Familial cortical tremor and epilepsy: A well-defined syndrome with genetic heterogeneity waiting for nosological placement in the ILAE classification.

Depienne and colleagues recently mapped to 5p15.31–p15 a French family with cortical tremor, myoclonus, and epilepsy [1]. This is the third locus identified in this condition, which was first recognized and linked to 8q23.3–q24.11 in Japanese pedigrees and then increasingly reported worldwide, with the locus 2p11.1–q12.2 identified in Italian families [2]. Of note, we have excluded a linkage to 5p15.31–p15 in three novel unreported families (data unpublished), and an additional locus on 7p15 has been preliminarily suggested in a Chinese pedigree [Xi and Wang, personal communication]. Despite the genetic heterogeneity of the syndrome, this is a well-delineated condition with remarkable features clearly distinguishing it from other myoclonic epilepsies [2]. Nevertheless, it is not yet officially recognized by the International League Against Epilepsy (ILAE), and its nosological placement is still debated. In particular, even if described with different acronyms (BAFME, FAME, FCMTE, ADCME, and others), the core of the syndrome includes the familial occurrence of a hand tremor with the electrophysiological features of cortical reflex myoclonus, myoclonus of the extremities, and tonic–clonic seizures often precipitated by sleep deprivation or photic stimulation. However, seizures may never occur in some individuals, whereas focal seizures (frontal, temporal, or occipital) may occur [1] and [2]. Age at onset is highly variable (11–50 years), but the disease usually starts within the second decade of life and follows a benign course in patients on antiepileptic therapy. In some cases, however, seizures may be frequent or unresponsive to treatment, and status epilepticus can occur in cases of drug withdrawal or inappropriate therapy [1] and [3]. Notably, Depienne et al. reported a worsening of the myoclonus in patients older than 60 years, resulting in walking impairment [1]. This finding is in accordance with a slow but significant progression of the disease over time. Accordingly, brain MRI spectroscopy [4] and neuropathological [5] studies have highlighted significant brain (i.e., cerebellar) changes in these patients. In conclusion, familial cortical tremor, myoclonus, and epilepsy constitute a unique syndrome which, in our opinion, should be appropriately placed in the middle between idiopathic and progressive myoclonic epilepsies. Therefore, use of acronyms including the term benign or adult (BAFME, FAME) should be critically reconsidered. The identification of causative genes probably requires an extensive and collaborative screening effort. It is hoped that identification of these genes may provide new relevant insights into the pathogenesis of myoclonic epilepsies.