Meyer Thomas, Schumann Peggy, Grehl Torsten, Weyen Ute, Petri Susanne, Rödiger Annekathrin, Steinbach Robert, Grosskreutz Julian, Bernsen Sarah, Weydt Patrick, Wolf Joachim, Günther René, Vidovic Maximilian, Baum Petra, Metelmann Moritz, Weishaupt Jochen H, Streubel Berthold, Kasper David C, Koc Yasemin, Kettemann Dagmar, Norden Jenny, Schmitt Philipp, Walter Bertram, Münch Christoph, Spittel Susanne, Maier André, Körtvélyessy Péter
Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Ambulanzpartner Soziotechnologie APST GmbH, Berlin, Germany.
Amyotroph Lateral Scler Frontotemporal Degener. 2025 Feb;26(1-2):162-171. doi: 10.1080/21678421.2024.2401131. Epub 2024 Sep 13.
To report the frequency of pathogenic gene variants in a screening program in amyotrophic lateral sclerosis (ALS), and the clinical practice of transition to an expanded access program (EAP) of tofersen treatment.
From October 2021 to February 2024, at 11 ALS centers in Germany genetic testing for , , and was performed. Patients were offered to opt for notification either about all genetic variants or variants relevant for tofersen therapy. The transition to the EAP with tofersen was assessed.
1935 patients were screened (94.7% sporadic ALS). 48.8% ( = 928) opted for notification of treatment-relevant information. Genetic variants were found as follows: (likely) pathogenic variants (class 4/5) 1.8% ( = 34), variants of unknown significance (class 3) 0.8% (= 16), (class 4/5) 0.9% (= 17) (class 4/5) 1.3% ( = 25), hexanucleotide repeat expansion 7.0% (= 135). In -ALS (encompassing class 3-5 variants, = 50), 68.0% ( = 34) reported a negative family history. 74.0% (= 37) of -ALS patients - which represent 1.9% of all participants of the screening program - were transitioned to tofersen. Median duration from start of genetic testing to treatment was 94 days (57 to 295 days). Eight patients declined treatment whereas five individuals died before initiation of therapy.
The finding of variants in patients with a negative family history underscores the need for a broad genetic screening in ALS. In -ALS, the treatment option with tofersen was mostly utilized. The wide range in the transition time to tofersen calls for a -ALS management program.
报告肌萎缩侧索硬化症（ALS）筛查项目中致病基因变异的频率，以及向托非生治疗扩展准入项目（EAP）过渡的临床实践情况。
2021年10月至2024年2月，在德国的11个ALS中心对[具体基因名称未给出]、[具体基因名称未给出]、[具体基因名称未给出]和[具体基因名称未给出]进行了基因检测。患者可选择接收关于所有基因变异或与托非生治疗相关变异的通知。评估了向托非生EAP的过渡情况。
共筛查了1935例患者（94.7%为散发性ALS）。48.8%（n = 928）选择接收与治疗相关信息的通知。发现的基因变异情况如下：（可能）致病变异（4/5类）1.8%（n = 34），意义未明的变异（3类）0.8%（n = 16），[具体基因名称未给出]（4/5类）0.9%（n = 17），[具体基因名称未给出]（4/5类）1.3%（n = 25），[具体基因名称未给出]六核苷酸重复扩增7.0%（n = 135）。在[具体基因名称未给出]-ALS（包括3 - 5类变异，n = 50）中，68.0%（n = 34）报告家族史阴性。74.0%（n = 37）的[具体基因名称未给出]-ALS患者（占筛查项目所有参与者的1.9%）过渡到了托非生治疗。从基因检测开始到治疗的中位时间为94天（57至295天）。8例患者拒绝治疗，5例患者在治疗开始前死亡。
在家族史阴性的患者中发现[具体基因名称未给出]变异凸显了在ALS中进行广泛基因筛查的必要性。在[具体基因名称未给出]-ALS中，托非生的治疗选择得到了广泛应用。向托非生过渡时间的广泛差异需要一个[具体基因名称未给出]-ALS管理项目。
