The varied genetic causes of progressive myoclonic epilepsies (PMEs) are becoming better understood through genetic analyses. A team of Italian researchers recently contributed to the understanding of these rare diseases by defining the clinical spectrum and etiology of PMEs, using a database developed by the Genetics Commission of the Italian League against Epilepsy (Franceschetti S, et al. Neurology. 2014;82:405-411).
PMEs include phenotypes arising from various causes, but all leading to myoclonic jerks frequently associated with seizures and progressive neurologic impairment. PMEs usually present in late childhood or adolescence, but adult-onset PMEs may be due to rare gene defects or immune or late degenerative disorders, the investigators pointed out.
Although most phenotypes have already been attributed to specific genetic defects, others have been identified more recently and are associated with novel mutations involving the PRICKLE1, SCARB2, and GOSR2 genes. The article sought to further describe these conditions by examining clinical and laboratory data from patients referred to 25 Italian epilepsy centers.
PMEs of undetermined origins were grouped using 2-step cluster analysis, based on categorical variables—positive family history, seizure characteristics, psychomotor delay preceding myoclonus onset, EEG paroxysms of polyspikes and waves (PSW), photosensitivity, pathologic magnetic resonance imaging (MRI) findings, and associated signs other than those included in the cardinal definition of PME. The analysis also included the continuous variables of age at the time of disease and myoclonus onset.
The database included 204 patients who were examined by 57 neurologists and were followed until the mean age of 33.3 years; 26 patients had died, at a mean age of 27.7 years, during the course of the study.
Most Frequently Identified Forms of PME
Unverricht-Lundborg disease (EPM1) was the most frequently occurring form of PME in the series, accounting for more than one third of the patients. EPM1 and CSTB gene mutations were diagnosed in 77 patients (37.7%). The mean age at disease onset was 11.4 years, with myoclonus appearing at a mean age of 13.5 years. Eight patients from 6 families with EPM1 due to compound heterozygosis with point or indel mutations on 1 allele had particular characteristics, including earlier age at disease onset (7.8 years), multiple seizure types, and cognitive impairment.
The second most frequent form (18.1%) was Lafora body disease (EPM2). Within these 37 patients with EPM2, mutations in the NHLRC1 (70.3%) or EPM2A gene (18.9%) or a positive skin biopsy (10.8%) was documented. The mean age at disease onset was 12.6 years, with a mean age at myoclonus onset of 15.1 years. Most patients had a severe disease course, and 16 patients died at a mean of 10 years after disease onset; however, some had milder phenotypes and a protracted disease course that lasted up to 24 years.
Rare Genetic Causes and Unidentified Forms
PMEs due to other genetic causes were rarer, and accounted for just 15.2% of the series. Within this group, a diagnosis of neuronal ceroid lipofuscinosis (NCL) accounted for 5.9%.
The patients with NCL had the most polymorphic clinical picture, ranging from childhood onset (with seizures and mental impairment) to a severe, almost pure myoclonic phenotype in adults. Most patients with NCL carried CLN6 mutations, and this mutation was universally associated with photosensitivity.
SCARB2 mutations were also identified as the cause of PME in several patients.
In 57 patients (27.9%), an underlying cause of PME was not determined. This group of patients included heterogeneous disorders characterized by variable clinical, neurophysiologic, and neuroimaging findings.
The age at disease onset for the group lacking an identifiable causative factor varied widely, from 1 to 38 years. In 19 patients, the appearance of cortical myoclonus marked the onset of the neurologic disorder alone, or with cerebellar signs or seizures. In the remaining 38 patients, signs of cortical myoclonus appeared years after cerebellar signs, tonic-clonic seizures, or cognitive dysfunction.
Two Disease Clusters Described
For patients with undetermined PMEs, the researchers identified 2 “clusters” that differed in terms of age at disease and myoclonus onset, but not in terms of MRI findings.
Cluster 1 (59.6%) consisted mainly of patients with an earlier onset of disease and myoclonus, psychomotor delay before PME presentation, more severe epilepsy, PSW elicited by intermittent photic stimulation, and the more common MRI findings of cerebral or cerebellar atrophy. All patients in cluster 1 had seizures other than myoclonic seizures, which recurred in 88% despite rational treatments.
Cluster 2 (40.4%) mainly included patients with a later onset and signs other than those of the classic PME phenotype. Only 47% had seizures other than myoclonic seizures.
At the time of the last observation, cognitive impairment was recorded in 76.6% of cluster 1 and 56.2% of cluster 2.
Personalization of Diagnostic Workup
The investigators determined important components of a “rational” diagnostic workup, as outlined below:
- In patients with early and typical PME presentations, CSTB, EPM2A, and EPM2B gene investigations should be a priority
- Because of the occurrence of severe illness in patients with variants of EPM1, molecular analysis of CSTB gene studies should also be done in patients with early-onset and polymorphic seizures
- The SCARB2 gene should be investigated in patients with phenotypic features resembling EPM1 but showing severe cortical myoclonus and preserved cognitive function
- Families of patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome should be carefully screened
- In patients with NCL, investigation of CLN genes should be considered.