Epilepsy, Familial Adult Myoclonic, 5

A number sign (#) is used with this entry because of evidence that familial adult myoclonic epilepsy-5 (FAME5) is caused by homozygous mutation in the CNTN2 gene (190197) on chromosome 1q32. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of familial adult myoclonic epilepsy, see FAME1 (601068).

Description

Familial adult myoclonic epilepsy-5 is an autosomal recessive neurologic disorder characterized by onset of seizures in adolescence, followed by the development of cortical myoclonic tremor later in life. Some patients may also have neuropsychiatric abnormalities (summary by Stogmann et al., 2013).

Clinical Features

Stogmann et al. (2013) reported a consanguineous Egyptian family in which 5 sibs, aged 11 to 14 years, had onset of seizures in adolescence. Seizure types included both complex partial seizures and generalized seizures, often with an olfactory, auditory, or visual aura suggesting a temporal lobe origin. EEG studies showed temporal epileptiform discharges, and brain MRI was normal in all but 1 patient, who had bilateral mesial temporal sclerosis. Seizures were well-controlled by medication in 4 patients. All 5 patients later developed cortical myoclonic tremor, with head nodding and twitching of the hands and fingers. EMG showed synchronous bursting of agonist and antagonist muscles with a frequency of 10 to 14 Hz and burst duration less than 50 ms, consistent with a cortical origin of myoclonus. Two patients had depressive symptoms and borderline intelligence, whereas 2 had average neuropsychologic test results.

Inheritance

The transmission pattern of FAME5 in the family reported by Stogmann et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of a consanguineous Egyptian family with cortical myoclonic epilepsy and tremor, Stogmann et al. (2013) found linkage to a 12.7-Mb interval on chromosome 1q31.3-q32.2 between SNPs rs927510 and rs724054 (lod score of 3.6).

Molecular Genetics

In affected members of an Egyptian family with FAME5, Stogmann et al. (2013) identified a homozygous frameshift mutation in the CNTN2 gene (190197.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in multiple controls. Sequencing of the CNTN2 gene in 189 patients with various epilepsy syndromes did not identify any pathogenic mutations.

Nomenclature

Striano et al. (2013) objected to the classification of this disorder as 'familial cortical myoclonic tremor with epilepsy (FCMTE)' because FCMTE is usually transmitted in an autosomal dominant manner and because the patients in the Egyptian family reported by Stogmann et al. (2013) did not undergo electrophysiologic studies showing cortical reflex myoclonus. Striano et al. (2013) suggested that the patients in the Egyptian family had a form of focal epilepsy of temporal lobe origin, and that the tremor observed was a result of antiepileptic therapy. In a reply, Stogmann et al. (2013) noted that the features in their patients conform to the core criteria of FCMTE, but acknowledged that some unusual features were present.