Autosomal Dominant Cortical Tremor Research Articles

Recent advances in benign adult familial myoclonus epilepsy

AbstractBenign adult familial myoclonus epilepsy (BAFME), also called familial cortical myoclonic tremor and epilepsy (FCMTE), autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME), and familial adult myoclonic epilepsy (FAME) is a disorder characterized by infrequent generalized seizures and tremulous myoclonus with an autosomal dominant mode of inheritance. The diagnosis of BAFME was previously based on clinical features and electrophysiological findings, but genetic analysis is now increasingly becoming important in the diagnosis after identification of repeat expansions; BAFME is caused by expansions of TTTCA and TTTTA repeats in SAMD12 (BAFME1), STARD7 (BAFME2), MARCHF6 (BAFME3), YEATS2 (BAFME4), TNRC6A (BAFME6), or RAPGEF2 (BAFME7). The findings strongly support a concept of “repeat motif–phenotype correlation” which we have proposed previously. Pathologically, BAFME1 patients carrying heterozygous expansions of TTTCA and TTTTA repeats do not show any obvious abnormal neuropathological findings in the central nervous system. These pathological findings, in addition to electrophysiological studies, suggest a dysfunctional neuronal circuit that causes enhanced excitability of the sensorimotor cortex. Autopsied brains of BAFME1 patients showed RNA foci consisting of UUUCA repeats in cortical neurons and cerebellar Purkinje cells. These findings suggest that RNA toxicity caused by UUUCA repeat expansions is involved in the pathogenesis of BAFME. Since our discovery of the causative gene for BAFME1, progress has been made in genetic studies of each type of BAFME, as well as in pathogenetic mechanisms of BAFME caused by TTTCA and TTTTA expansions. Here, we present a comprehensive review on recent advances focusing on expanded TTTCA and TTTTA repeats in BAFME.

Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in the SAMD12 gene.

Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy is a non-progressive disorder characterized by distal tremors. Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported globally with different genetic predispositions of autosomal dominant inheritance with a high degree of penetrance. In south India, Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported in a large cohort of 48 families, in which the genetic defect was not identified. This report pertains to the whole-genome analysis of four individuals followed by repeat-primed PCR for 102 patients from a familial cohort of 325 individuals. All the patients underwent extensive clinical evaluation including neuropsychological examinations. The whole-genome sequencing was done for two affected and two unaffected individuals, belonging to two different families. The whole-genome sequencing analysis revealed the repeat expansion of TTTTA and TTTCA in intron 4 of the SAMD12 gene located on chromosome 8 in the patients affected with Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy, whereas the unaffected family members were negative for the similar expansion. Further, the repeat-primed PCR analysis of 102 patients showed the expansion of the TTTCA repeats in the intron 4 of SAMD12 gene. All patients registered for this study belong to a single community called “Nadar” whose nativity is confined to the southern districts of India, with reported unique genetic characteristics. This is the largest and most comprehensive single report on clinically and genetically characterized Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy patients belonging to a unique ethnic group worldwide.

Autosomal dominant cortical tremor, myoclonus and epilepsy.

The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.

Autosomal Dominant Cortical Tremor, Myoclonus, and Epilepsy Syndrome mimicking Juvenile Myoclonic Epilepsy.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) syndrome is a genetically heterogeneous and under-recognized disease characterized by tremulous movements mimicking essential tremor, myoclonus, and rare generalized tonic-clonic seizures. Here we described the clinical and electrophysiological features of three siblings with ADCME syndrome mimicking juvenile myoclonic epilepsy (JME). Three siblings (two females and one male) diagnosed with ADCME were analyzed by electroencephalogram (EEG), somatosensory evoked potentials, and accelerometric recordings. The results were compared with 14 JME patients without tremor and 14 with essential tremor (ET). The shared features of the siblings were cortical tremor, myoclonia, epilepsy, migraine, and psychiatric symptoms. In all siblings, tremor had started before myoclonic epilepsy associated with 4-6 Hz generalized spike and wave discharges. The N20-P25 and P25-N35 amplitudes were substantially higher in the three siblings with ADCME. Although tremor frequencies were similar to those of the ET group, the siblings had mild interrupting low-amplitude myoclonus, suggestive of cortical tremor, in the accelerometric analysis. We presented a detailed clinical evaluation with electrophysiological confirmation of ADCME syndrome in a Turkish family. This rare clinical picture might be misdiagnosed as JME and should be kept in mind to ensure correct diagnosis and to provide a homogenous group for genetic studies.

Psychiatric comorbidities in patients from seven families with autosomal dominant cortical tremor, myoclonus, and epilepsy.

The objective of this report was to assess the psychiatric comorbidity in a group of patients affected by autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME). Reliable and validated psychodiagnostic scales including the BDI (Beck Depression Inventory), STAI-Y1 and 2 (State-Trait Anxiety Inventory - Y; 1 and 2), MMPI-2 (Minnesota Multiphasic Personality Inventory - 2), and QoLIE-31 (Quality of Life in Epilepsy Inventory - 31) were administered to 20 patients with ADCME, 20 patients with juvenile myoclonic epilepsy (JME), and 20 healthy controls. There was a higher prevalence of mood disorders in patients with ADCME compared to patients with JME and healthy controls, particularly depression (p=0.035 and p=0.017, respectively) and state anxiety (p=0.024 and p=0.019, respectively). Trait anxiety was not different from JME (p=0.102) but higher than healthy controls (p=0.017). The myoclonus score positively correlated with both state (rho: 0.58, p=0.042) and trait anxiety (rho: 0.65, p=0.011). These psychiatric features were also often associated with pathological traits of personality: paranoid (OR: 25.7, p=0.003), psychasthenia (OR: 7.0, p=0.023), schizophrenia (OR: 8.5, p=0.011), and hypomania (OR: 5.5, p=0.022). Finally, in patients with ADCME, decreased quality of life correlated with these psychiatric symptoms. Patients with ADCME show a significant psychiatric burden that impairs their quality of life. A comprehensive psychiatric evaluation should be offered at the time of diagnosis to detect these comorbidities and to treat them.

Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Editorial

In 1990, Ikeda et al. described an action and postural tremor that originated from the cerebral cortex and was thus termed “cortical tremor.” Due to its peculiar electrophysiological features, this involuntary movement was considered to be a variant of cortical reflex myoclonus [1]. Cortical tremor was then recognized to occur in Japanese families often in association with tonic– clonic seizures, and this observation led to the definition of an autosomal dominant trait named Benign Adult Familial Myoclonic Epilepsy (BAFME), which was mapped on chromosome 8q [2, 3]. Over the past decade, several European kindreds with overlapping clinical features have been reported under different acronyms, such as autosomal dominant cortical myoclonus and epilepsy and familial cortical myoclonic tremor with epilepsy (FCMTE) [4–7]. The available literature now suggests a worldwide distribution (more than 60 families have been reported) and genetic heterogeneity, yet with evidence that 2p11.1-q12.2 is a major locus for the kindreds of European origin [8]. Most affected individuals experience tonic–clonic seizures, which begin later than “tremor.” Seizures are generally rare (about five to ten episodes during life) and are not preceded by any warning. However, in some cases, they may be heralded by progressively increasing myoclonic jerks. Precipitating factors such as sleep deprivation, emotional stress, pain, and photic stimulation are often reported [3, 7]. In some cases, severe myoclonus can alter the quality of life. Although the epilepsy is usually benign, in rare cases, patients may present with drug-resistant complex partial seizures and focal EEG abnormalities [4]. Patients usually have normal cognition; however, mildto-moderate mental retardation may be present in some cases, especially in a more advanced age [6, 9]. Both the severity of seizures and the use of antiepileptic drugs could contribute to cognitive impairment. Cerebellar symptoms are usually mild: postural ataxia, downbeat nystagmus, impaired smooth pursuit. MRI may demonstrate a cerebellar atrophy. A pseudo-parkinsonism has also been reported. FCTME is usually diagnosed between the ages of 20 and 45 years. Myoclonus and EEG abnormalities progressively worsen from early to late adulthood. Clonazepam and sodium valproate are usually effective therapies. Thus far, the pathophysiological and biochemical bases of this condition remain poorly understood. Mutations in genes encoding ion channels have been excluded by several authors [3–7]. Patients typically show giant somatosensory evoked potentials and strong corticoand intermuscular coherence in the 8to 30-Hz range, thus suggesting an underlying cortical hyperexcitability, which can be the result of a decreased cortical inhibition by the cerebellum via its cerebello-thalamocortical projections [6]. Indeed, rare post-mortem histological studies have shown evidence of cerebellar pathology reminiscent of SCA type 6 [3, 5], and although P. Striano (*) Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Largo Gaslini 5, Pediatric Neurology and Muscular Diseases Unit, Padiglione 16, IV Piano, 16147 Genoa, Italy e-mail: pstriano@email.it

Natural history and long-term evolution in families with autosomal dominant cortical tremor, myoclonus, and epilepsy

To investigate for the first time the natural history and long-term evolution of "familial cortical tremor, myoclonus, and epilepsy." We evaluated the clinical, electrophysiologic, and treatment data of 14 patients from three families linked to 2p11.1-q12.2. A simplified scale was used to score myoclonus severity. Electroencephalography (EEG) studies were reviewed for the evaluation of background activity, paroxysmal abnormalities, and photoparoxysmal response. Data were organized for age groups. Correlation and logistic regression analysis were performed. Patients' mean age was 47.8 ± 22.0 years (range 20-86 years). Mean age at disease onset was 20.2 ± 7.8 years (range 11-40 years); mean follow-up duration was 14.0 ± 5.8 years (range 7-28 years). Evaluation at different age groups revealed a gradual, progressive worsening of the myoclonus in 10 patients (71.4%). Two subjects aged >80 years showed myoclonus interfering with autonomous walking. Myoclonus severity was correlated with disease duration (p<0.001) and patients' age (p=0.001). Six patients (42.8%) experienced seizures, usually between the second and sixth decades of life. Evaluation of EEG long-term evolution revealed progressive slowing of background activity in parallel with the gradual worsening of myoclonus. In contrast, paroxysmal activity and photosensitivity were particularly evident during the intermediate phases of the disease. In addition, psychiatric and neuropsychological dysfunction occurred in more than one third of the patients. We provide data for a slight age-dependent progression and the presence of neuropsychiatric and neuropsychological dysfunction in this unique syndrome, for which the definition of familial or autosomal dominant cortical tremor, myoclonus, and epilepsy (FCTME/ADCME) seems to be, therefore, more appropriate.

Introduction

Introduction

PO3.2 Electrophysiological Studies in a Thai Family with Autosomal Dominant Cortical Myoclonic Tremor with Epilepsy (ADCME)

PO3.2 Electrophysiological Studies in a Thai Family with Autosomal Dominant Cortical Myoclonic Tremor with Epilepsy (ADCME)

Idiopathic Generalized Epilepsies: A Review and Modern Approach

Idiopathic Generalized Epilepsies: A Review and Modern Approach

Syndromes of Idiopathic Generalized Epilepsies Not Recognized by the International League Against Epilepsy

This chapter assesses probable epileptic syndromes within the idiopathic generalized epilepsies (IGE) that have not yet been recognized by the International League Against Epilepsy (ILAE). Jeavons syndrome, a purely reflex IGE that predominantly manifests with eyelid myoclonia and electroencephalogram (EEG) abnormalities on eye closure, is the most distinct and undisputed of the syndromes. Another is autosomal-dominant cortical tremor, myoclonus, and epilepsy, a purely monogenic disorder that has been documented in numerous reports, mainly from Japan and Italy. Perioral myclonia with absences is certainly a seizure type that may constitute an IGE syndrome when it is associated with a number of other clinical and EEG manifestations. Similarly, many patients suffer for years from phantom absences, a type of mild absence, before a first generalized tonic-clonic seizure that usually occurs in adulthood. Both perioral myoclonia with absences and phantom absences are clinically significant because they are probably lifelong and are associated with a very high incidence (around 50%) of absence status epilepticus that may escape diagnosis and appropriate treatment. The position of early childhood IGE, which manifests mainly with typical absence seizures that are distinctly different from childhood absence epilepsy and other recognized IGE syndromes, is less clear. The prevalence of these syndromes is significant. Their identification allows better clinical management and is important for genetic research and counselling. In addition, their recognition permits application of exclusion criteria for a more purified definition and a better understanding of the true boundaries of the other IGE syndromes already accepted by the ILAE.

Autosomal dominant cortical tremor, myoclonus and epilepsy: many syndromes, one phenotype

The association of cortical tremor, myoclonus and epileptic seizures has been reported in many Japanese and European families with different acronyms. We reviewed the familial cases presenting the clinical picture of autosomal dominant cortical tremor, myoclonus and epilepsy and analysed the phenotypic differences between the pedigrees, according to the recent genetic acquisitions. We concluded that BAFME, FAME, FEME, FCTE and ADCME are the same clinical entity even if genetically heterogeneous, with Japanese families linked to 8q24 and Italian ones to 2p11.1-q12. A third locus could also be involved. Further studies should better clarify the electrophysiological features of this condition and identify the underlying molecular defects.