Antonella Riva1, Alessandro Orsini2, Marcello Scala3, Vittoria Taramasso4, Laura Canafoglia5, Giuseppe d'Orsi6, Maria Teresa Di Claudio6, Carlo Avolio6, Alfredo D'Aniello7, Maurizio Elia8, Silvana Franceschetti5, Giancarlo Di Gennaro7, Francesca Bisulli9, Paolo Tinuper9, Maria Tappatà9, Antonino Romeo10, Elena Freri11, Carla Marini12, Cinzia Costa13, Vito Sofia14, Edoardo Ferlazzo15, Adriana Magaudda16, Pierangelo Veggiotti17, Elena Gennaro18, Angela Pistorio19, Carlo Minetti3, Amedeo Bianchi20, Salvatore Striano21, Roberto Michelucci9, Federico Zara22, Berge Arakel Minassian23, Pasquale Striano24. 1. Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy. Electronic address: antonella.riva@edu.unige.it. 2. Pediatric Clinic, Department of Clinical and Experimental Medicine, Università di Pisa, Pisa, Italy. 3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy; Pediatric Neurology and Muscular Disease Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy. 4. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy. 5. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 6. Epilepsy Centre-S.C. Neurologia Universitaria, Policlinico Riuniti, Foggia, Italy. 7. IRCCS "NEUROMED", Pozzilli, Isernia, Italy. 8. Unit of Neurology and Clinical Neurophysiopathology, Oasi Research Institute, IRCCS, Troina, Italy. 9. IRCCS Istituto delle Scienze Neurologiche di Bologna, Epilepsy Center (Reference Center for Rare and Complex Epilepsies - EpiCARE), Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. 10. Pediatric Neurology Unit and Epilepsy Center, Department of Neuroscience, "Fatebenefratelli e Oftalmico" Hospital, Milano, Italy. 11. Department of Pediatric Neuroscience, IRCCS Foundation, Carlo Besta Neurological Institute, Milan, Italy. 12. Child Neurology and Psychiatric Unit, Salesi Pediatric Hospital, United Hospitals of Ancona, Ancona, Italy. 13. Neurology Clinic, S.M. Misericordia Hospital, Departement of Medicine, University of Perugia, Perugia, Italy. 14. Dipartimento "G.F Ingrassia", Università degli Studi di Catania, Catania, Italy. 15. Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Germaneto, Catanzaro, Italy. 16. Epilepsy Center, Department of Clinical and Experimental Medicine, AOU Policlinico "G. Martino", Messina, Italy. 17. Department of the Mother and Child Health, Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 18. UOC Laboratorio di Genetica Umana, IRCCS Istituto Giannina Gaslini, Genova, Italy. 19. Pediatric Neurology and Muscular Disease Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy. 20. Department of Neurology and Epilepsy Centre, San Donato Hospital, Arezzo, Italy. 21. Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, Napoli, Italy. 22. Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy. 23. Pediatric Neurology, University of Texas Southwestern and Dallas Children's Medical Centre, Dallas, TX, USA. 24. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy; Pediatric Neurology and Muscular Disease Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy. Electronic address: strianop@gmail.com.
Abstract
BACKGROUND: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up. METHODS: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale. RESULTS: Age range was 12.2-46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant. CONCLUSIONS: This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.
BACKGROUND: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up. METHODS: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale. RESULTS: Age range was 12.2-46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant. CONCLUSIONS: This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.
Authors: E M Chan; D E Bulman; A D Paterson; J Turnbull; E Andermann; F Andermann; G A Rouleau; A V Delgado-Escueta; S W Scherer; B A Minassian Journal: J Med Genet Date: 2003-09 Impact factor: 6.318
Authors: Matthew S Gentry; Zaid Afawi; Dustin D Armstrong; Antonio Delgado-Escueta; Y Paul Goldberg; Tamar R Grossman; Joan J Guinovart; Frank Harris; Thomas D Hurley; Roberto Michelucci; Berge A Minassian; Pascual Sanz; Carolyn A Worby; Jose M Serratosa Journal: Epilepsy Behav Date: 2020-01-10 Impact factor: 2.937
Authors: Subramaniam Ganesh; Antonio V Delgado-Escueta; Toshimitsu Suzuki; Silvana Francheschetti; Concetta Riggio; Giuiliano Avanzini; Adrian Rabinowicz; Saeed Bohlega; Julia Bailey; Maria E Alonso; Astrid Rasmussen; Alfredo E Thomson; Adriana Ochoa; Aurelio J Prado; Marco T Medina; Kazuhiro Yamakawa Journal: Hum Mol Genet Date: 2002-05-15 Impact factor: 6.150
Authors: B A Minassian; J R Lee; J A Herbrick; J Huizenga; S Soder; A J Mungall; I Dunham; R Gardner; C Y Fong; S Carpenter; L Jardim; P Satishchandra; E Andermann; O C Snead; I Lopes-Cendes; L C Tsui; A V Delgado-Escueta; G A Rouleau; S W Scherer Journal: Nat Genet Date: 1998-10 Impact factor: 38.330