Familial Cortical Myoclonic Tremor and Epilepsy, an Enigmatic Disorder: From Phenotypes to Pathophysiology and Genetics. A Systematic Review

The FCMTE phenotype; core characteristics and less common findings

Pathophysiology

Cortical hyperexcitability can be considered the hallmark of FCMTE. However, cerebellar changes have been described in neuroimaging and pathology studies.

Genetic linkage, proposed mutations

In several FCMTE pedigrees, causative mutations have been proposed (Table 5). In a Dutch pedigree a mutation in CTNND2, supported by functional tests, has recently been discovered.39 However, functional tests have not been performed for every mutation.80 Linkage studies indicated several loci: 8q23.3-8q24.13 (FCMTE1)24–27; 2p11.1-q12.2 (FCMTE2)8,9,16,17,29–34; 5p15.31-p15 (FCMTE3)29,36–41; and 3q26.32-3q28 (FCMTE4).43 Furthermore, there are several families (Chinese, Spanish, Italian, South African) in which 2p and/or 8q linkage was excluded.10,62,66,81 Below we summarize the findings in FCMTE1–4 and FCMTE-like disorders.

Linkage to the FCMTE1 locus on chromosome 8q23.3-8q24.13 was found in several Japanese families24–26 and one Chinese family.27 In the Chinese pedigree a single nucleotide variant (SNV) was identified in the SLC30A8 (solute carrier family 30 [zinc transporter]) gene after whole-exome sequencing (WES).27 However, there is no expression of this gene in the brain, making it irrelevant.27 Besides, sequence and copy number variant analysis of the genes located on the 8q23.3-8q24.13 locus did not reveal any mutation.26

Linkage to the FCMTE2 locus on chromosome 2p11.1-q12.2 was found in Italian,8,9,17,29–33 Spanish,29,34 and Australian/New Zealand pedigrees (with European ancestors).16 A founder haplotype was identified in Italian FCMTE2 pedigrees from the same geographical area.17,29 A mutation in two Italian family members within the FCMTE2 locus was found on the α2-adrenergic receptor subtype B (ADRA2B) gene with next-generation sequencing (NGS).46 Identity by descent mapping (IBD), which is able to detect genetic loci with an ancestral segment among pedigree unrelated individuals, refined the FCMTE2 locus to 2p11.1-q11.1 without excluding the ADRA2B mutation.29 In a Spanish pedigree, WES indicated an SNV in the aminocarboxymuconate semialdehyde decarboxylase (ACMSD) gene encoding for an enzyme that is part of the kynurenine pathway of tryptophan and linked to neurodegenerative diseases and epilepsy.48

FCMTE3, with linkage to 5p15.31-p15, has been identified in two Chinese families,40,41 a Dutch pedigree,39 and a French family.29,36–38 In the Dutch family after WES, a mutation was found in the CTNND2 gene.39 Knockdown of Ctnnd2 in cortical mouse neurons led to abnormal neuronal sprouting which resembled abnormal Purkinje cell morphology in deceased FCMTE patients.39 However, in the French family a mutation in SEMA5A (semaphorin-5A) and CTNND2 genes was excluded using direct sequencing.36 Carr et al.10 have named their South African pedigree FAME3; however, only analysis to exclude the linkage areas 2p and 8q was performed.

FCMTE4, with linkage to 3q26.32-3q28, has recently been discovered in a Thai family.43 No causative gene has yet been identified. Two candidate genes have been proposed for FCMTE4: HTR3D (5-hydroxytryptamine receptor 3D) and KCNMB3 (calcium-activated potassium channel subunit beta-3), which encode for ion channel receptors.29

Other proposed mutations include a missense mutation on 8q22.3 in ubiquitin protein ligase E3 component n-recognin 5 (UBR5) within a Japanese pedigree, linked to Angelman syndrome and autosomal recessive juvenile parkinsonism.59 In a Chinese family, a missense mutation at 22q13.1 in PLA2G6 (phospholipase A2 Group VI) was found using WES.47 Pathogenicity is hypothetical. PLA2G6 mutations have also been linked to infantile neuroaxonal dystrophy and the enzyme encoded by PLA2G6 is involved in the synthesis of arachidonic acid; abnormal metabolism of arachidonic acid could lead to neuronal hyperexcitability.47

Diagnostic criteria and clinical spectrum

The pedigrees presented in this review share the core features of FCMTE, including autosomal dominant inheritance, distal myoclonic tremor with signs of cortical reflex myoclonus, and/or generalized tonic–clonic seizures. Myoclonus is typically the first symptom, while seizures, usually occurring later in the disease course, are a common reason for patients to seek medical care. However, seizures might in a number of cases be the first symptom.56

EEG findings in FCMTE include generalized spikes/waves and photoparoyxsmal or photomyogenic responses. Other possible clinical features include mild progression of symptoms with aging,16,17,21,57–59 and proximal myoclonus, potentially leading to gait disorders, across linkage types or European/Asian descent.16,17,37,46,56–58,61,65,67 Both are not major inclusion criteria but phenomena that are frequently observed and seem to be part of the disease spectrum.

Focal EEG abnormalities and a slower posterior dominant rhythm might be features of FCMTE.56,74 Also, EEG may show generalized spikes and waves preceding later onset of epilepsy.58

FCMTE is differentiated from other tremor-like disorders (including ET) with electrophysiological recordings.32 FCMTE can be differentiated from the progressive myoclonus epilepsy syndromes and juvenile myoclonic epilepsy (JME) in the absence of severe cognitive decline and absence of severe ataxia.82 Unlike FCMTE, JME presents with myoclonus in the morning and shows no features of cortical reflex myoclonus.82

Criteria for the diagnosis of FCMTE are the following:

1. Distal action and postural tremor/fine myoclonus, accompanied by generalized tonic-clonic seizures in at least one family member. Also, mild progression of symptoms with aging and proximal muscle myoclonus can be present.

2. Electrophysiological measures support the diagnosis: giant SEP and LLR point to cortical hyperexcitability; polymyography showing discharges of <50 ms suggest cortical myoclonus; and EEG-EMG coherence analysis or JLA can support a cortical origin of the tremulous movements.

3. Autosomal dominant inheritance of epilepsy and “tremor”/myoclonus within the family.

4. No other cause for tremor, epilepsy. No other symptoms must be present like ataxia, parkinsonism, dementia, dystonia, spasticity.

Are phenotypical differences related to specific mutations?

Differences in symptomatology have been reported, possibly linked to different mutations.1 Japanese and Chinese pedigrees, linked to 8q (FCMTE1; also known as BAFME) suffer from a more “benign” form of FCMTE with age of onset in the third decade, infrequent seizures, and no cognitive decline.24,25,27 Usually, FCMTE1 patients present with rhythmic distal myoclonus of the upper extremities, but more extensive involvement of the lower extremities and facial muscles has also been reported.24,68,83

Pedigrees with linkage to 2p (FCMTE2) exhibit a more severe form of myoclonus (proximal involvement) that progresses with aging and leads to gait disability.16,17,46 Specific for Italian 2p pedigrees, psychiatric comorbidity is frequently present.13 Atypical symptoms in pedigrees with a possibly pathogenic mutation were present in Spanish 2p ACMSD patients (n:1 parkinsonism and mild ataxia)48 and in 2p ADRA2B patients (focal seizures and age-related dementia).46

Linkage to 5p (FCMTE3) in two Chinese pedigrees is related to a benign course with age of onset in the fourth decade, and, during short-term follow-up, no disease progression.40,41 However, in French FCMTE3 pedigrees, progression of symptoms, gait disability, frontal syndrome, cognitive changes, and logopenic syndrome were described.61,67 Also, in a Dutch FCMTE3 pedigree subjective cognitive decline was present.39

In a Thai pedigree, with linkage to 3q (FCMTE4), myoclonus presented earlier, in the second decade, and seizures started in the third decade.43 No cognitive decline was present.43

In patients with unknown linkage the following findings were reported: clinical anticipation was present in Asian pedigrees (measured with rating scales).19–21 Mild cognitive decline was present in Asian patients.21,57 European patients (or with European ancestors) suffered from mild cognitive decline,8–12,17,39,47,48 focal seizures,16,46 mild ataxia and/or gait instability,16,17,37,38,48 nystagmus,14 dysarthria,10,38 and migraine.15–18 Atypical features were also described in a Turkish family, including absence seizures, early onset of seizures (14–17 years), negative LLR (while using AEDs), and frequent myoclonic seizures (once a month).18

There are a number of possible explanations for the reported phenotypical differences between pedigrees/FCMTE types. Firstly, different mutations, extensively described in a limited number of pedigrees, could lead to clinical diversity.39,46–48,59 For instance, more severe disease course,17,36 cognitive decline,67 and/or the pathological/neuroimaging changes in the cerebellum1,51,53 might be related to specific FCMTE mutations. Secondly, the clinical differences could be co-incidental or based on comorbidity, either related or unrelated to FCMTE. Other possible explanations might be differences in genetic trait other than FCMTE; heterogenic prescription regimes, including AED use per country, or environmental factors. A third explanation is reporting bias. Documentation, investigations, and follow-up differ substantially between pedigrees.

Pathophysiology

The primary symptoms of FCMTE, cortical myoclonus, and epilepsy seem to have their origin in the sensorimotor cortex. Electrophysiology findings indicate cortical hyperexcitability with generalized spikes and waves on EEG, giant SEP, LLR, and reduced cortical inhibition in TMS studies9,14,78 and cortical activity preceding the onset of movement (EEG-EMG back averaging and coherence analysis), confirmed with combined EMG/fMRI.72,77,84

Cerebellar changes might be a key feature of FCMTE. Pathology findings in three Dutch patients1,14,50 and one South African patient10 report severe loss of Purkinje cells with dendritic sprouts, neuronal loss in the dentate nucleus and microglia activation with limited changes in the sensorimotor cortex. Use of AEDs might result in loss of Purkinje cells. Notwithstanding, cerebellar pathology findings in FCMTE patients differ from changes seen in patients with chronic idiopathic epilepsy who used phenytoin85 and rats chronically exposed to valproic acid.86 Also, Dutch patients who did not use AEDs had a downbeat nystagmus upon hyperventilation, indicating cerebellar dysfunction.14 Moreover, a mutation in CTNND2 was found in the same Dutch pedigree, probably related to FCMTE3, as the gene CTNND2 is located on the same linkage area.39 A mutant version of this gene was responsible for abnormal neuronal sprouting in mouse neurons, resembling cerebellar pathology findings in the same Dutch pedigree.39 In a French FCMTE3 pedigree a mutation in CTNND2 was excluded using direct sequencing.37 It could be there are several mutations located on the same linkage area or the mutation was undetectable due to the technique used.

Pathological cerebellar involvement is in line with cerebellar signs in European FCMTE pedigrees; these include downbeat nystagmus,14 mild ataxia (although possibly difficult to judge in the presence of tremulous myoclonus),37,38 dysarthria,10,38 and imaging findings revealing cerebellar involvement.51,53,79

Further evidence for cerebellar involvement in FCMTE arises from imaging studies in FCMTE, indicating functional connectivity changes between the cerebellum and cortical/subcortical structures.52 Supratentorial gray matter loss outside the motor circuit might be secondary.70 Also, cerebellar atrophy and ataxia have frequently been noted in patients with epilepsy.87 Repetitive TMS over the cerebellar cortex was able to reduce seizure frequency in drug-resistant epilepsy.87,88 The cerebellum might be involved in psychiatric disorders.89 In several FCMTE pedigrees anxiety and depressive comorbidity was reported.13,56 With aging, Purkinje cells become atrophic in healthy adults and the amount of white matter is reduced in the cerebellum.90 The degeneration of Purkinje cells might be enhanced in FCMTE patients leading to defective compensatory input to cortical structures. Clinically, this could explain the later onset of seizures and the worsening of symptoms with aging.16 Moreover, cortical hyperexcitability seems to increase with aging in Japanese patients, reflected by higher giant SEP amplitude.73

Pathology, imaging, genetic, and clinical findings indicate cerebellar changes. This offers a possible explanation for the decreased cortical inhibition. Deficient stimulation of the dentate nucleus by Purkinje cells in the cerebellum may lead to increased cortical facilitation via the cerebello-thalamo-cortical loop, a hypothesis already raised for cortical myoclonus and epilepsy.54,87,91 Purkinje cell changes might however not be the (sole) explanation for the symptoms observed in FCMTE.

The cerebellar changes might be specific for certain FCMTE types, with the strongest evidence for FCMTE3. Future research is needed to indicate whether cerebellar involvement, including pathological cerebellar changes, is a general finding in FCMTE. In some FCMTE types it might be co-existent, secondary due to primary cortical pathology, or even absent.

Possible candidate genes

Possible candidate causative genes include a trinucleotide repeat expansion or channelopathy.80 Purkinje cell changes in deceased Dutch FCMTE patients show striking similarities with those found in spinocerebellar ataxia (SCA) type 6, characterized by ataxia and downbeat nystagmus.1,50 Patients from the same Dutch FCMTE pedigree also have a downbeat nystagmus.14 SCA type 6 is caused by a CAG repeat in a calcium channel CACNA1A heavily expressed in the cerebellum.92 Other observations that might also point to a trinucleotide repeat expansion or channelopathy underlying FCMTE include in Asian FCMTE pedigrees, progressively earlier onset of the disease with increasing severity in successive generations19–21; presence of migraine15–18 analogues to hemiplegic migraine with mutations in calcium channels93; and the recognition that certain epilepsy syndromes are channelopathies.45,94 Recently, an autosomal recessive form of FCMTE has been recognized with a single base pair deletion in CNTN2, crucial for the stability of potassium channels.45 A channelopathy could involve cerebellar cells and/or induce functional cortical changes.50,92

Several genes have been identified as potentially causative in FCMTE. A gain of function mutation in the ADRA2B gene has been found in Italian FCMTE2 pedigrees that could potentially alter the neuronal firing pattern and even reduce gamma-aminobutyric acid (GABA) neurotransmission.46 A reduction in cortical GABA neurotransmission has been associated with cortical myoclonus in rats, progressive myoclonus epilepsy and Unverricht–Lundborg disease characterized by cortical myoclonus and ataxia along with seizures.91 Treatment with AEDs increasing GABA neurotransmitter levels can relieve the symptoms of FCMTE.

Another neurotransmitter implied in the pathophysiology of FCMTE2 is serotonin.48 A mutation in the ACMSD gene, encoding for an enzyme that is part of the kynurenine pathway, might lead to the accumulation of waste products.48 In mice, seizures could be induced when injecting these kynurenines in the brain ventricles.95

In Dutch FCMTE3 patients, a mutation in CTNND2, supported by functional tests in mice, seems to be responsible for abnormal neuronal sprouting.39 Hypothetically, the pathology findings in the cerebellum and the disease itself are caused by the CTNND2 mutation.39

Other proposed mutations/linkage studies have not yet elucidated the pathophysiology of FCMTE and have provided conflicting results, including proposed mutations outside the known linkage areas (UBR5, PLA2G6)47,59 and a pedigree from Canada (NOL3 mutation)49 without seizures, possibly reflecting another illness. The lack of progress might be due to the inability of next-generation sequencing techniques to detect exon rearrangements, trinucleotide repeat expansion, and copy number variants.80 Even a deletion in an intron might lead to defective splicing of a gene as in Unverricht–Lundborg disease.96 New algorithms and WGS might lead to a breakthrough.97,98

Future genetic studies should focus on mutations in proteins expressed in the cerebellum, involved in neuronal outgrowth, calcium, sodium, or potassium signaling, GABA neurotransmission, and genes which interact with the SCAs or other diseases with cortical myoclonic symptoms.80

Limitations

Reporting bias may have influenced our results. The number of patients and follow-up differ between pedigrees. Across studies, rating scales for motor symptoms and cognitive functioning differ or have not been reported. Therefore, symptoms might have been underreported, for instance cerebellar dysfunction and cognitive deterioration in certain pedigrees.14 Additional investigations (MRI, electrophysiology, pathology) have not always been performed, in some cases leading to diagnostic uncertainty, but more often raising questions with respect to generalizability of findings across pedigrees. For instance, both the imaging and the pathology findings involving cerebellar changes have largely been confined to a South African patient (linkage exclusion 2p, 8q), a Dutch pedigree (FCMTE3), and Chinese patients (linkage exclusion 2p, 8q) making the generalizability of the findings problematic.10,39,51–53,65,70 Several mutations (ACMSD, ADRA2B, UBR5, PLA2G6) have been proposed but pathogenicity has still to be proven.46–48,59

Conclusion

FCMTE, also known under different names and acronyms, is a clinical entity not (yet) listed by the ILAE. It is characterized by cortical tremor/fine myoclonus and generalized tonic–clonic seizures with autosomal dominant inheritance. Proximal myoclonus and mild progression with aging are part of the spectrum. Electrophysiology recordings show features of cortical reflex myoclonus. Valproate (not recommended in women of childbearing age) or levetiracetam, with or without clonazepam reduce symptoms. Gabapentin should be prescribed cautiously.

FCMTE is a heterogeneous disorder, and is likely to include a variety of different conditions with mutations of different genes. Additional symptoms have frequently been reported and can be co-incidental or based on genetic differences. Pathophysiological mechanisms remain to be elucidated, but pathology, genetic, and imaging studies have given clues that indicate cerebellar involvement. The cerebellar changes might lead to reduced cortical inhibition. Alternatively, underlying genetic changes induce both cerebellar and cortical changes. Genetic heterogeneity is present in linkage studies. Several causative genes have been suggested. However, functional tests have not always been performed.

Pathophysiology and genetic studies indicate that future genetic studies should focus on mutations involving Purkinje cell outgrowth, channelopathies, or genes responsible for neurotransmitter synthesis.

PubMed search

Conducted on 15-11-2017, articles were sought from 01-01-2011 to 15-11-2017.

((((cortical tremor myoclonus) OR cortical tremor epilepsy) OR (((((“Tremor”[Mesh]) AND “Myoclonus”[Mesh]) AND “Epilepsy”[Mesh])) OR ((cortical tremor [tiab] AND epilepsy [tiab] AND myoclonus [tiab])))) OR (((((((((((“Epilepsy, Myoclonic, Benign Adult Familial, Type 1”[Supplementary Concept]) OR (“Tremor”[Mesh] AND “Epilepsy”[Mesh])) OR (“Tremor”[Mesh]) AND “Myoclonus”[Mesh])) OR (“Epilepsy”[Mesh] AND “Myoclonus”[Mesh])) OR (autosomal dominant [tiab] AND “Epilepsy”[Mesh]) AND “Myoclonus”[Mesh])) OR (autosomal dominant [tiab] AND “Tremor”[Mesh] AND “Myoclonus”[Mesh])) OR (familial [tiab] AND “Epilepsy”[Mesh] AND “Myoclonus”[Mesh])) OR (familial [tiab] AND “Tremor”[Mesh] AND “Myoclonus”[Mesh])) OR (benign course [tiab] AND “Epilepsy”[Mesh] OR benign course [tiab] AND epilepsy [tiab])) OR (”Tremor”[Mesh] AND “Myoclonus”[Mesh] OR tremor [tiab] AND myoclonus [tiab] OR epilepsy [tiab] AND myoclonus [tiab])))) OR (Autosomal dominant cortical myoclonus and epilepsy OR Benign adult familial myoclonic epilepsy OR Cortical tremor OR Familial adult myoclonic epilepsy OR Familial cortical myoclonic tremor OR Familial cortical myoclonic tremor with epilepsy OR Familial cortical tremor with epilepsy OR Familial essential myoclonus and epilepsy OR Familial benign myoclonus epilepsy of adult onset OR Heredofamilial tremor and epilepsy).