Table 1
Familial Cortical Tremor/Myoclonus Syndromes
| Acronym | |
|---|---|
| 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 |
Figure 1
Article Selection Flowchart. Literature search for the identification of new pedigrees, genetic/linkage or imaging studies since our last review.1 Thirty-three articles were eligible for analysis: 17 reported on clinical and electrophysiology findings with or without linkage analysis, nine reported on neuroimaging, and seven reported on new potential pathogenic mutations. Abbreviations: DAT-SPECT, Dopamine Transporter, Single Photon Emission Computed Tomography; DTI, Diffusion Tensor Imaging; FCMTE, Familial Cortical Myoclonus Tremor And Epilepsy; fMRI, Functional Magnetic Resonance Imaging; 1H-MRS, Proton Magnetic Resonance Spectroscopy; VBM, Voxel Based Morphometry.
Table 2
Described Pedigrees (2011–2017) with Core Disease Characteristics
| Descent | Genetics | Origin, # Family | Clinical features | Electrophysiology | Imaging (cases) | Additional Symptoms, Other Findings | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Myoclonus | Seizures | Seizure Type | JLA | Giant SEP | LLR | EEG | |||||
| Age at Onset mean and (range) | |||||||||||
| Asian | 8q, SLC30A8 | Chinese, 127 | 26 (13–36) | 34 (29–40) | GTC | n.d. | + | + | n.a. | n.a. (1) | No CA; M lower limbs (n:2) |
| 8q, UBR5 | Japanese, 158 | ? | ? | G | n.d. | n.d. | n.d. | n.d. | n.a. (1) | M worse aging | |
| 22q, PLA2G6 | Chinese, 147 | 29 (21–38) | 39 (36–46) | G, GTC, Ph | n.d, | + | + | PSW, PMR | n.a. (1) | M rest; Head; Lower limbs (n:1) | |
| 5p | Chinese, 240,41 | >18 | > 30 | G, GTC, Ph | n.d. | + | n.d. | PSW, PRA | n.d. | Non-progressive; Headache | |
| 3q | Thai, 143 | 19 (10–33) | 25 (19–33) | G, GTC | + | + | + | PSW, SW, PPR, PMR | n.d. | Early-onset seizures | |
| 8q, n.d. | Chinese, 921 | 31 (15–59) | 36 (19–64) | GTC, Ph | n.d. | + | + | G-E, Sp, Sw | n.d. | S before M (n:5); Headache; M worse aging; | |
| Higher severe M, AED use | Night blindness; Mild cognitive decline; CA | ||||||||||
| n.d. | Chinese, 155 | 30 (20–40) | 39 (28–48) | GTC | n.d. | n.d. | n.d. | E, Sp, Sw | + (7) | Rest fMRI abnormalities | |
| n.d. | Indian, 4856 | 25 maj (14–40) | GTC, CP, Ph | n.d. | + | n.d. | PSW, F, PPR | n.a. (48) | Anxiety (83%); Unique HLA Nadar community | ||
| Seizures possibly first symptom 48% | |||||||||||
| n.d. | Indian, 157 | >15 | ? | GTC | n.d. | n.d. | n.d. | PSW, Sw, PPR | n.a. (3) | Cognitive decline; M axial; M worse aging | |
| European | 2p | Italian, 117 | 28 (19–40) | 34 (5–63) | GTC, M, Ph | + | + | + | G-E, PSW, Sw, PPR | n.a. (?) | Psychiatric comorbidity; M worse aging; |
| Gait disability; Cognitive decline (n:2); Migraine; | |||||||||||
| TMS reduction rest motor threshold | |||||||||||
| 2p | New Zealand/Australia, 116 | Median 15 (4–60) | Median 44 (18–76) | GTC, F | + | + | + | PSW, PMR | n.a. (7), + (1) | Migraine; M head, legs, ‘drop attacks’; M worse aging; | |
| European ancestors | Severe M before S around sleep onset | ||||||||||
| 2p, ACMSD | Spain, 148 | >17 (17–23) | 19 (17–22) | GTC, PSG | n.d. | + | + | PSW, PPR | + (2) | Parkinsonism (n:1); Cognitive decline (n:1); | |
| M, Ph | Mild ataxia unaffected patient (n:1) | ||||||||||
| 2p, ADRA2B | Italian, 146 | (18–50) | ? | GTC, CP, F | + | + | + | G paroxysmal activity | n.a. (3) | Cognitive imparity (n:1); Age-related dementia | |
| n.d. | South Africa, 158 | 16 (12–20) | 39 (30–45) | GTC | n.d. | + | + | G-E, TLE, PSW | n.d. | ADL and MRS affected by M severity; | |
| European descent | Gait dysfunction; Facial M (n:2); M worse aging; | ||||||||||
| No (ataxia/cognitive decline) after 30 years | |||||||||||
| n.d. | Turkish, 118 | > 13 (13–16) | > 17 (14–17) | GTC, F, A, M | n.d. | + | – | n.d. | n.a. (3) | Frequent M seizures (1× month); Migraine; | |
| Higher than ET and JME | Drop attacks; Psychiatric comorbidity | ||||||||||
[i] Abbreviations: A, Absence; ACMSD, Aminocarboxymuconate Semialdehyde Decarboxylase; ADL, Activities of Daily Living; ADRA2B, α2-Adrenergic Receptor Subtype B; AED, Anti-epileptic Drug; CA, Clinical Anticipation; CP, Complex Partial; EEG, Electroencephalography; ET, Essential Tremor; F, Focal; fMRI, Functional Magnetic Resonance Imaging; G, Generalized; G-E, Generalized Epileptiform; giant SEP, Giant Somatosensory Evoked Potential; GTC, Generalized Tonic–Clonic; HLA, Humane Leukocyte Antigen; JLA, Jerk Locked Back Averaging; LLR, Long Latency Reflex; JME, Juvenile Myoclonic Epilepsy; M, Myoclonic/Myoclonus; maj, Majority; MRS, Myoclonus Rating Scale; n, Number; n.a., No Abnormalities; n.d., Not Done; Ph, Photosensitivity; PLA2G6, Phospholipase A2 Group 6; PMR, Photomyoclonic Response; PPR, Photoparoxysmal Response; PRA, Paroxysmal Rate Abnormalities; PSG, Partial Secondarily Generalized; PSW, Polyspike-Wave Complexes; S, Seizures; SLC30A8, Solute Carrier Family 30 (zinc transporter), Member 8; Sp, Spikes; Sw, Slow Waves; SW, Spike Wave Complexes; TLE, Temporal Lobe Epileptiform; TMS, Transcranial Magnetic stimulation; UBR5, Ubiquitin Protein Ligase E3 Component n-Recognin 5; +, Abnormal; –, Normal; # family, Number of Described Families; ?, Not Known.
Table 3
Described Pedigrees (up until 2011) with Core Disease Characteristics1
| Descent | Genetics | Origin, # Family | Clinical features | Electrophysiology | Structural | Additional Symptoms, Other Findings | Summary | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Tremor, Myoclonus | Seizures | Seizure Type | JLA | giant SEP | LLR | EEG | Imaging (cases) | PA (cases) | |||||
| Age at Onset (mean) | |||||||||||||
| Asian | 8q | Japanese, 524,25 | 18–45 | ? | GTC | + | + | + | G-PSW, PPR, | atr (3) n.a. | n.d. | – | Classical phenotype |
| maj >30 | PSW, PMR | (>14) | Age at onset at adulthood | ||||||||||
| Infrequent seizures | |||||||||||||
| n.d. | Japanese, 355–7,68,69,83,99–104 | 16–70 | 17–54 | GTC, Ph | + | + | + | PSW, PPR, SW, Sp | atr (3) n.a. (25) | n.a. (4) | Rare: night blindness, | No other neurological signs | |
| maj >25 | maj >30 | inf (11) | behavioral arrest | Electrophysiological abnormalities | |||||||||
| Excl 2p, 8q | Chinese, 166 | 5–? | ? | GTC, M | n.d. | n.d. | n.d. | M, SW, PSW | n.d. | n.d. | Schizophrenia in family | Classical phenotype with | |
| (34) | Slow waves | earlier age of onset in the | |||||||||||
| 13/? | youngest generations | ||||||||||||
| Presymptomatic changes | |||||||||||||
| detected | |||||||||||||
| European | 2p | Italian, 78,9,30–33 | 11–50 | 12–59 | G, GTC, Ph, | + | + | + | Sp, SW, PPR, | atr (3) | n.d. | Visuospatial impairment; | Symptoms appear earlier |
| maj >20 | maj >25 | CP, M | Also in presymptomatic | PMR, GPA, PSW, SW | n.a. (27) | Eyelid twitching; Voice | Complex partial seizures | ||||||
| 3/79 | tremor; Cognitive | Mild cognitive impairment | |||||||||||
| Absent in 1 pedigree9 | impairment; TMS cortical | ||||||||||||
| hyperexcitability, normal | |||||||||||||
| sensorimotor integration | |||||||||||||
| n.d. | Italian, 112 | 12–57 | 5–18 | GTC, Abs | + | + | + | Sp, SW, PPR | atr (2) | n.d. | – | ||
| Turkish, 115 | 29–? | 30 | GTC | n.d. | n.d. | n.d. | G-Sp, SW, PPR | n.a. (1) | n.d. | Migraine | |||
| 5p | French, 136–38 | 10–47 (30.8) | 24–41 | GTC, Ph, | + | + | + | Sp, PPR, PS | n.d. | n.d. | Progression in gait symptoms; Sensitivity to exercise; GTC preceding M (5/16); | Later onset | |
| (29.1) | CM, PS | Dysarthria; Ophthalmic migraine; | No cognitive impairmentGait disordersIndication of progression | ||||||||||
| 5p, CTNND2 | Dutch, 12,11,14,39,50,77 | 12– 45 (23.5) | 13– 44 (43) | GTC, M, Ph | – | + | + | SW, PPR | atr (2) | +(3) | TMS cortical hyperexcitability; | Cerebellar dysfunction | |
| n.a. (2) | nystagmus; slight cognitive decline | Frequent seizures; Cognitive impairment; Progression in symptoms | |||||||||||
| Excl 2p, 8q | Spanish, 181 | 30–60 (41) | 30–67 (44.6) | GTC | + | + | + | G-PSW | n.a. (5) | n.d. | Childhood onset, Pyramidal signs | ||
| Italian, 162 | 3–12 | 23–34 | GTC, CM | + | + | + | SW, PMR, Sp | n.d | n.d | Prominent photic induced | |||
| Ph | myoclonus and epilepsy; | ||||||||||||
| Changing symptoms with age; | |||||||||||||
| Mild axial ataxia; Behavioral disorder | |||||||||||||
| South African, 210 | 13–31 (20.9) | ? | GTC | + | + | + | Abnormal background, | atr (8) | +(1) | Frequent seizures; | |||
| Intermarriage with | PSW, Sp | n.a. (2) | Cognitive impairment; Signs of | ||||||||||
| European settlers | pyramidal and cerebellar dysfunction; | ||||||||||||
| Progression in symptoms | |||||||||||||
Abbreviations: Abs, Absence; atr, Atrophy; CM, Cortical Myoclonus; CP, Complex Partial; CTNND2, Catenin Delta 2; EEG, Electroencephalography; excl, Excluded; G, Generalized; GPA, Generalized Paroxysmal Activity; giant SEP, Giant Somatosensory Evoked Potential; GTC, Generalized Tonic–Clonic; inf, Infarct; JLA, Jerck Locked Back 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 Response; PSW, Polyspike-Wave Complexes; PS, Partial Seizures; Sp, Spikes; SW, Spike-Wave Complexes; TMS, Transcranial Magnetic Stimulation; +, Abnormal; –, Normal; #, Number Of Described Families; ?, Not Known.
Table 4
Imaging Findings across Pedigrees
| Reference | Origin, Linkage | Imaging Modality | Design | Cerebellum | Other Findings in FCMTE |
|---|---|---|---|---|---|
| Buijink et al.53 | Dutch, 5p | MRI (VBM) | 8 FCMTE, 45 ET, 39 HS | Total volume; Crus I; lobules IX, X ⬇ | n.d. |
| Total/local cerebellar volume | |||||
| Buijink et al.51 | Dutch, 5p | MRI (DTI) | 7 FCMTE, 8 ET, 5 HS | Cerebellum ⬇ | n.d. |
| Fractional anisotropy; MDV | |||||
| Magnin et al.67 | French, 5p | DAT-SPECT, MRI | Case report (n:1) | Atrophy: cerebellum ⬇ | Atrophy: cortical structures ⬇ |
| Magnin et al.61 | Case report (n:2) | DAT: striatum; cortical perfusion ⬇ | |||
| Striano et al.79 | Italian, 2p | 1H-MRS | 11 FCMTE, 11 HS, Neurochemical ratios | Cho/Cr ratio ⬆ | n.a. |
| Long et al.52 | Chinese, excl. 2p, 8q | RS fMRI (BOLD) | 11 FCMTE, 15 HS | DN: R crus I with L frontal + R lobule IX ⬇ | n.d. |
| Functional connectivity | AN: L lobule VIII with temporal, | ||||
| R putamen and L crus I ⬆ | |||||
| CN: L lobule VIIb and R frontal ⬆ | |||||
| Long et al.65 | Chinese, excl. 2p, 8q | 1H-MRS | 12 FCMTE, 12 HS, Neurochemical ratios | NAA/Cho ratio ⬇ | n.a. |
| Zeng et al.70 | Chinese, excl. 2p, 8q | RS fMRI + VBM | 11 FCMTE, 15 HS | n.d. | Gray matter: R hippocampus; R temporal ⬇ |
| Gray matter; Functional connectivity | L orbitofrontal; L prefrontal ⬇ | ||||
| FC: R hippocampus with R parietal ⬆ | |||||
| cingulate, L precuneus, L precentral gyrus ⬆ | |||||
| Wang et al.55 | Chinese, n.d. | RS fMRI | 7 FCMTE, 7 ET, 10 HS | n.d. | R fusiform gyrus; cingulate ⬇ |
| BOLD; ALFF | Frontal lobe ⬆ |
[i] Abbreviations: ALFF, Amplitude Of Low Frequency Fluctuation; AN, Attention Network; BOLD, Blood-Oxygen-Level Dependent; Cho, Choline; CN, Control Network; Cr, Creatinine; DAT, Dopamine Transporter; DAT-SPECT: Dopamine Transporter, Single Photon Emission Computed Tomography; DN, Default Network; DTI, Diffusion Tensor Imaging; ET, Essential Tremor; excl, Exclusion; FCMTE, Familial Cortical Myoclonus Tremor And Epilepsy; FC, Functional Connectivity; HS, Healthy Subjects; 1H-MRS, Proton Magnetic Resonance Spectroscopy; L, Left; MDV, Mean Diffusivity Volume; MRI, Magnetic Resonance Imaging; n, Number; n.a., No Abnormalities; NAA, n-Acetylaspartate; n.d., Not Done; R, Right; RS fMRI, Resting State Functional Magnetic Resonance Imaging; VBM, Voxel Based Morphometry; ⬆ Increase; ⬇ Decrease.
Table 5
Mutations Found in Different Pedigrees
| Reference | FCMTE linkage | Origin | Gene, Chromosome | Patients/pedigrees | Mutation | Causative? |
|---|---|---|---|---|---|---|
| Cen et al.27 | FCMTE1 | Chinese | SLC30A8, 8q24.11 | N:2, N1 | Missense, p.Y69F, c.206A>T | No expression in the brain |
| Felix Marti-Masso et al.48 | FCMTE2 | Spanish | ACMSD, 2q21.3 | N:3, N:1 | SNV, p.Trp26Stop, c.77G>A | Linked to PD, PME, ULD |
| De Fusco et al.46 | FCMTE2 | Italian | ADRA2B, 2q11.2 | N:2, N:2 | Indel, c.675_686delTGGTGGGG | H: gain of function, altered cortical |
| CTTTinsGTTTGGCAG | rhythmic activity | |||||
| Rootselaar et al.39 | FCMTE3 | Dutch | CTNND2, 5p15 | N:3, N:1 | Missense, p.Glu1044Lys | Abnormal neuronal sprouting in mice |
| Gao et al.47 | FCMTE# | Chinese | PLA2G6, 22q13.1 | N:3, N1 | Missense, p.Ala159Thr, c.475C > T | Linked to INAD, KS, EODP |
| Kato et al.59 | FCMTE# | Japanese | UBR5, 8q22.3 | N5, N1 | Missense, p.Arg1907His, c.5720G>A | Linked to AS, ARJP |
| Russel et al.49 | FCM# | Canada | NOL3, 16q22.1 | N:1, N:1 | Missense, c.61G>C | No giant SEP or symptoms in Nol3- mice |
[i] Abbreviations: ACMSD, Aminocarboxymuconate Semialdehyde Decarboxylase; ADRA2B, α2-Adrenergic Receptor Subtype B; ARJP, Autosomal Recessive Inherited Juvenile Parkinsonism; AS, Angelman Syndrome; CTNND2, Catenin Delta 2; EODP, Early Onset Dystonia Parkinsonism; FCMTE, Familial Cortical Myoclonic Tremor And Epilepsy; FCM, Familial Cortical Myoclonus; giant SEP, Giant Somatosensory Evoked Potential; H, Hypothesis; INAD, Infantile Neuroaxonal Dystrophy; KS, Karak Syndrome; N, Number; NOL3, Nucleolar Protein 3; PD, Parkinson Disease; PLA2G6, Phospholipase A2 Group 6; PME, Progressive Myoclonus Epilepsy; SLC30A8, Solute Carrier Family 30 (zinc transporter), Member 8; SNV, Single Nucleotide Variant; UBR5, Ubiquitin Protein Ligase E3 Component n-recognin 5; ULD, Unverricht–Lundborg Disease; -, Negative; #, Unknown linkage.