Neurodevelopmental issues emerging as patients live longer
About 43% of children with early-onset spinal muscular atrophy (SMA) were reported to have neurodevelopmental problems in a recent international survey of clinicians.
Such issues, including intellectual disabilities, speech delays, or problems with social communication and interaction, have not historically been considered a key part of the disease presentation, but have come to light as these young patients are now living longer with better treatments.
“The monitoring and investigation of these non-motor comorbidities [co-existing conditions] will be crucial to improve the therapeutic efficiency of treatments in SMA,” researchers wrote.
The findings were published as a letter to the editor, titled “The emerging spectrum of neurodevelopmental comorbidities in early-onset Spinal Muscular Atrophy,” in the European Journal of Paediatric Neurology.
SMA type 1, the most common form of SMA, is also one of the most severe. With symptoms usually evident in the first six months of life, these patients typically do not live past age 2 when left untreated.
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Early-onset SMA patients living longer with arrival of DMTs
However, within the last decade, the emergence of disease-modifying therapies (DMTs) for SMA has changed the landscape. Patients with early-onset SMA are now living longer and achieving motor milestones, like sitting, standing, and walking with support, that have never been reached before in this population.
Still, less is known about the neurodevelopment of these children as they age. Recent research has indicated that children with SMA type 1 may score below average on tests of cognition and communication.
While such findings are in contrast to the traditional view that SMA is purely a disease affecting motor and muscle function, they are “in line with what many clinicians are observing now that most of these children are on treatment and therefore survive longer and can be followed in their overall development,” the researchers wrote.
To learn more, the researchers sent a survey to clinical practices worldwide to better understand the neurodevelopment of children with early-onset SMA. The survey, sent out between June 2022 and January 2023, included 32 clinical sites in 13 countries.
Semi-structured and open-ended questions asked about the occurrence of neurodevelopmental problems in early-onset SMA patients, including developmental delays, intellectual disabilities, speech problems, social deficits, and autism spectrum disorder.
Whether it is a matter of nature or nurture or a combination of both, this international survey highlights the need to monitor and investigate more in depth the cognitive and social-communication development of babies with early onset SMA as part of their standard of care.
Neurodevelopmental problems reported in 272 of 624 patients
Overall, neurodevelopmental problems were reported in 272 out of 624 patients, who had a mean age of 57 months, or about 4.7 years.
All but two of these 272 children were diagnosed with SMA type 1, whereas two patients had been diagnosed with SMA presymptomatically. All were treated with SMA-targeted DMTs starting at a median age of 5.6 months.
While 84 children had undergone a formal assessment to diagnose their neurodevelopmental issues, the problems for most children, the remaining 188, were informally observed by parents or clinicians. Most children were ultimately referred for rehabilitation services.
“Although in the present survey we cannot exclude an under- or over-representation of the real prevalence of neurodevelopmental comorbidities, as not all patients underwent a formal neurodevelopmental assessment, this represents an alarming 43% of the whole population of children with early onset SMA,” the researchers wrote.
SMA is characterized by a lack of the SMN protein. Previous research has indicated that levels of SMN are normally highest in early development, when it is presumed to be critical for brain development. DMTs for SMA in various ways aim to boost SMN production.
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Most children started treatment after symptom onset
Most children here were started on treatment after their symptoms had already emerged, “raising the question whether severely reduced levels of SMN during a critical period of early brain development could be responsible for these novel neurodevelopmental phenotypes [characteristics],” the researchers wrote.
It is also possible that delayed motor development or increased time spent in the hospital early in life might affect communicative and social development.
“Whether it is a matter of nature or nurture or a combination of both, this international survey highlights the need to monitor and investigate more in depth the cognitive and social-communication development of babies with early onset SMA as part of their standard of care, in order to provide guidance to caregivers on how to detect difficulties early and optimize development,” the researchers concluded.
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