Amador Maria-Del-Mar, Muratet François, Teyssou Elisa, Banneau Guillaume, Danel-Brunaud Véronique, Allart Etienne, Antoine Jean-Christophe, Camdessanché Jean-Philippe, Anheim Mathieu, Rudolf Gabrielle, Tranchant Christine, Fleury Marie-Céline, Bernard Emilien, Stevanin Giovanni, Millecamps Stéphanie
Institut du Cerveau et de la Moelle épinière (M.-D.-M.A., F.M., E.T., G.S., S.M.), ICM, Inserm U1127, CNRS UMR7225, Sorbonne Université; Département de Neurologie (M.-D.-M.A.), Assistance Publique Hôpitaux de Paris (APHP), Centre de Référence SLA Ile de France, Hôpital de la Pitié-Salpêtrière; Département de Génétique et Cytogénétique (G.B.), Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, APHP, Hôpital Pitié-Salpêtrière, Paris; Centre SLA-MNM (V.D.-B.), Service de Neurologie et Pathologie du Mouvement, Hôpital Roger Salengro, Centre Hospitalier Universitaire (CHU) de Lille; Service de Rééducation Neurologique Cérébrolésion (E.A.), Hôpital Swynghedauw, CHU de Lille; Service de Neurologie (J.-C.A., J.-P.C.), CHU de Saint-Etienne; Service de Neurologie (M.A., G.R., C.T., M.-C.F.), Hôpital de Hautepierre, CHU de Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (M.A., G.R., C.T.), Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (FMTS) (M.A., G.R., C.T.), Université de Strasbourg; Centre de Référence SLA de Lyon (E.B.), Hôpital Neurologique P. Wertheimer, Hospices Civils de Lyon, CHU de Lyon, Bron; and Ecole Pratique des Hautes Etudes (G.S.), Paris Sciences Lettres Research University, France.
Neurol Genet. 2019 Nov 13;5(6):e374. doi: 10.1212/NXG.0000000000000374. eCollection 2019 Dec.
The aim of this study was to evaluate whether mutations in , known to cause SPG18, a recessive hereditary spastic paraplegia (SP) responsible for the degeneration of the upper motor neurons leading to weakness and spasticity restricted to the lower limbs, could contribute to amyotrophic lateral sclerosis (ALS), a distinct and more severe motor neuron disease (MND), in which the lower motor neurons also profusely degenerates, leading to tetraplegia, bulbar palsy, respiratory insufficiency, and ultimately the death of the patients.
Whole-exome sequencing was performed in a large cohort of 200 familial ALS and 60 sporadic ALS after a systematic screening for hexanucleotide repeat expansion. variants identified by exome analysis were validated using Sanger analysis. Segregation of the identified variant with the disease was checked for all family members with available DNA.
Here, we report the identification of mutations in patients with a primarily SP evolving to rapid progressive ALS, leading to the death of the patients. These mutations segregated with the disease in a dominant (V168M) or recessive (D300V) manner in these families or were found in apparently sporadic cases (N125S).
Inheritance of mutations appears to be, within the MND spectrum, more complex that previously reported. These results expand the clinical phenotype of mutations to a severe outcome of MND and should be considered before delivering a genetic counseling to -linked families.
本研究旨在评估已知可导致SPG18（一种隐性遗传性痉挛性截瘫，可导致上运动神经元退化，进而引起仅局限于下肢的无力和痉挛）的 突变是否会导致肌萎缩侧索硬化症（ALS），这是一种不同的且更为严重的运动神经元疾病（MND），其中下运动神经元也会大量退化，导致四肢瘫痪、延髓麻痹、呼吸功能不全，并最终导致患者死亡。
在对200例家族性ALS和60例散发性ALS的大型队列进行六核苷酸重复扩增的系统筛查后，进行了全外显子组测序。通过外显子组分析鉴定出的 变体使用桑格分析进行验证。检查所有有可用DNA的家庭成员中鉴定出的变体与疾病的分离情况。
在此，我们报告在主要表现为SP并进展为快速进展性ALS的患者中鉴定出 突变，这些突变导致患者死亡。在这些家族中，这些突变以显性（V168M）或隐性（D300V）方式与疾病分离，或在明显散发的病例中发现（N125S）。
在MND范围内， 突变的遗传似乎比先前报道的更为复杂。这些结果将 突变的临床表型扩展至MND的严重结局，在为与 相关的家族提供遗传咨询之前应予以考虑。
