Epilepsy, Familial Adult Myoclonic, 1
A number sign (#) is used with this entry because of evidence that familial adult myoclonic epilepsy-1 (FAME1) is caused by a heterozygous 5-bp repeat expansion (TTTCA(n)) in the SAMD12 gene (618073) on chromosome 8q24.
DescriptionFamilial cortical myoclonic tremor associated with epilepsy (FCMTE) is characterized by an autosomal dominant inheritance, adult-onset cortical myoclonus, and seizures in 40% of patients. Myoclonus is usually the first symptom and is characterized by tremulous finger movements and myoclonus of the extremities (summary by Depienne et al., 2010). FAME1 tends to occur in patients of Japanese or Han Chinese descent (summary by Cen et al., 2018).
Genetic Heterogeneity of Familial Adult Myoclonic Epilepsy
See also FAME2 (607876), caused by mutation in the ADRA2B gene (104260) on chromosome 2q11; FAME3 (613608), which maps to chromosome 5p15; FAME4 (615127), which maps to chromosome 3q26.32-q28; FAME5 (615400), caused by mutation in the CNTN2 gene (190197) on chromosome 1q32; FAME6 (618074), caused by mutation in the TNRC6A gene (610739) on chromosome 16p12; and FAME7 (618075), caused by mutation in the RAPGEF2 gene (609530) on chromosome 4.
Progressive myoclonic epilepsy is a more severe disorder (see, e.g., EPM1, 254800).
Clinical FeaturesIkeda et al. (1990) reported 2 Japanese patients with a disorder characterized by adult-onset of nonprogressive postural and action finger tremor, seizures, and a family history of the condition. EMG showed that the tremor was associated with a relatively rhythmic discharge at a rate of 9 Hz, resembling essential tremor (see ETM1, 190300). However, electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop C-reflexes, and premovement cortical spikes by the jerk-locked averaging method (JLA), suggesting a cortical origin. Treatment with adrenergic beta-blockers was ineffective, but anticonvulsants such as clonazepam, valproate, and primidone were effective. Ikeda et al. (1990) concluded that the involuntary movements, or 'cortical tremors,' were a form of cortical reflex myoclonus.
Kuwano et al. (1996) presented pedigrees of 5 Japanese kindreds with benign adult familial myoclonic epilepsy (BAFME) inherited in a clear autosomal dominant pattern. One of the families had previously been described by Yasuda (1991). Affected patients had myoclonus or epilepsy and abnormal EEG findings, particularly photosensitivity in the EEG. The age of onset of the disorder was between 18 and 50 years. Analysis for a CAG expansion in the DRPLA gene (607462), which causes dentatorubral-pallidoluysian atrophy (DRPLA; 125370), a disorder with myoclonus and epilepsy as features, showed normal results. Linkage analysis using DNA polymorphisms in the DRPLA gene excluded it as a site for the mutation.
Terada et al. (1997) described 6 patients from 3 families with autosomal dominant familial cortical myoclonic tremor manifesting as rhythmic involuntary movements in their upper and lower extremities that were induced particularly by posture and action. All patients had adult onset (mean 37 years). Three patients had rare episodes of 'loss of consciousness,' which were not described further. EEG showed generalized spike and wave complexes and photoparoxysmal responses in 4 patients. Electrophysiologic studies reflected cortical reflex myoclonus. Terada et al. (1997) emphasized the distinction of this disorder from essential tremor and essential myoclonus (159900), as well as from progressive myoclonic epilepsy (see, e.g., 254800) and DRPLA.
Okino (1997) reported 3 families with adult-onset myoclonic epilepsy. Onset of the myoclonus was between the third and fifth decades, followed by rare generalized tonic-clonic seizures (GTCS). The condition appeared to be autosomal dominant and was not progressive. Electrophysiologic analyses showed polyspikes on EEG, giant wave SEPs, enhanced C-reflexes, and a preceding wave on JLA, all suggesting that the myoclonus originated in the cerebral cortex.
Elia et al. (1998) described a European family with cortical tremor, epilepsy, and mental retardation inherited in an autosomal dominant pattern. All 4 living patients examined had nonprogressive postural and action 6- to 8-Hz tremor of the fingers, which was aggravated by emotional stress. Three patients had GTCS, which was well-controlled with treatment (phenobarbital and/or benzodiazepines). The 2 youngest patients in a later generation had a more severe phenotype, with earlier onset of symptoms (age 5 years) and moderate mental retardation. All patients showed diffuse spike-wave complexes on EEG and a photoparoxysmal response. Giant SEPs, enhanced C-reflex, and premyoclonus spike on JLA occurred in all patients.
Cen et al. (2018) reported 105 patients from 18 Han Chinese pedigrees with FAME1. Clinical details were limited. The mean age at onset of cortical tremor was 30 years (range, 12-59). Generalized tonic-clonic seizures occurred in about 75% of patients, with a mean age at onset of 37 years (range, 18-64). Between 80% and 90% of patients who underwent studies showed giant SEPs and long-latency cortical reflexes.
InheritanceThe transmission pattern of FAME1 in the families reported by Ishiura et al. (2018) was consistent with autosomal dominant inheritance. However, affected individuals in 3 families had homozygous repeat expansions, consistent with autosomal recessive inheritance. The phenotype in the individuals with homozygous mutations was more severe than that of their family members with heterozygous mutations. Homozygous patients had an earlier age at onset as well as cognitive decline associated with brain atrophy.
MappingBy linkage analysis in a large Japanese kindred with BAFME, Mikami et al. (1999) assigned the gene responsible for this disorder to the distal portion of 8q. A maximum 2-point lod score of 4.31 with D8S555 was obtained at a recombination fraction of 0.0; the maximum multipoint lod score was 5.42 for the interval between D8S555 and D8S1779. Mikami et al. (1999) gave a cytogenetic localization of 8q23.3-q24.11. Mikami et al. (1999) concluded that the locus for benign adult familial myoclonic epilepsy is distinct from 3 other epilepsy-related loci on 8q: familial febrile convulsions-1 (FEB1; 121210) on 8q13-q21; KCNQ3 (602232) on 8q24; and childhood absence epilepsy (ECA1; 600131) on 8q24.
Plaster et al. (1999) investigated 4 previously reported Japanese kindreds with familial adult myoclonic epilepsy (FAME). They defined the FAME locus as a 4.6-cM region on chromosome 8q24 with a maximum lod score of 4.86 flanked by markers D8S514 and D8S1804. Plaster et al. (1999) noted that FAME had not been identified outside of Japan.
Mori et al. (2011) reanalyzed the Japanese family reported by Yasuda (1991) and Mikami et al. (1999) using 10K SNP arrays and additional microsatellite markers in a genomewide linkage analysis. The FAME1 locus was mapped to a 7.16-Mb region between SNPs rs1898287 and rs2891799 on chromosome 8q23.3-q24.13 (maximum 2-point lod score of 6.0 for marker rs1021897). Sequence analysis and copy-number variant analysis of all 38 genes localized in the candidate region were performed, but no pathogenic mutation was identified.
Genetic Heterogeneity
Van Rootselaar et al. (2002) reported a large Dutch family in which 13 members had cortical tremor and epilepsy. Inheritance was autosomal dominant. Tremulous movements resembling essential tremor were first noticed between ages 12 and 45 years. Generalized tonic-clonic seizures and myoclonic seizures began between 20 and 63 years, usually after the tremor. Symptom progression and severity varied from mild to severe. Several affected family members had cognitive impairment with short-term memory loss and attention deficits. There were no pyramidal or cerebellar signs, and electrophysiologic studies suggested cortical hyperexcitability. Certain antiepileptic medications were useful. Linkage analysis excluded the locus on 8q23. By postmortem examination of a 68-year-old Dutch woman from the family reported by van Rootselaar et al. (2002), van Rootselaar et al. (2004) found cerebellar degeneration with neuronal loss, loss of Purkinje cell dendritic trees, and gliosis. The patient had had progressive irregular trembling of the limbs since age 35, and myoclonic and generalized tonic-clonic seizures since age 38. At 68, she showed memory deficits, hyperactive reflexes, action tremor, myoclonus, and intractable seizures.
Carr et al. (2007) reported 2 large families from the Western Cape province of South Africa with generalized tonic-clonic seizures and myoclonus. The mean age at onset was 20 years (range 13 to 31). Myoclonus predominantly affected the trunk and upper limbs but was also observed in the lower limbs. Hand tremor became apparent on posture holding. Additional features included nystagmus, abnormal pursuit, dysarthria, hyperreflexia, cerebellar ataxia, and cerebellar atrophy. A number of patients also had progressive cognitive impairment, resulting in dementia in some. EEG studies were abnormal in the majority of patients, with polyspike and wave activity and/or clear epileptogenic activity. Postmortem examination of 1 patient showed cerebellar atrophy and cerebellar neuronal loss. Several patients died in their thirties and forties. The families were of mixed ancestry, predominantly resulting from intermarriage between the original inhabitants of the area, the Khoi-San, and early settlers of European origin. Carr et al. (2007) noted that the phenotype was more severe and showed earlier onset than typical FAME1. The phenotype was also progressive, falling within the spectrum of progressive myoclonic epilepsies (see, e.g., EPM1; 254800). Linkage analysis excluded FAME1 and FAME2. Striano et al. (2008) commented that the phenotype described by Carr et al. (2007) was more severe than typically seen for FAME, and suggested that the disorder described by Carr et al. (2007) should be placed within the group of progressive myoclonic epilepsies. Striano et al. (2008) suggested that the designation 'FAME' be reserved for familial nonprogressive cortical tremor and epilepsy.
Molecular GeneticsIn affected members of 49 Japanese families with FAME1, Ishiura et al. (2018) identified a heterozygous 5-bp expanded TTTCA(n) insertion in a noncoding region within intron 4 of the SAMD12 gene (618073.0001). The mutation was found by a combination of linkage analysis of 6 families and whole-genome sequencing of 1 family. Subsequent families were identified by targeted analysis of the SAMD12 gene. The TTTCA(n) repeat expansion was associated with an upstream 5-bp TTTTA(n) repeat expansion in all families, although in 1 family (F6115), the TTTCA(n) repeat expansion was found between 2 TTTTA(n) expansions. The TTTCA(n) expansion was not observed in the reference sequence or in 1,000 control individuals, whereas the TTTTA(n) repeat was found in the reference sequence and an expanded TTTTA(n) repeat was found in 5.9% of controls, suggesting that the TTTCA(n) expansion is responsible for the phenotype. Four patients from 3 families had homozygous repeat expansions, which was associated with a more severe phenotype. Neuropathologic examination of brain tissue from 6 patients using a probe targeting the UUUCA repeat showed accumulation of abnormal RNA foci in cortical neurons and, to a lesser extent, in Purkinje cells. Western blot analysis showed decreased levels of SAMD12 protein in patient brains. One patient with homozygous repeat expansions had mild and diffuse loss of Purkinje cells or Purkinje cells with halo-like amorphous materials around the cytoplasm, referred to as 'somatic sprouts,' suggesting possible degeneration. These histologic abnormalities were not detected in the brains of patients with heterozygous repeat expansions or in controls. RNA-seq analysis of patient brains showed transcriptional dysregulation and accumulation of altered repeat motifs. There was an inverse correlation between repeat length and age at onset of epilepsy and myoclonic tremor. Affected members from 2 additional families (F9283 and F8241) were found to have similar heterozygous abnormal expansions of TTTCA and TTTTA repeats in introns of the TNRC6A (610739.0001) and RAPGEF2 (609530.0001) genes, respectively. The finding of identical expanded-repeat motifs in separate genes strongly suggested that the expression of RNA molecules containing expansions of UUUCA and UUUUA repeats per se is involved in the pathogenesis of the disorder, rather than altered physiologic function of individual genes.
In affected members of 18 Han Chinese families with FAME1, Cen et al. (2018) identified a heterozygous 5-bp expanded TTTCA(n) repeat in intron 4 of the SAMD12 gene. The mutation was found by a combination of linkage analysis in 11 informative families followed by detailed analysis of repetitive motifs within the candidate region. The TTTCA(n) insertion was located between an Alu element and polymorphic TTTTA(n) repeats. Repeat-primed PCR demonstrated cosegregation of the expanded TTTCA(n) insertion with the disorder in all 18 families. The size of the insertion in patients was estimated to be at least 105 repeats; the insertion was not found in 119 Chinese control individuals. Haplotype analysis of 5 Chinese pedigrees and 3 Japanese FAME1 pedigrees (Ishiura et al., 2018) showed a shared core haplotype containing the pathogenic TTTCA(n) insertion, consistent with a founder effect between the 2 countries. The haplotype had a frequency of 0.226 in the 1000 Genomes Project database for the Chinese population. Functional studies of the SAMD12 mutation were not performed, but Cen et al. (2018) postulated that the expanded repeat would form RNA foci resulting in neurotoxicity, similar to that observed in SCA37 (615945), which results from a heterozygous 5-bp ATTTC(n) expanded repeat insertion in the DAB1 gene (603448.0001).
Population GeneticsThe studies of Ishiura et al. (2018) and Cen et al. (2018) indicated that FAME1 is particularly frequent in the Chinese and Japanese populations, consistent with a founder effect.
NomenclatureIn a review of this disorder, van Rootselaar et al. (2005) noted that multiple descriptive names and acronyms have been used in the literature to refer to the same constellation of symptoms. The authors proposed 'familial cortical myoclonic tremor with epilepsy' (FCMTE) as a unifying term.