Progressive myoclonic epilepsies: definitive and still undetermined causes

Abstract

Objective: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy.

Methods: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis.

Results: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings.

Conclusions: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Figure 1. Age at disease and myoclonus onset in patients with genetically identified progressive myoclonic epilepsies

Gray segments of columns refer to the period before disease onset, yellow segments to the presentation of neurologic signs, and red segments to the presentation of myoclonus. The end of the columns defines the patients' ages at the time of the last observation. Columns representing EPM1 and EPM2 are based on mean values, whereas the other columns refer to individual patients. HD = Huntington disease; MERRF = myoclonic epilepsy with ragged-red fibers; NCL = neuronal ceroid lipofuscinosis; NPC = Niemann-Pick disease type C; SMA = spinal muscular atrophy.

Figure 2. Age at disease and myoclonus onset in patients with undetermined progressive myoclonic epilepsies belonging to clusters 1 and 2

Note that most of the patients in cluster 1 experienced early onset of disease and myoclonus (A, B), whereas those in cluster 2 experienced more variable but predominantly late onset (C, D) of neurologic symptoms and myoclonus.

Figure 3. Characteristics distinguishing patients with undetermined progressive myoclonic epilepsies

Cluster 1 included more patients in whom psychomotor (PM) delay preceded the appearance of cortical myoclonus, EEG paroxysms evoked by intermittent photic stimulation, and atrophic changes in the cerebral cortex or cerebellum, whereas cluster 2 included a larger number of patients with associated signs exceeding the typical progressive myoclonic epilepsies presentation (A). Recurrent and polymorphic seizures were more common in cluster 1 (B), whereas almost half of the patients in cluster 2 had no seizures (other than myoclonic) (C). Sz = seizures; TC = tonic-clonic.