Italian cohort of Lafora disease: Clinical features, disease evolution, and genotype-phenotype correlations

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:424

Article

Riva, Antonella^1,2  Orsini, Alessandro³  Scala, Marcello^2,4  Taramasso, Vittoria²  Canafoglia, Laura⁵  d'Orsi, Giuseppe⁶  Di Claudio, Maria Teresa⁶  Avolio, Carlo⁶  D'Aniello, Alfredo⁷  Elia, Maurizio⁸  Franceschetti, Silvana⁵  Di Gennaro, Giancarlo⁷  Bisulli, Francesca^9,10  Tinuper, Paolo^9,10  Tappata, Maria^9,10  Romeo, Antonino^11,12  Freri, Elena¹³  Marini, Carla¹⁴  Costa, Cinzia¹⁵  Sofia, Vito¹⁶  Ferlazzo, Edoardo¹⁷  Magaudda, Adriana¹⁸  Veggiotti, Pierangelo¹⁹  Gennaro, Elena²⁰  Pistorio, Angela⁴  Minetti, Carlo^2,4  Bianchi, Amedeo²¹  Striano, Salvatore²²  Michelucci, Roberto^9,10  Zara, Federico^1,2  Minassian, Berge Arakel^23,24  Striano, Pasquale^2,4 

[1] IRCCS Ist Giannina Gaslini, Unit Med Genet, Genoa, Italy

[2] Univ Genoa, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, Genoa, Italy

[3] Univ Pisa, Dept Clin & Expt Med, Pediat Clin, Pisa, Italy

[4] IRCCS Ist Giannina Gaslini, Pediat Neurol & Muscular Dis Unit, Genoa, Italy

[5] Fdn IRCCS Ist Neurol Carlo Besta, Milan, Italy

[6] SC Neurol Univ, Policlin Riuniti, Epilepsy Ctr, Foggia, Italy

[7] IRCCS NEUROMED, Pozzilli, Isernia, Italy

[8] IRCCS, Oasi Res Inst, Unit Neurol & Clin Neurophysiopathol, Troina, Italy

[9] IRCCS Ist Sci Neurol Bologna, Reference Ctr Rare & Complex Epilepsies EpiCARE, Epilepsy Ctr, Bologna, Italy

[10] Univ Bologna, Dept Biomed & Neuromotor Sci, Bologna, Italy

[11] Fatebenefratelli & Oftalmico Hosp, Dept Neurosci, Pediat Neurol Unit, Milan, Italy

[12] Fatebenefratelli & Oftalmico Hosp, Dept Neurosci, Epilepsy Ctr, Milan, Italy

[13] IRCCS Fdn, Carlo Besta Neurol Inst, Dept Pediat Neurosci, Milan, Italy

[14] United Hosp Ancona, Salesi Pediat Hosp, Child Neurol & Psychiat Unit, Ancona, Italy

[15] Univ Perugia, SM Misericordia Hosp, Dept Med, Neurol Clin, Perugia, Italy

[16] Univ Catania, Dipartimento GF Ingrassia, Catania, Italy

[17] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Catanzaro, Italy

[18] AOU Policlin G Martino, Dept Clin & Expt Med, Epilepsy Ctr, Messina, Italy

[19] Fdn IRCCS Policlin San Matteo, Dept Mother & Child Hlth, Pediat Unit, Pavia, Italy

[20] IRCCS Ist Giannina Gaslini, UOC Lab Genet Umana, Genoa, Italy

[21] San Donato Hosp, Dept Neurol & Epilepsy Ctr, Arezzo, Italy

[22] Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Naples, Italy

[23] Univ Texas Southwestern, Pediat Neurol, Dallas, TX USA

[24] Dallas Childrens Med Ctr, Dallas, TX USA

关键词: Lafora disease;    EPM2A;    EPM2B;    Epilepsy;    Progressive myoclonus;    Neurodegeneration;   

DOI  :  10.1016/j.jns.2021.117409

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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