Rimoldi Martina, Magri Francesca, Meneri Megi, Gagliardi Delia, Ada Sansone Valeria, Albamonte Emilio, Ottoboni Linda, Comi Giacomo Pietro, Mercuri Eugenio, Tiziano Francesco Danilo, Ronchi Dario, Corti Stefania
Medical Genetic Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Neuromuscular and Rare Diseases Unit, IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Neurol Genet. 2025 Aug 27;11(5):e200286. doi: 10.1212/NXG.0000000000200286. eCollection 2025 Oct.
Spinal muscular atrophy 5q (SMA) is a motor neuron disorder caused by recessive pathogenic variants in the gene, which encodes the survival motor neuron (SMN) protein. While the majority of patients with SMA exhibit homozygous deletions in , a minority (2%-5%) of patients with SMA harbor an deletion plus a single nucleotide variant on the second allele, which can be identified through direct gene sequencing. The comprehensive characterization of patients with SMA is increasingly crucial considering emerging therapies and newborn screening initiatives.
Over the past 20 years, we confirmed a molecular diagnosis of SMA in 149 patients consisting of 138 postnatal and 11 prenatal cases, through a quantitative molecular approach (real-time PCR and/or multiplex ligation-dependent probe amplification) associated with direct sequencing.
We identified homozygous deletions in 142 probands (95%). The remaining 7 patients (5%) displayed heterozygous deletion in compound with a different molecular defect. Notably, 1 patient presented with an intronic variant necessitating mRNA transcript analysis, a process that extended the time to diagnosis.
The identification of small pathogenic variants in patients with SMA is of paramount importance for enhancing diagnosis and prognosis, deciphering response variations to existing treatments, and designing novel therapies tailored to address these genetic variants. We propose a paradigm shift from current guidelines, particularly for patients with a heterozygous deletion and a clinically compatible SMA phenotype, especially when reduced SMN transcript levels are evident. In such cases, expedited therapy initiation, including reversible treatments like nusinersen or risdiplam, is recommended without waiting for the completion of the molecular testing, thus minimizing delays in crucial therapeutic interventions.
5q脊髓性肌萎缩症（SMA）是一种由基因隐性致病变异引起的运动神经元疾病，该基因编码生存运动神经元（SMN）蛋白。虽然大多数SMA患者在基因中表现为纯合缺失，但少数（2%-5%）SMA患者在第二个等位基因上存在基因缺失加单核苷酸变异，可通过直接基因测序识别。考虑到新出现的治疗方法和新生儿筛查计划，对SMA患者进行全面特征分析变得越来越重要。
在过去20年中，我们通过与直接测序相关的定量分子方法（实时PCR和/或多重连接依赖探针扩增），对149例患者进行了SMA的分子诊断确认，其中包括138例产后病例和11例产前病例。
我们在142例先证者（95%）中鉴定出纯合基因缺失。其余7例患者（5%）表现为杂合基因缺失并伴有不同的分子缺陷。值得注意的是，1例患者出现内含子变异，需要进行mRNA转录本分析，这一过程延长了诊断时间。
识别SMA患者中的小致病变异对于提高诊断和预后、解读对现有治疗的反应差异以及设计针对这些基因变异的新疗法至关重要。我们建议从当前指南进行范式转变，特别是对于具有杂合基因缺失和临床兼容SMA表型的患者，尤其是当SMN转录水平明显降低时。在这种情况下，建议在不等待分子检测完成的情况下加快治疗启动，包括使用如诺西那生或利司扑兰等可逆性治疗，从而最大限度地减少关键治疗干预的延迟。
