The “wait and see” approach to treatment in children with expected spinal muscular atrophy puts patients at risk of irreversible symptoms, according to new guidelines.
Spinal muscular atrophy is the most common form of neurodegenerative disease in children and is caused by defects in the SMN1 gene. Spinal muscular atrophy patients currently have access to three approved disease-modifying therapies. These treatments are most effective when administered early in the progression of the disease.
Previous guidelines on the condition have suggested a “watchful waiting” strategy for treating infants who have two copies of the SMN2 gene. Multiple copies of SMN2 may compensate for the defect of SMN1, making it possible for the first symptoms of spinal muscular atrophy to appear later in childhood and even in adulthood.
The study has been published in the Journal of Neuromuscular Diseases.
Spinal muscular atrophy treatment has been subject to debate
The researchers found that a surprisingly large proportion of infants with four copies of the SMN2 gene, who decided to postpone treatment, showed the first signs of the disease between the ages of one and a half and four years.
“The discussion in the spinal muscular atrophy treatment community about the appropriate timing of therapy always includes the possibility that the disease might not manifest until adulthood, and many years of treatment could be avoided,” explained lead investigator Dr Katharina Vill, Department of Paediatric Neurology and Developmental Medicine and LMU Centre for Children.
“However, there is a lack of detailed knowledge about the type and timing of initial symptoms. With the availability of new medications there is an urgent need to gain more knowledge about the ‘how and when’ of spinal muscular atrophy onset,” she added.
Spinal muscular atrophy is caused by a biallelic defect in the SMN1 gene, however, the closely related gene, SMN2, can improve this deficiency.
Most individuals with two or three copies of SMN2 begin to show symptoms in the first months of life. Patients with four or more copies of the gene tend to develop symptoms later in life, they also generally have milder symptoms.
The guidelines suggesting the “watchful waiting approach, were revised in 2020 to recommend pre-symptomatic treatment. However, no suggestion was made regarding when to begin therapy.
The study examined 18 children born between January 2018 and January 2021. Long-term follow-up was available for 15 children. All the children learned to sit independently and walk with assistance at the ages expected in healthy children.
New guidelines have yielded positive results
Swallowing and feeding were normal were also normal in all the participating children. In 2020, when the treatment guidelines were changed, pre-symptomatic treatment was recommended to all patient families in the study.
“The change in treatment strategy midway through the pilot led to different parental decisions regarding how to proceed, particularly for children born in the first two years of the pilot. These families had initially been told that a wait-and-see strategy was acceptable, and several wanted to stick with it,” said Dr Vill.
Out of the 15 patient families, eight decided to start pre-symptomatic therapy with Nusinersen or Risdiplam. None of the children using these treatments showed any symptoms of spinal muscular atrophy.
The remaining seven families who did not start pre-symptomatic therapy were closely monitored by the researchers. Out of these patients, five showed disease onset before the age of four years old.
The researchers accept that initiation of early treatment is more expensive for the general healthcare system, but they highlight that spinal muscular atrophy causes a high economic impact in terms of health and social costs. The research team also emphasised that the quality of life for the affected children is extremely impaired.
“While the sample size is small, a very high number of children (five out of seven) became symptomatic in the first four years of life, with at least one showing irreversible symptoms. The proportion was much higher than expected,” Dr Vill said.
“Children with four copies of SMN2 have the most favourable genetic conditions for a good outcome under therapy. The ‘wait and see’ strategy might entail the risk of irreversible deficits for these patients. We recommend encouraging parents to start a treatment regimen early in childhood. If the parents decide to wait, follow-up should be performed with extreme care,” she concluded.