Epilepsia, 50(5):1284–1288, 2009 doi: 10.1111/j.1528-1167.2008.01976.x
BRIEF COMMUNICATION
Clinical, neuropsychological, neurophysiologic, and genetic features of a new Italian pedigree with familial cortical myoclonic tremor with epilepsy *yAntonio Suppa, *yAlfredo Berardelli, zxFrancesco Brancati, {Massimo Marianetti, zGiuseppe Barrano, {Concetta Mina, z#Antonio Pizzuti, and *Giulio Sideri *Department of Neurological Sciences, Sapienza University of Rome, Rome, Italy; yNeuromed Institute, Sapienza University of Rome, Rome, Italy; zCSS IRCCS, Mendel Institute, Rome, Italy; xDepartment of Biomedical Sciences and Aging Research Center, Ce.S.I., G. d’Annunzio University Foundation, Chieti, Italy; {Department of Neurology and ORL, Sapienza University of Rome, Rome, Italy; and #Department of Experimental Medicine and Pathology, Sapienza University of Rome, Rome, Italy
SUMMARY 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
A number of families with an autosomal-dominant syndrome comprising tremor, myoclonic jerks, epilepsy, and cognitive impairment have been described under various names. Two recent reviews suggested considering all families as having a single syndrome (Striano et al., 2005; van Rootselaar et al., 2005) and proposed the term ‘‘familial cortical myoclonic tremor with epilepsy’’ (FCMTE) (van Rootselaar et al., 2005). FCMTE is considered a genetically heterogeneous condition with known linkage to chromosome 8q24 (Mikami et al., 1999; Plaster et al., 1999) and to chromosome 2p11.1-q12.2 (Guerrini et al., 2001; De Falco et al., 2003; Striano et al., 2004). This report describes the clinical, neuropsychological, neurophysiologic, and genetic features of a new Italian family with FCMTE. Accepted October 23, 2008; Early View publication February 13, 2009. Address correspondence to Prof. A. Berardelli, Department of Neurological Sciences, Sapienza University of Rome, Viale dell’Universit, 30, 00185 Rome, Italy. E-mail:
[email protected] Wiley Periodicals, Inc. ª 2009 International League Against Epilepsy
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. KEY WORDS: Myoclonus, Tremor, Epilepsy, Cognitive impairment, Transcranial magnetic stimulation.
Materials and Methods Subjects 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.
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1285 An Italian Family with FCMTE
Figure 1. Family pedigree showing haplotypes at the benign adult familial myoclonic epilepsy (BAFME)2 locus on chromosome 2p11. 1-q12.2. A common haplotype shared by the clinically affected individuals (black symbols) and a recombination event in individual II:2 possibly places the lower boundaries of the locus between markers D2S2175 (98,151 Mb) and D2S21AC (99,147 Mb). The upper flanking marker D2S2161 previously identified in Guerrini et al., 2001 is placed at 85,140 Mb (not shown). Epilepsia ILAE
Neuropsychological evaluation 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). Neurophysiologic study 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), shortinterval 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. Genetic analysis 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 Epilepsia, 50(5):1284–1288, 2009 doi: 10.1111/j.1528-1167.2008.01976.x
1286 A. Suppa et al. 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 Neuropsychological evaluation Subject Test WAIS-FSIQ WAIS-VIQ WAIS-PIQ WAIS-DI MMSE Rey’s 15 Words-IR Rey’s 15 Words-DR Digit span Rey’s Complex Figure IR Rey’s Complex Figure DR Corsi’s Block Tapping test FAB Digit Span backward Corsi’s backward Phonological Verbal Fluency Trail Making Test A Trail Making Test B Raven’s Progressive Matrices Attentive Matrices Rey’s Complex Figure copy Judgement of Line Orientation Test (JLOT) Street’s Completion Test Token test AAT
II:3
II:2
III:1
III:2
Cutoff
101 104 97 )10% 28 36.7 5.2 6.0 11.9 14 4.8 17 4 3.8 27 62 102 20.8 60 36 24 4 29.3 9
95 104 84 )2% 27.9 42.1 5.5 6.5 9.8 9.4 3.5 17 4.5 3.5 60.9 68 104 20.3 42.3 21.6 18 4 28.5 8
75 80 72 )7% 26.2 23.9 1.5 4.8 7.5 3.8 3.5 13 2.8 1.5 20.7 65 158 23.7 48.5 30.3 79 3 27.8 8
51 51 48 )33% 24.2 21.9 2.5 3.8 0 0 2.5 6 1.8 0 13.7 156 400 10.1 39.5 9 7 1 26.8 8
‡80 ‡80 ‡80 £20% £239 ‡285 ‡47 ‡38 II:3: ‡9.9; II:2: ‡15.7; III:1-III:2: ‡17 II:3: ‡9; II:2: ‡15.9; III:1-III:2: ‡17 ‡3.5 ‡16.5 ‡3.8 ‡3.5 ‡17.4 £94 £283 ‡19 ‡31 ll:3: ‡28.9.; ll:2: ‡33; 111:1-111:2: ‡34 ‡20 II:3: ‡5.7; II:2-III:1-III:2: ‡6.1 ‡265 ‡8
Bold values indicate pathologic values. The cutoff scores for the four subjects tested are reported.
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.
Results Clinical and MRI examination Psychomotor development was normal in subjects II:2 and II:3, and in the clinically unaffected members of the Epilepsia, 50(5):1284–1288, 2009 doi: 10.1111/j.1528-1167.2008.01976.x
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
