of surface electrodes placed over the forearm flexors and extensor muscles of upper limbs. Standard electroencephalography (EEG), somatosensory evoked potentials (SEPs), and C-Reflex were recorded according to standard techniques. Back-averaging EEG with muscle jerks recorded in the extensor forearm muscles was also performed in the affected members. Transcranial magnetic stimulation (TMS) was delivered with a magnetic stimulator (Magstim 200–The Magstim Company Ltd., Whitland, South West Wales, U.K.) connected to a figure-of-eight coil placed over the optimum scalp position of the left hemisphere to elicit motor evoked potentials (MEPs) in the contralateral right first dorsal interosseus (FDI) muscle. Motor threshold at rest (MTh) and during contraction (AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF), short afferent inhibition (SAI) and long afferent inhibition (LAI) were studied according to standard techniques (Chen et al., 2008). Data are expressed as mean ± SD. Student t-test for unpaired data was used to compare TMS data in clinically affected subjects with those of 10 age-matched healthy subjects.
Linkage analysis was performed by genotyping 10 microsatellite markers spanning the BAFME1 (benign adult familial myoclonic epilepsy) 8q24 locus (D8S270, D8S1784, D8S1694, and D8S514) and the BAFME2 2p11.1-q12.2 locus (D2S428, D2S2333, D2S2216, D2S113, D2S2175, and D2S2209). To saturate the BAFME2 locus we generated two novel highly informative markers (D2S21AC and D2S27CA) in accordance with the University of California Santa Cruz draft of the human genome database (available at: http://www.genome.ucsc.edu) and the Tandem repeat finder software. Two-point logarithms of odds (lod) scores were generated with the FASTLINK version of the MLINK program (Cottingham et al., 1993), assuming an equal male–female recombination rate, autosomal-dominant inheritance, reduced penetrance (0.8), a gene frequency of 0.0001, and equal allele frequencies for each marker. Haplotypes were manually constructed, and phase was assigned based on the minimum number of recombinants.
Clinical and MRI examination
Psychomotor development was normal in subjects II:2 and II:3, and in the clinically unaffected members of the family (I:2, II:1, and II:4). Subjects III:1 and III:2 had cognitive impairment since childhood and abnormal developmental milestones. The clinically affected members of the family complained of finger and voice tremor starting at an age ranging from 14 to 18 years. Tremor progressively worsened causing difficulties in skilled motor tasks. Subjects II:3 and III:2 both had at the age of 2 years an episode of febrile convulsion that lasted <15 min. Clinically affected members had generalized tonic–clonic seizures, and subject III:2 had rare complex partial seizures characterized by head and gaze deviation and alteration of consciousness with secondary generalization. Seizures started at the age of 25 years for subject II:2, at 56 for II:3, at 28 for III:1, and at 18 for III:2. In the clinically affected subjects, photic stimulation was the main provoking factor that induced seizures. In the clinically affected members, tremor and seizures were partially improved by valproate and clonazepam but not by phenobarbital and propranolol therapy. In clinically affected patients, tremor was present at rest and particularly during the maintenance of a posture or during action, predominantly in the upper limbs. Subjects also had voice tremor and eyelid twitching, particularly during blinking and attempted eye closing. Myoclonic jerks were rarely present in the upper limb muscles. The clinically unaffected members of the family had a normal neurologic examination.
MRI scan showed mild generalized corticosubcortical and cerebellar atrophy in subjects II:2 and II:3 and normal appearances in the other clinically affected members.
According to the Diagnostic and Statistical manual of Mental disorders IV Revised (DSM IV), subject III:1 had a borderline intelligence quotient (IQ), subject III:2 had mild-to-moderate mental retardation, and subjects II:3 and II:2 had medium IQ scores. All patients had higher verbal IQ scores than performance IQ scores. In the clinically affected members, the Mini Mental State Examination Test (MMSE) and Wechsler Adult Intelligence Scale Revised (WAIS-ID) disclosed no cognitive deterioration. Abstract reasoning was impaired only in the patient with mental retardation (III:2). Verbal memory and executive functions were moderately impaired in subjects III:2 and III:1. Visual memory was below average for subjects III:2, III:1, and II:2. All clinically affected subjects had visuospatial impairment, which was more evident in patients with lower IQ scores (Table 1).
In the clinically affected members, postural tremor was characterized by irregular electromyography (EMG) activity in the forearm extensors and flexors muscles at the frequency of 8–12 Hz. In the clinically affected members, EEG showed generalized paroxysmal activity with spike-and-wave, polyspike-and-wave complexes, or both (photoparoxysmal response). Intermittent photic stimulation occasionally triggered a photomyoclonic response. Back-averaging EEG showed that myoclonic jerks in the extensor forearm muscles were not preceded by a cortical potential in the frontal leads. EEG recordings in the clinically unaffected members of the family were within the normal range.
In the clinically affected members of the family, SEPs and C-Reflex were within the normal range. The TMS study showed that the clinically affected members of the family had reduced MTh (FCMTE: 28 ± 0.8%; healthy subjects: 37 ± 4.4%; p < 0.01) and shorter CSP duration than age-matched healthy subjects (FCMTE: 95 ± 17.3 ms; healthy subjects: 130 ± 8.2 ms; p < 0.01). The clinically affected members of the family also had reduced SICI (FCMTE: 94 ± 20%; healthy subjects: 65 ± 10%; p = 0.01). ICF, SAI, and LAI were normal.
Haplotype reconstruction excluded the BAFME1 locus in this family (data not shown). A common haplotype spanning the BAFME2 locus on the pericentromeric region of chromosome 2 segregates in all clinically affected members but not in lod score of 1.12 for both markers D2S2216 and D2S2175 (theta = 0; penetrance = 0.8). A recombination event in individual II:2 between markers D2S2175 and the newly generated D2S21AC placed the possible lower BAFME2 locus boundary at 99,147 Mb. The upper boundary of BAFME2 locus (D2S2161) was located at 85,140 Mb (Guerrini et al., 2001), thus defining a minimum common interval of approximately 14 Mb pericentromeric to chromosome 2.
Clinically affected members of the family had tremor, myoclonus, epilepsy, and cognitive impairment compatible with a diagnosis of FCMTE (van Rootselaar et al., 2005; Striano et al., 2005). Epilepsy was mainly characterized by generalized tonic–clonic seizures or complex partial seizures followed by generalization.
The neuropsychological assessment demonstrated that all the clinically affected members had a visuospatial impairment that was more evident in patients with low IQ scores. In this family, visuospatial impairment was present even in members who had received no medications for several years and who rarely experienced seizures. Our patients’ visuospatial impairment suggests an involvement of the “ventral pathway” related to a temporal lobe dysfunction, as demonstrated by the low scores on the Street’s completion test.
EEG recordings suggested generalized cortical hyperexcitability. The lack of a premovement cortical potential in the back-averaging recording agrees with previous findings that in families with cortical tremor, myoclonic jerks are not always preceded by an EEG correlate (van Rootselaar et al., 2005). TMS in the clinically affected members showed reduced MTh, CSP, and SICI, suggesting hyperexcitability of primary motor cortex (M1), probably due to a γ-aminobutyric acid (GABA)ergic impairment (Guerrini et al., 2001; van Rootselaar et al., 2007). When we used the SAI and LAI techniques, both tests yielded normal findings, arguing against abnormal sensorimotor integration in this family. Although the pathophysiology of FCMTE has been attributed to abnormal excitability of primary motor cortex, primary sensory cortex, or both (van Rootselaar et al., 2005; Striano et al., 2005), our finding of normal sensorimotor integration suggests that in this family M1 plays a major role in the pathophysiology of tremor and myoclonus.
Clinically affected individuals shared a common haplotype of approximately 14 Mb in the pericentromeric region of chromosome 2. This observation suggests a narrowing of the BAFME2 locus between 85,140, and 99,147 Mb of chromosome 2 (Fig.1). Whereas the BAFME1 locus was mapped in Japanese families, all families linked to BAFME2 are of Italian origin. In 53 affected individuals from 5 Italian families with FCMTE, Madia and colleagues (2008) have recently found a common haplotype at the BAFME 2 locus, thus suggesting a possible founder effect.
In conclusion, we report an Italian family with FCMTE whose distinctive features are a visuospatial impairment and an increased excitability of primary motor cortex with normal sensorimotor integration.
The authors are grateful to Dr. Elisa Pisaneschi for the LOD score calculation.
None of the authors has any conflict of interest to disclose.
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.