Familial Cortical Myoclonic Tremor with Epilepsy and Cerebellar Changes: Description of a New Pathology Case and Review of the Literature

Sarvi Sharifi; Eleonora Aronica; Johannes H. T. M. Koelman; Marina A. J. Tijssen; Anne-Fleur van Rootselaar

doi:10.5334/tohm.119

Figures & Tables

Table 1.

Familial Cortical Tremor/Myoclonus Syndromes with Benign Course

ADCME	Autosomal dominant cortical myoclonus and epilepsy
BAFME	Benign adult familial myoclonic epilepsy
Crt Tr	Cortical tremor
FAME	Familial adult myoclonic epilepsy
FCMT	Familial cortical myoclonic tremor
FCMTE	Familial cortical myoclonic tremor with epilepsy
FCTE	Familial cortical tremor with epilepsy
FEME	Familial essential myoclonus and epilepsy
FMEA	Familial benign myoclonus epilepsy of adult onset
HTE	Heredofamilial tremor and epilepsy

Table 2.

Clinical and Electrophysiological Features of Relatives of the Dutch Familial Cortical Myoclonic Tremor with Epilepsy Pedigree, in Whom Additional Tests Were Performed16–18, 22, 23, 53

Tremor	Myocl Seiz	GTCS	EEG	g-SEP	LLR	PA	Polymyography	Coherence	fMRI	TMS	Eye move
II:3	811	F	40	44?	44	VPA, PHT	±	n.d.	n.d.	+	n.d.	n.d.	n.d.	n.d.	n.d.
II:11	681	F	+	?	+	PB, CBZ	s-w	n.d.	n.d.	+	n.d.	n.d.	n.d.	n.d.	n.d.
III:1	60	M	45	–	52	VPA, CBZ	s-w	+	–	n.d.	+	+	+	+	+
III:5	57	M	30	30	43	OCB, CZP	s-w	–	?	n.d.	+	+	+	+	+
III:102	501	F	38	–	42	VPA, CZP	±	+	+	+	+	+	+	+	+
III:19	51	M	19	20	20	PB, VPA, CBZ	s-w	n.d.	n.d.	n.d.	+	+	+	n.d.	n.d.
III:20	54	M	12	13?	31	VPA, CZP	?	n.d.	n.d.	n.d.	+	+	+	n.d.	n.d.
IV:1	41	M	22	–	–	–	normal	+	+	n.d.	+	+	+	+	+
IV:2	39	F	20	–	–	–	normal	+	+	n.d.	+	+	+	+	+
IV:8	27	F	12	–	–	–	normal	+	+	n.d.	+	+	+	+	+
IV:9	21	F	+	–	–	–	n.d.	+	+	n.d.	n.d.	n.d.	n.d.	n.d.	+

Abbreviations: AEDs, antiepileptic drugs; CBZ, clobazam; Coherence, corticomuscular and intermuscular coherence analysis; CZP, clonazepam; EEG, electroencephalogram; Eye move, eye movement recordings; F, female; FCMTE, familial cortical myoclonic tremor with epilepsy; fMRI, functional magnetic resonance imaging; g-SEP, giant sensory evoked potential; GTCS, generalized tonic–clonic seizure; LLR, long latency reflex; M, male; Myocl Seiz, myoclonic seizure; n.d., not done; OCB, oxcarbamazepine; PA, neuropathology post-mortem; PB, phenobarbital; PHT, phenytoin; s-w, spike-wave complexes; TMS, transcranial magnetic stimulation; VPA, valproic acid.

+, present or performed; –, not observed or none; ±, some, not specific; ?, not known.

1 Age of death.

2 Current case.

Pedigree of the Dutch Family with Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE).
▪, affected male; •, affected female; ^•, possibly affected; □,○, no established diagnosis; /, diseased; PA, pathological investigations performed; *, one or more additional functional tests performed. The described patient is indicated by an arrow.

Histological Findings in the Cerebellum.
(A) Hematoxylin and eosin: loss of Purkinje cells ; insert, cell with abnormal morphology and unclear outlines of the cytoplasmic membrane. (B) Bielschowski silverstaining: empty baskets (arrows and insert in B). (C–F) Calbindin staining: presence of numerous Purkinje cells with radial sprouting (arrows in C–E and insert in E), reduced and abnormal dendritic arborization of Purkinje cells in the molecular layer (ml; asterisks in D), with swelling of dendritic arborizations (F). (G) Neurofilament staining: swellings of Purkinje cell axons (torpedoes) within the granular layer (gl). Scale bars: A, D: 80 µm; B–C: 160 µm; E–F: 40 µm; G and insert in B: 30 µm; inserts in A and E: 20 µm.

Table 3.

Described Pedigrees with Core Disease Characteristics

Age at Onset (mean)
Asian	8q	Japanese, 57, 8	18–45 maj >30	?	GTC	+	+	+	G-PSW, PPR, PSW, PMR	atr (3) n.a. (>14)	n.d.	–	Classical phenotypeAge at onset at adulthoodInfrequent seizuresNo other neurological signsElectrophysiological abnormalities
Asian	n.d.	Japanese, 3526–28,32,33,36,37,61,63–66	16–70 maj >25	17–54 maj >30	GTC, Ph	+	+	+	PSW, PPR, SW, Sp	atr (3)n.a. (25)inf (11)	n.a. (4)	Rare: nightblindness, behavioral arrest
Excl 2p, 8q	Chinese, 12	5–?(34)	?	GTC, M	n.d.	n.d.	n.d.	M, SW, PSWSlow waves13/? presymptomatic changes detected	n.d.	n.d.	Schizophrenia in family	Classical phenotype with earlier age of onset in the youngest generations
European	2p	Italian, 71,4,6,9–11	11–50maj >20	12- 59maj >25	G, GTC, Ph, CP, M	+	+	+	Sp, SW, PPR, PMR, GPA, PSW, SW	atr (3)n.a. (27)	n.d.	Visuospatial impairment; Eyelid twitching; Voice tremor; Cognitive impairment;TMS cortical hyperexcitability, normal sensorimotor integration	Symptoms appear earlierComplex partial seizuresMild cognitive impairment
	Also in presymptomatic 3/711Absent in 1 pedigree11
	n.d.	Italian, 138	12–57	5–18	GTC, Abs	+	+	+	Sp, SW, PPR	atr (2)	n.d.	–
	Turkish, 135	29–?	30	GTC	n.d.	n.d.	n.d.	G-Sp, SW, PPR	n.a. (1)	n.d.	Migraine
	5p	French, 13, 15, 30	10–47 (30.8)	24–41(29.1)	GTC, Ph, CM, PS	+	+	+	Sp, PPR, PS	n.d.	n.d.	Progression in gait symptoms; Dysarthria; Ophthalmic migraine; sensitivity to exercise;GTC preceding M (5/16);	Later onsetNo cognitive impairmentGait disordersIndication of progression
Excl 2p, 8q	Spanish, 15	30–60 (41)	30–67 (44.6)	GTC	+	+	+	G-PSW	n.a. (5)	n.d.	–	Childhood onsetPyramidal signsCerebellar dysfunctionFrequent seizuresCognitive impairmentProgression in symptoms
Excl 2p, 8q	Dutch, 114, 16, 17, 22, 23	12–45 (23.5)	13–44 (43)	GTC, M, Ph	–	+	+	SW, PPR	atr (2)n.a. (2)	+ (3)	TMS cortical hyperexcitability; nystagmus slight cognitive decline
Italian, 113	3–12	23–34	GTC, CMPh	+	+	+	SW, PMR, Sp	n.d.	n.d	Prominent photic induced myoclonus and epilepsy; changing symptoms with age; Mild axial ataxia; behavioral disorder
South African, 212Intermarriage between original inhabitants and European settlers	13–31 (20.9)	?	GTC	+	+	+	Abnormal background,PSW, Sp	atr (8)n.a. (2)	+ (1)	Frequent seizures; cognitive impairment; signs of pyramidal and cerebellar dysfunction, progression in symptoms

[i] Abbreviations: Abs, absence; atr , atrophy; CM, cortical myoclonus; CP, complex partial; EEG, electroencephalography; excl, excluded; G, generalized; GPA, generalized paroxysmal activity; G-SEP, giant sensory evoked potential; GTC, generalized tonic-clonic; inf, infarct; JLA, jerk locked averaging; LLR, long latency reflex; maj, majority; M, myoclonic; n.a., no abnormalities; n.d., not done; PA, pathology; Ph, photosensitivity; PMR, photomyoclonic response; PPR, photoparoxysmal responses; PSW, polyspike-wave complexes; PS, partial seizures; Sp, spikes; SW, spike-wave complexes; TMS, transcranial magnetic stimulation.

[ii] +, abnormal; –, normal; # family, number of described families; ?, not known;

Familial Cortical Myoclonic Tremor with Epilepsy and Cerebellar Changes: Description of a New Pathology Case and Review of the Literature

Figures & Tables

Table 1.

Familial Cortical Tremor/Myoclonus Syndromes with Benign Course

Table 2.

Clinical and Electrophysiological Features of Relatives of the Dutch Familial Cortical Myoclonic Tremor with Epilepsy Pedigree, in Whom Additional Tests Were Performed16–18, 22, 23, 53

Figure 1.

Pedigree of the Dutch Family with Familial Cortical Myoclonic Tremor with Epilepsy (FCMTE).

Figure 2.

Histological Findings in the Cerebellum.

Table 3.

Described Pedigrees with Core Disease Characteristics

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