Abstracts

Rationale: Progressive myoclonus epilepsies (PMEs) are a clinically and genetically heterogeneous group of rare, genetic disorders with action myoclonus, tonic-clonic seizures, and ataxia being the core features. The paradigmatic form is Unverricht-Lundborg disease (ULD), where cognition is essentially preserved. ULD is caused by mutations in CSTB, but there are "ULD-like" phenotypes due to recently discovered (e.g., SCARB2, GOSR2) and other yet to be identified genes. Other PMEs with additional features, like dementia, are due to mutations in additional genes such as NHLRC1 and EPM2A that cause Lafora disease. The precise clinical diagnosis of PMEs is challenging and a significant proportion of PME cases remain without a molecular diagnosis. We aimed to further characterize the molecular genetic architecture of the unsolved PMEs. Methods: Through a worldwide collaboration we have collected 84 unrelated, molecularly unsolved patients with PME. The extent of previous genetic studies varied, but all cases were negative for CSTB mutations. We employed exome sequencing to identify the underlying genetic causes in these unsolved cases. We analyzed the data seeking pathogenic autosomal recessive or dominant/de novo, sex-linked and mitochondrial DNA mutations. Results: We molecularly solved 26 of 84 cases (31.0%). Thirteen cases were due to de novo mutations, one mutation was autosomal dominantly inherited, and 12 were autosomal recessively inherited. We identified a recurrent de novo missense mutation in a voltage-gated potassium channel, not previously linked to human disease, as a novel major cause for PME. Eleven unrelated exome-sequenced and two additional patients in a secondary cohort had this mutation. The patients with the mutation were clinically similar to ULD at onset; seizures began between 6-14 years, myoclonus was severe and cognition was relatively preserved. Progression usually necessitated a walking aid by late teenage. Ten patients had mutations in known PME genes, most with atypical presentations, leading to diagnoses of Lafora disease, sialidosis, neuronal ceroid lipofuscinosis, neuroserpinopathy and PME with AFG3L2 mutation. Finally, we identified a pathogenic mutation in PRNP adding chronic prion disease to the list of causes of PME and probably pathogenic mutations in SACS and TBC1D24 which have not previously been associated with PME. Conclusions: Exome sequencing is a powerful and unbiased way to dissect the molecular basis of heterogeneous disorders. Our data broaden the clinical spectrum associated with known PME genes and of those initially linked to other related disorders. Importantly, we identified one novel PME gene accounting for a large number of unsolved cases and established an important role for de novo mutations in PME. Together these findings will aid in molecular diagnostics, genetic counseling, and potential therapeutic interventions in PME.