Familial Adult Myoclonic Epilepsy: Clinical and Genetic Approach to an Under-recognized Disease

Abstract

Introduction:

Familial Adult Myoclonic Epilepsy (FAME) is an autosomal dominant disease characterized by cortical tremor, myoclonus and epileptic seizures. In this article, we aimed to review the main clinical characteristics, pathophysiology and diagnostic work-up of this disease to increase awareness.

Method:

PubMed and Web of Science databases were used and all types of articles available in full text and Englishwere selected

Results:

The first symptom of this rare condition is involuntary tremor-like finger movements that appear often in the second decade. Generalized tonic-clonic and myoclonic seizures are the most common types of seizures which develop later in the course of the disease. Additional clinical symptoms enlarging the clinical spectrum have been described, such as cognitive decline, migraine, night blindness. Electroencephalography shows usually normal background activity with/without generalized spike and wave activities. Giant somato-sensory evoked potentials (SEP) and long loop latency reflexes which indicate the cortical origin can be detected. Genetic side of the disorder is rather complicated, linkage analyses defined four independent loci on chromosome 2, 3, 5 and 8. Recent studies disclose abnormal pentanucleotide repeat expansions of intronic TTTCA and TTTTA that are involved in the pathogenesis of FAME.

Conclusion:

However, as it is not classified as an individual epileptic syndrome by the ILAE, there are still some question marks about this under-recognized disease. The insidious progression of the clinical findings and similarity in phenotypes may lead to misdiagnosis. Clinical and electroclinical international collaborations may help distinguish FAME from other myoclonic epilepsies including juvenile myoclonic epilepsy and slow-progressive forms of progressive myoclonic epilepsy and movement disorders like essential tremor.

INTRODUCTION

Familial Adult Myoclonic Epilepsy (FAME) is a rare autosomal dominant disorder featured by adolescent-adult onset myoclonus, generalized tonic-clonic seizures and cortical tremor (1,2). This rare condition was first described in Japanese families (3,4). Later on, many cases were reported in different countries and described with different acronyms (BAFME, FEME, ADCME, FCMTE, FCMT, FMEA and others). The pathophysiology and genetic causes of this slowly progressive disease still remain not fully elucidated. Due to the lack of systematic population-based studies, its prevalence is not well-known but it is estimated to be less than 1/35,000 (5).

Clinical Features

Characteristics like age of onset, insidious clinical course, presence of cortical tremor are features differentiating FAME from other genetic generalized epilepsies. Although the age of onset of the disease is variable, symptoms occur between the ages 10–60, often in the second decade (2,6,7). The first and defining symptom in affected individuals is low amplitude, continuous-arrhythmic tremor. The term ‘cortical tremor’ was first described by Ikeda et al. (4). It was used to refer to postural and action-induced hand tremor that mimic essential tremor but it presents along with electrophysiological manifestations of cortical myoclonus. Even though this tremor is particularly prominent in the distal upper extremities, it can also be seen in the proximal muscle groups including the facial muscles, especially the eyelids (3,8). Stimulating the palm may facilitate the occurrence of these involuntary movements. Unprovoked or light-triggered generalized tonic-clonic seizures can be seen in the third or fourth decade of life. They are not often accompanied by aura but myoclonus may be seen just before the seizure (5,9–11). The presence of absence seizures are rare but have been described in some Italian families (12). As with other genetically generalized epilepsies, photic stimulation, emotional stress, alcohol and sleep deprivation can trigger both tonic-clonic and myoclonic seizures. The disease may be accompanied by comorbidities such as photosensitivity, depression and migraine (13,14). Although drug-resistant focal seizures, night blindness or cognitive dysfunction may occur (15,16) rarely in some families, the disease usually shows an insidious and mild course in addition to these initial clinical findings (6). However, worsening of cortical tremor and myoclonus is common with advancing age. Although FAME is generally considered to have a “benign” prognosis, some life threatening conditions such as status epilepticus have also been reported. Frequent falls can lead to injuries and increasingly affect the quality of life. Clinical findings of FAME are shown in Figure 1.

Figure 1.

Clinical findings of familial adult myoclonic epilepsy.

Highlights

• FAME is characterized by cortical tremor, myoclonus and epileptic seizures.

• Clinical findings and electrophysiological examinations are important in the diagnosis.

• Pentameric repeat expansions play an essential role in patients with FAME.

• FAME should be considered separately from other myoclonic epilepsies.

• There is a need for increased awareness for this unique genetic disease

Electrophysiological findings

In addition to the typical clinical findings, electrophysiological examinations are also important in the diagnosis. These examinations include back-averaging, C-reflex (or long loop reflex) and somato-sensory evoked potentials (SEP) apart from the generalized epileptiform EEG features (17). In EEG recordings background activity is mostly normal, but slowing in posterior rhythms can be observed. Generalized spike waves with photoparoxymal and synchronous photomyogenic response can be found in response to photic stimulation (18). Besides the generalized findings, focal epileptiform anomalies have been reported in some cases (8). Similar to other diseases with cortical myoclonus, FAME patients have shown giant SEP waves indicating a cortical origin (19,20). Tojima et al. evaluated 49 patients with cortical myoclonus, out of whom 16 were diagnosed as FAME and they recorded high frequency oscillations in all FAME cases (20). These results suggested that this could be a very helpful tool for FAME diagnosis. Similar to these results, in our groups’ previous study, in a family where tremor, myoclonus, epilepsy, migraine and psychiatric symptoms are common in all siblings, ‘polimyoclonus’ seen in the distal parts of the hand and all involved patients showed significantly higher N20-P25 and P25-N35 amplitudes in electrophysiological investigations (21). In addition, although their tremor frequencies seem similar to the essential tremor group, mild intermittent low amplitude myoclonus was found suggestive of cortical tremor in accelerometric analysis. Though giant SEP amplitudes cannot usually be suppressed with anti-seizure drugs (ASDs), it should not be forgotten that other detected electrophysiological findings can be suppressed by ASDs. C-Reflex which is not detected at rest in healthy subjects and reflects cortical excitability was found in these cases. High frequency arrhythmic and/or semirhythmic burst-like changes of approximately 50 msec duration, synchronous with agonist and antagonist muscles, are typical for cortical myoclonus. Burst times in myoclonus of FAME patients are often much shorter than in subcortical originated myoclonus (1,11,22).

Genetics

Familial adult myoclonic epilepsy has a heterogeneous and complex genetic structure and its underlying genetic cause has been unclear for a long time. However, linkage analysis studies suggest well-defined responsible loci on chromosomes 2, 3, 5, 8. In relation to FAME, a large Japanese family consisting of 27 cases in which 17 individuals were affected were examined firstly and a genetic locus was detected on the distal long arm of chromosome 8 (8q23.3-24.11) (23). The same genetic locus was also detected in Chinese families (24). However, the locus 8q. 23.3-q24.1 was excluded in a study consisting of a European family with 18 affected members (25). Similar to this study, the same linkage was also excluded in a Dutch family diagnosed as FAME. The results occurring in these European families indicated that different genetic loci might also play a role in the pathogenesis (9,25). Thereafter, Guerrini et al. reported a new linkage to chromosome 2p11.1-q12.2 in 8 patients with focal seizures with a slightly different phenotype (8). Same results were confirmed in European family members with different phenotypes (26–28). On the other side, loci mapped on 5p15.31-p15.1 and 3q26.32-q28 were identified in families of French, Thai and Chinese origins, respectively (29–31). Kato et al. described a missense/nonsense variant co-segregated with the disease in the UBR5 gene (32). Recently, a complex intronic pentameric expansion affecting different genes, followed by a pentameric insertion has been identified as the underlying cause of this unique condition (33–35). Ishura et al. identified the mutation of FAME linked to chromosome 8q24, defining an abnormal expansion of TTTTA and TTTCA repeats in intron 4 of SAMD12 in 49 of 51 families, whereas these repeats were not detected in control groups (36). These results have been confirmed by Lei et al., who detected TTTTA expansions in 90.9% of their group (37). These findings demonstrated that repeat expansions in TTTTA and TTTCA play an essential role in patients with clinical features of FAME. However, the products of the proteins encoded by these genes have different functions and different intracellular locations. The pathogenic mechanism may be in common or related to the same network or pathway. Findings of repeat expansions that do not affect the production of associated proteins may support this idea. It is also conceivable that, because the expansion is somatically unstable, it gives rise to toxic RNA species (38).

Pathophysiology

The pathophysiological basis of FAME still remains a mystery. Presence of spike/slow wave activity in EEG, giant SEPs, C reflex studies indicate that cortical hyperexcitability may be the source of cortical myoclonus (39,40). Postmortem studies have shown evidence of cerebellar pathology. Microglia activation and neuronal loss in the dentate nucleus and severe Purkinje cell loss support the pathophysiological involvement of the cerebellum while sensorimotor cortex shows no changes. Also cortical excitability is thought to be the result of decreased cortical inhibition by the cerebellum via cerebello-thalamocortical projections (22,39,40). Besides the neuropathological contributions, neuroimaging also provides supportive findings for the effect of the cerebellum. While magnetic resonance (MR) examinations of affected individuals are usually normal, functional neuroimaging may offer some additional clues. In one proton MR-spectroscopic study, significantly increased cerebellar choline/creatinine levels were found in genetically confirmed 11 FAME cases compared to controls. Increased choline levels are thought to be due to chemical and functional changes in the cell membrane (41). This indicates that dysfunctions of the cerebellum are pathologically the cornerstone of the disease.

Treatment Strategies

There are currently neither specific symptomatic nor preventive treatment options approved for FAME. Clinical treatment is based on ASDs that control seizures with a limited effect on myoclonus. Levetiracetam and benzodiazepines (especially clonazepam) are considered as first-line treatments (42). There have been case reports of myoclonic status following the use of drugs with the potential risk for increasing tremor and myoclonus such as gabapentin (43). Response to valproic acid may be variable, since it may negatively affect the clinical course by worsening the tremor. Cortical tremor is not responsive to beta-blockers and L-dopa/Carbidopa therapies (5,44). Therefore, there is a need for new multi-center clinical trials with new options.

Differential Diagnosis

In clinical practice, FAME should primarily be differentiated from other tremor-related diseases including essential tremor. In the early stages of the disease, those patients who did not have prominent myoclonus and/or epileptic seizures can be diagnosed as essential tremor and can receive inappropriate treatments. The lack of treatment responsiveness to beta-blockers, absence of head or voice tremor may be helpful in the differential diagnosis. In this regard, electrophysiological findings of cortical tremor may also be supportive. On the other hand, progressive myoclonic epilepsy (PME) and juvenile myoclonic epilepsy ( JME) should be in the first line of the differential diagnosis, given the predominating seizure types and age of onset (11,13). Although FAME is less severe than PMEs, it has a slow but progressive course with cognitive decline and worsening of both tremor and myoclonus. In addition, it is also known that these cases were diagnosed as JME at the onset of the disorder, thus their worsening was unexpected and discouraging for both the family and the attending physician. The usual absence of cortical reflex myoclonus findings, and the myoclonus that is seen typically in the early stages in JME cases should be kept in mind as clinical clues.

CONCLUSION

Due to the association of frequent psychiatric comorbidities and slow progression, FAME is a complex disease to diagnose and treat. It is not yet recognized by the ILAE syndrome classification, pointing out to the importance of new research on this intriguing condition. There is a need for increased awareness for this unique genetic disease, and typical clinical features should be considered separately from other myoclonic epilepsies. Screening of cases with atypical features of JME with certain markers, performing tremor examinations along with SEP and accelerometry in addition to clinical examination, performing neuropsychological tests to evaluate the presence of cognitive deterioration and confirming FAME cases by planning whole exome sequencing followed by pentamer repeat examinations may support clinical phenotyping. Proper counseling to the family and the individual is critical for FAME, which does not affect the reproductive potentials of these patients. In conclusion, we would like to highlight that FAME is a novel genetic entity with its own clinical characteristics and mysterious genetic findings. Elucidating the pathogenesis of this condition will provide further insight into a possible individualized treatment approach of this unique pentamer repeat expansion disease.