The pedigree reconstruction showed 25 affected members (six deceased) over four generations, without consanguineous marriages, in which FCMTE segregates with an autosomal dominant inheritance (Fig. 1). Among the 31 members assessed directly, 16 were considered affected (Table 1) and six uncertain.
Table 1. Clinical, neurophysiologic, and neuroradiologic features of the affected members studied
|Pts||Sex/Age (years)||Clinical features||Neurophysiology||NE myoclonus severity +/++/+++||Therapy|
|CMT onset years/progression||Seizures type/onset (years)||Other||Interictal EEG/photosensitivity||g-SEP/C-reflex||BA|
|III-4||F/58||40/||GTCS/40||CI, headache||na||na||na||++ FR||CNZ, L-dopa|
|III-8||F/62||20/||GTCS/37||Headache||G/+||na||na||+++ (LL)||VPA, BZP|
|III-11||F/56||30/||–||Psych (PA, GAD)||na||na||na||+++||CDD|
|III-16||F/51||30/||–||CI||Burst of diffuse slow W and intermixed L post S/na||na||na||+++ (E), FR||–|
|III-20||F/64||40/||M/63||Migraine||Burst of diffuse sharply contoured slow W > ant/na||na||+||+++||CDD (AED ceased)|
|III-22||F/55||unk||M, GTCS/unk||–||na/na||na||na||+||CNZ (VPA ceased)|
|III-24||M/57||unk||GTCS/30||–||Burst of diffuse slow W/+||na||na||±||VPA|
|III-27||F/65||unk/||M, GTCS/29||Psych (D), CI||G/−||+/+||na||+++ (LL, O) FR||SNRI (VPA ceased)|
|III-34||F/60||unk||–||–||Bursts of diffuse slow W and S > R ant/na||na||na||+||–|
|IV-3||F/35||20/||–||Psych (PA, SA)||N||na||na||+||– (SSRI ceased)|
|IV-10||F/44||30/||M/42||Psych (D)||Diffuse slow W and intermixed S > ant/+||na||+||+++ (LL, O)||PZP, Trazodone|
|IV-13||M/39||30/||–||–||Runs of diffuse theta activity/na||na||na||+||–|
|IV-21||M/29||19/||M, GTCS/24||Migraine||G/+||−/+||+||++ (on CBZ)||CBZ (VPA)|
|IV-25||F/34||30/unk||GTCS/34||Psych (PA, D)||G/+||+/+||na||+||LEV, PZP, SNRI|
|IV-26||M/22||20/||–||Psych (PA)||Not specific/na||na||na||+ (LL)||PZP, TCA, SSRI|
Figure 1. Pedigree of the family. Roman and Arabic numerals above the symbols denote generation and individual, respectively. Haplotypes are represented as vertical series of alleles. The disease-linked haplotype is shown in red.
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All 16 affected members studied (M/F = 5/11; mean age of 47.8 years; range: 22–65) have CMT and 10 patients (62.5%) experienced additional infrequent generalized seizures. CMT was the first symptom in most cases, with a mean age at onset of 28.1 years (mean calculated on 11 individuals; range 19–40). Only in one case (III-15) did the seizures precede CMT by a few years. This patient had a moderate-severe intellectual disability evident since preschool age and attributed to a questionable perinatal injury. Since the age of 5 years he has also experienced infrequent GTCS treated with valproate (VPA).
CMT showed a wide intrafamilial variability. Most patients had a small-amplitude CMT localized on the upper limbs only during posture maintenance or action, with minimal impairment of daily activities. Instead, about half the patients had frequent asynchronous, proximal myoclonias of higher amplitude superimposed on the postural, irregular oscillations of the extremities. The myoclonic jerks were often triggered by emotional stress, sleep deprivation, and, overall, intense photic stimulation. Lower limb involvement, together with the slow progression of CMT, was the principal factor of severe disability in these patients. In particular, the proband reported a progressive gait impairment with several falls and has been wheelchair bound since 64 years of age. The NE in this patient showed an impaired balance and slight deficit in coordination, without clear cerebellar signs or findings of peripheral polyneuropathy at the nerve conduction study.
In the 10 patients with associated generalized epileptic seizures, the mean age at onset of seizures was 33.8 years (range 5–63 years). Eight patients experienced GTCS, in some cases evolving from clusters of photoinduced myoclonias of rising intensity. Two patients experienced a few prolonged episodes of irregular, generalized myoclonic jerking provoked by photic stimulation and followed by a fall, without loss of consciousness. They have never experienced GTCS.
On the first evaluation, half the patients were on antiepileptic medications, mostly VPA with benefit, confirming the efficacy of this drug in FCMTE treatment. One patient, previously erroneously diagnosed with partial epilepsy and treated with carbamazepine, presented with a severe myoclonus, improved after switching to VPA.
One patient (III-4) was on L-dopa therapy. She had a left frontal stroke and presented with memory impairment and right hypertonia associated with bilateral upper limbs CMT. Neuroimaging was negative in all other cases.
Two other patients (III-16 and III-27) who complained of a memory impairment, made errors on temporal orientation, registration, and recall and showed frontal release signs at NE. A formal neuropsychological evaluation in patient III-27 showed some alterations in verbal reasoning and attention, with Mini Mental State Evaluation (MMSE) (Folstein et al., 1975) results within normal limits.
Six patients had a history of mood depression and/or anxiety, with panic attacks in three cases and a major depressive episode with a suicide attempt in one. All these patients were on psychiatric treatment only (except for patient IV-3 who discontinued antidepressant drugs during pregnancy). Moreover, in one patient with CMT and previous “provoked” GTCS, antiepileptic treatment was discontinued following a diagnosis of personality disorder with conversion. Two patients (III-22, IV-18) with GTCS and mild CMT were diagnosed with juvenile myoclonic epilepsy. The mean delay in diagnosis was 19.8 years (calculated on 14 patients).
Of the 30 individuals enrolled in the genetic study, 14 were affected (III-4, III-8, III-16, III-20, III-22, III-24, III-27, III-34, IV-3, IV-10, IV-13, IV-21, IV-25, IV-26) 10 unaffected (III-1, III-30, III-32, IV-2, IV-12, IV-16, IV-27 and the three spouses III-9, III-25, and III-33), and 6 of uncertain phenotype. We considered uncertain the cases with a negative or doubtful anamnesis and NE and without a polygraphic study available (III-28, III-29, IV-6, IV-22). A member of the last generation (V-1) was too young to define her clinical status with certainty. Another individual (IV-17) had a history of febrile seizures at the age of 2 years, and from 18 to 19 years of age experienced several prolonged episodes of diffuse, violent jerking, without consciousness impairment. His events were previously interpreted as nonepileptic. Our NE did not disclose CMT, and the EEG was negative. We could not perform further neurophysiologic investigations and considered this case uncertain.
A polygraphic study was conducted in 15 patients (eight studied in loco); 11 were affected. Surface EMG showed bursts of pseudorhythmic myoclonias at 7–15 Hz, without apparent cortical correlates in all the affected cases (Fig. 2). However, back-averaging of the EEG time-locked to myoclonus onset in the rectified first dorsal interosseus (FDI) EMG demonstrated a clear premyoclonic wavelet on the contralateral hemisphere (Fig. 3A,B), suggestive of a cortical origin of the myoclonus in all patients tested (III-20, IV-10, IV-21). The time course of topographic scalp voltage distribution showed that a central positivity was evident, peaking between 40 and 20 msec before the myoclonus, but the Global Field Power maximum was reached between −10 and −5 msec, corresponding to a centroparietal negativity with a frontopolar positivity (Fig. 3C,D). This configuration suggests that the cortical generator is likely equivalent to a tangentially oriented dipole with the center of mass located in the sensorimotor region, thus implying an involved cortex lying within a vertically oriented sulcus.
Figure 2. EEG-EMG polygraphic records of individual IV:21 show, on EMG channels, Repetitive phasic potentials corresponding to myoclonias, frequently occurring in long-lasting and pseudo-rhythmic sequences at 7–15 Hz, synchronous and asynchronous over agonist and antagonist muscles, without apparent cortical correlates. R., right; L., left; Delt., deltoid; Flex., flexor carpi radialis; Ext., extensor carpi radialis; FDI, first dorsal interosseous; Th. Res., thoracic respirogram.
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Figure 3. Back-averaging of the EEG timelocked to the myoclonus onset in the rectified FDI EMG of the left (A) and right (B). In both cases a biphasic wave over the contralateral hemisphere, of higher voltage in the centroparietal area, precedes the EMG by about 6 msec (Global Field Power maxima). The corresponding representation in cortical maps by a colorimetric scale shows the topographic distribution of the dipole (C, D). Epilepsia © ILAE
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Moreover, high-amplitude somatosensory evoked potentials (g-SEPs) were recorded in two of three patients tested, and long latency EMG responses (C-reflex) were recognized in the abductor pollicis brevis (APB) muscle after stimulation of the median nerve in all the three patients tested. TMS was performed in only one patient (IV-21), showing a mild reduction of rest motor threshold.
Interictal EEG showed generalized epileptiform abnormalities (diffuse spike/polyspike-wave discharges) in 4 of 11 affected members tested (25% of the total). The EEG was normal in three cases, whereas it showed frequent runs of diffuse slow activity with intermixed epileptiform activity in four patients (Fig. 4). A photoparoxysmal response (grade 1–4 according Waltz classification) was detected in five patients (31%).
Figure 4. EEG-EMG polygraphic records of indivdual III.34, EEG channels: Bursts of diffuse sharply contoured slow waves with frontopolar emphasis followed by fast activity and runs of rhythmic 5–6 Hz theta activity prevalent over the frontocentral regions.
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