Clinical and motor functional evaluation of patients with bi-allelic disease-causing variants in SMN1 gene and two copies of SMN2 treated in the pre-symptomatic stage

Background: Spinal Muscular Atrophy linked to chromosome 5 (SMA-5q) is a rare genetic disorder that leads to progressive muscle weakness and atrophy. Patients with SMA-5q can be diagnosed in a pre-symptomatic phase through newborn screening or when there is a sibling with SMA-5q. Early diagnosis enables prompt intervention and improves patient outcomes. Objective: To describe the experience of a specialized neuromuscular center in the treatment of pre-symptomatic SMA-5 patients and to analyze the clinical aspects during a follow-up period up to 57 months (range 1-57; average 16.3 months). Methods: Six SMA-5q patients started treatment in a pre-symptomatic phase and have been monitored in a neuromuscular center specialized in motor neuron diseases, from August 2019 to May 2024. Neurological examination, motor scale and respiratory assessments have been performed by a multidisciplinary team at the diagnosis, every 3 months during the first year of follow-up and every 6 months thereafter. Information on adverse effects have also been collected. Results: All six pre-symptomatic patients had homozygous deletion in SMN1 gene and 2 copies of SMN2. Four patients were diagnosed by newborn screening and have been followed from 1 to 10 months old (mean 5.75 months). They started risdiplam between 25 and 29 days of age (mean 26.75 days). One of them started risdiplam recently and remains asymptomatic at 2 months old, but still does not have a comparative motor scale. The other three risdiplam-treated patients achieved maximum score on Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) at 4 months old. All risdiplam-treated patients have adequate development for their age, but two of them switched treatment to zolgensma at 6 and 9 months old because it is a single dose therapy. Two patients were younger siblings of SMA-5q patients and had an intrauterine diagnosis. They started nusinersen between 2 and 7 days old (mean 4.5 days) and have been followed from 18 to 57 months (mean 37.5 months). They both changed treatment to zolgensma because they were experiencing weakness in their limbs. One of them received zolgensma at 5 months old, reached maximum CHOP INTEND score at 6 months old and started walking at 1 year and 4 months old. The other patient received zolgensma at 1 year and 6 months old, reached maximum CHOP INTEND score at 1 year old and started walking at 1 year and 10 months old. None of the patients presented dysphagia or need for ventilatory support. Patients who received zolgensma reported these adverse effects: one had fever and vomiting, one thrombocytopenia and two elevated hepatic transaminases. One patient who received risdiplam had anemia. Conclusion: The positive outcomes observed in our cohort underscore the importance of early diagnosis and intervention. By demonstrating consistency with clinical trials, our findings further support the efficacy of current treatment approaches for SMA-5q.