Milan, Italy – A study coordinated by Stefania Corti and Dario Ronchi of the Dino Ferrari Center at the University of Milan and the Policlinico Hospital of Milan has identified and characterized rare genetic variants in patients with spinal muscular atrophy (SMA), a serious, rare neuromuscular disease that damages motor neurons and affects approximately 1 in 6,000 to 10,000 people, causing progressive muscle weakness. The research—led by Martina Rimoldi and published in Neurology Genetics—analyzed 149 SMA patients over the past 20 years, identifying single nucleotide variants in the SMN1 gene, associated with heterozygous deletions, in 5% of cases. The authors consider this discovery particularly relevant in the era of new gene therapies for SMA, as comprehensive genetic characterization is essential for accessing treatments and understanding variations in therapeutic response.
“The identification of these rare variants is crucial to improving the diagnosis and prognosis of patients with SMA,” says Corti, co-lead of the study. “With the advent of innovative therapies such as nusinersen, onasemnogene abeparvovec, and risdiplam, an accurate and timely genetic diagnosis can make a difference in a patient’s treatment journey,” he emphasizes. “Our integrated diagnostic approach, which combines quantitative techniques such as real-time PCR and direct sequencing, represents a paradigm shift in current guidelines,” remarks Ronchi, co-lead of the study. “We recommend considering early initiation of therapy in patients with a heterozygous SMN1 deletion and a compatible clinical phenotype, without waiting for the completion of all molecular testing. It is essential to emphasize that currently, patients with rare variants escape neonatal screening, potentially delaying treatment. This need must be addressed with timely comprehensive analyses in the future.”
The study was conducted with the support of the Smaldone family in memory of Mrs. Maria Domenica Smaldone, whose contribution made this important research possible, which will have a tangible impact on the lives of many SMA patients and their families, according to a statement.
The study has important therapeutic implications, the authors assure. Patients with missense variants such as p.(Tyr130Cys)—they explain—present milder phenotypes and may respond differently to available therapies compared to patients with nonsense variants. Furthermore, the identification of modifying variants in the Smn2 gene, such as c.859G>C and c.835-44A>G, allows for personalized treatment, adapting the type and intensity of therapy based on the specific genetic profile; predicting therapeutic response, because the identified variants may influence the efficacy of nusinersen and risdiplam, which act by modulating Smn2 splicing; optimizing the timing of intervention, initiating reversible treatments such as nusinersen or risdiplam immediately in suspected cases, without waiting for complete genetic characterization; and developing new therapeutic strategies. Rare variants, in fact, may require specific therapeutic approaches or drug combinations.
“These modifying variants help us better understand the phenotypic variability observed in patients and can guide personalized treatment decisions,” comments Giacomo P. Comi, director of the Dino Ferrari Center. “The presence of variants such as c.859G>C in homozygous form can significantly improve prognosis and influence the choice of the most appropriate treatment.” Among the most significant findings, the statement specifies, is the identification of patients with Smn1/Smn2 hybrid genes, a rare condition that can elude standard screening but has specific therapeutic implications, as demonstrated by the positive response to treatment with nusinersen in one of the study patients.
The research, the researchers conclude, confirms the importance of newborn screening for SMA, already available in several Italian regions, and the need to implement advanced molecular diagnostic approaches to identify even the rarest forms of the disease that elude traditional screening. Early diagnosis is crucial because treatments are more effective if started before symptoms appear; gene therapies such as onasemnogene abeparvovec have optimal administration windows; and motor neuron degeneration is irreversible, making timely intervention crucial.
Contact
Stefania Corti – Neurology Professor