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

Abstract

Background: Autosomal dominant familial cortical myoclonic tremor and epilepsy (FCMTE) is characterized by distal tremulous myoclonus, generalized seizures, and signs of cortical reflex myoclonus. FCMTE has been described in over 100 pedigrees worldwide, under several different names and acronyms. Pathological changes have been located in the cerebellum. This systematic review discusses the clinical spectrum, treatment, pathophysiology, and genetic findings.Methods: We carried out a PubMed search, using a combination of the following search terms: cortical tremor, myoclonus, epilepsy, benign course, adult onset, familial, and autosomal dominant; this resulted in a total of 77 studies (761 patients; 126 pedigrees) fulfilling the inclusion and exclusion criteria.Results: Phenotypic differences across pedigrees exist, possibly related to underlying genetic differences. A ''benign'' phenotype has been described in several Japanese families and pedigrees linked to 8q (FCMTE1). French patients (5p linkage; FCMTE3) exhibit more severe progression, and in Japanese/Chinese pedigrees (with unknown linkage) anticipation has been suggested. Preferred treatment is with valproate (mind teratogenicity), levetiracetam, and/or clonazepam.Several genes have been identified, which differ in potential pathogenicity.Discussion: Based on the core features (above), the syndrome can be considered a distinct clinical entity. Clinical features may also include proximal myoclonus and mild progression with aging. Valproate or levetiracetam, with or without clonazepam, reduces symptoms. FCMTE is a heterogeneous disorder, and likely to include a variety of different conditions with mutations of different genes. Distinct phenotypic traits might reflect different genetic mutations. Genes involved in Purkinje cell outgrowth or those encoding for ion channels or neurotransmitters seem good candidate genes.

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

“…FAME is an autosomal dominant, very slowly progressive condition characterized by cortical tremor affecting mainly the hands, frequently associated with generalized myoclonic and sometimes tonic-clonic seizures, and, more rarely, focal seizures 1–3 . This condition was first described in Japan as benign adult familial myoclonic epilepsy (BAFME), and subsequently also referred to as familial cortical myoclonic tremor with epilepsy (FCMTE) or autosomal dominant cortical myoclonus and epilepsy (ADCME).…”

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

“…FAME (also referred to as Familial Cortical Myoclonic Tremor and Epilepsy or Benign Adult onset Familial Myoclonic Epilepsy [OMIM phenotypic series: PS601068]) is characterised by cortical myoclonic tremor and overt myoclonic and later generalised tonic-clonic seizures (GTCS) 1 . Onset of symptoms occurs in the second to third decade with variable expressivity within and between families; anticipation has been noted in some families 1 . The frequency of GTCS varies from 15 to 100% in 22 different families reported here (Table 1) 2 .…”

“…There is one report of autosomal recessive FAME caused by mutation in CNTN2 where the phenotype was disputed 7,8 . Candidate genes and variants that fall within these common linkage intervals have been suggested for chr2 ( ADRA2B ) and chr5 ( CTNND2 ); however, none of these genes have been shown to be allelic in all FAME families with linkage to the same interval 1 . We previously showed using identity-by-descent mapping that there are at least four distinct founder loci linked to FAME2 (OMIM:607876) on chr2 9 .…”

Transcranial magnetic stimulation as a tool to understand genetic conditions associated with epilepsy

“…Familial cortical myoclonic tremor with epilepsy (FCMTE), also known as familial adult myoclonic epilepsy (FAME), autosomal dominant cortical myoclonus and epilepsy (ADCME), and benign adult familial myoclonic epilepsy (BAFME), is characterized by myoclonus affecting the limbs distally and generalized tonic-clonic seizures, with onset in the second or third decade. 58 Additional features may include mild cerebellar signs and cognitive decline. 58 The inheritance pattern is autosomal dominant and, recently, inserted pentamer repeats, presumed to lead to RNA toxicity, have been identified in STARD7, SAMD12, TNRC6A and RAPGEF2, [59][60][61] in keeping with previously implicated loci.…”

“…58 Additional features may include mild cerebellar signs and cognitive decline. 58 The inheritance pattern is autosomal dominant and, recently, inserted pentamer repeats, presumed to lead to RNA toxicity, have been identified in STARD7, SAMD12, TNRC6A and RAPGEF2, [59][60][61] in keeping with previously implicated loci. 58 Compared to controls, six members of a Dutch FCMTE pedigree had reduced SICI at ISIs 2 and 3 ms. 62 Compared to controls, four members of an Italian family affected with FCMTE were reported to have a significantly lower rMT, reduced duration of CSP, and reduced SICI.…”