Ostrozovicova Miriam, Tamas Gertrud, Dušek Petr, Grofik Milan, Han Vladimir, Holly Petr, Jech Robert, Kalinova Katarina, Klivenyi Peter, Kovacs Norbert, Kulcsarova Kristina, Kurca Egon, Lackova Alexandra, Lee Hamin, Lewis Patrick, Magocova Veronika, Marekova Maria, Murphy David, Necpal Jan, Pinter David, Rabajdova Miroslava, Růžička Evžen, Serranova Tereza, Smilowska Katarzyna, Soos Krisztina, Straka Igor, Svorenova Tatiana, Valkovic Peter, Zarubova Katerina, Gdovinova Zuzana, Houlden Henry, Rizig Mie, Skorvanek Matei
Pavol Jozef Safarik University and University Hospital of L. Pasteur and UCL Queen Square Institute of Neurology.
Semmelweis University.
Res Sq. 2024 May 29:rs.3.rs-4378197. doi: 10.21203/rs.3.rs-4378197/v1.
Pathogenic variants in are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.
[基因名称]中的致病变异是帕金森病（PD）最常见的遗传风险因素之一。最近，鲜为人知的p.L1795F变异被提出是PD的一个强大遗传风险因素，然而，目前文献中还缺乏更多相关家族病例。在CEGEMOD联盟中，对来自中欧9个运动障碍中心的多中心早发和家族性PD队列（n = 220），利用全外显子组测序数据筛查罕见的[基因名称]变异。我们鉴定出4例携带杂合p.L1795F变异的PD病例。所有4例均表现为运动不能-强直型PD表型，伴有严重运动波动的早发，2例接受左旋多巴肠凝胶（LCIG）治疗，2例植入丘脑底核深部脑刺激（STN DBS）；所有4例晚期治疗对运动波动的效果均不理想。我们的数据还表明，与研究较多的p.G2019S相比，p.L1795F可能是中欧目前已知最常见的致病性亮氨酸重复激酶2（LRRK2）变异，在中欧队列的PD病例中占1.81%，在家族性PD病例中占3.23%。连同正在进行的LRRK2抑制剂临床试验，这一发现强调了PD基因研究中迫切需要更多的种族多样性。
