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. 2023 Aug;64(8):e170-e176.
doi: 10.1111/epi.17634. Epub 2023 Jun 8.

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy

Elena Gardella  1   2   3   4 , Roberto Michelucci  5 , Hanne M Christensen  6 , Christina D Fenger  1 , Chiara Reale  1   7 , Patrizia Riguzzi  5 , Elena Pasini  5 , Luca Albini-Riccioli  8 , Valentina Papa  9 , Maria Pia Foschini  10 , Giovanna Cenacchi  9   11 , Francesca Furia  1   3 , Dragan Marjanovic  12 , Trine B Hammer  1   13 , Rikke S Møller  1   3   4 , Guido Rubboli  1   4   12   14
Affiliations

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy

Elena Gardella et al. Epilepsia. 2023 Aug.

Abstract

IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with IRF2BPL-related disorders previously reported. Our three probands, aged 28-40 years, harbored de novo nonsense variants in IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the "coiled-coil" domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME.

Keywords: IRF2BPL; ataxia; cerebellar signs; neurodevelopmental disorder; progressive myoclonus epilepsy.

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References

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