TY - JOUR

T1 - IRF2BPL as a novel causative gene for progressive myoclonus epilepsy

AU - Gardella, Elena

AU - Michelucci, Roberto

AU - Christensen, Hanne M.

AU - Fenger, Christina D.

AU - Reale, Chiara

AU - Riguzzi, Patrizia

AU - Pasini, Elena

AU - Albini-Riccioli, Luca

AU - Papa, Valentina

AU - Foschini, Maria Pia

AU - Cenacchi, Giovanna

AU - Furia, Francesca

AU - Marjanovic, Dragan

AU - Hammer, Trine B.

AU - Møller, Rikke S.

AU - Rubboli, Guido

N1 - Publisher Copyright: © 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - ataxia

KW - cerebellar signs

KW - IRF2BPL

KW - neurodevelopmental disorder

KW - progressive myoclonus epilepsy

U2 - 10.1111/epi.17634

DO - 10.1111/epi.17634

M3 - Journal article

C2 - 37114479

AN - SCOPUS:85161641927

VL - 64

SP - e170-e176

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 8

ER -