Riva Antonella, Orsini Alessandro, Scala Marcello, Taramasso Vittoria, Canafoglia Laura, d'Orsi Giuseppe, Di Claudio Maria Teresa, Avolio Carlo, D'Aniello Alfredo, Elia Maurizio, Franceschetti Silvana, Di Gennaro Giancarlo, Bisulli Francesca, Tinuper Paolo, Tappatà Maria, Romeo Antonino, Freri Elena, Marini Carla, Costa Cinzia, Sofia Vito, Ferlazzo Edoardo, Magaudda Adriana, Veggiotti Pierangelo, Gennaro Elena, Pistorio Angela, Minetti Carlo, Bianchi Amedeo, Striano Salvatore, Michelucci Roberto, Zara Federico, Minassian Berge Arakel, Striano Pasquale
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.
Pediatric Clinic, Department of Clinical and Experimental Medicine, Università di Pisa, Pisa, Italy.
J Neurol Sci. 2021 May 15;424:117409. doi: 10.1016/j.jns.2021.117409. Epub 2021 Mar 20.
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.
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.
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.
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.
拉福拉病（LD）的特征为进行性肌阵挛、难治性癫痫和认知功能恶化。这种复杂的神经退行性疾病由EPM2A/EPM2B基因的致病变异引起，该基因编码两种重要的糖原代谢酶，即拉福林和malin。目前缺乏长期随访数据。我们描述了一组26例意大利患者的临床特征和基因检测结果，并进行了长期临床随访。
通过直接基因测序或靶向重测序基因panel鉴定EPM2A/EPM2B致病变异患者。采用简化残疾量表评估疾病进展、运动功能和智力表现。采用马高达量表对自发性/动作性肌阵挛严重程度进行评分。
年龄范围为12.2 - 46.2岁（平均：25.53±9.14）。发病年龄为10至22岁（平均：14.04±2.62）。平均随访时间为11.48±7.8年。26例患者中有12例（46%）保留行走能力，13例（50%）保留言语功能。在9例（35%）EPM2A患者中的1例（11%）以及17例（65%）EPM2B患者中的6例（35%）中，观察到随访≥4年后疾病进展较慢且保留行走和言语功能。7例（41.2%）EPM2B患者的随访时间>10年，其中2例携带纯合p.(D146N)致病变异。
本研究支持携带EPM2A突变的患者总体疾病预后较差，行走和言语功能严重恶化。然而，在携带p.(D146N)致病变异的EPM2B患者中观察到致残症状出现延迟，这表明潜在的致病变异可能仍会影响LD的严重程度。
