Abstract
Spinal muscular atrophy (SMA) is currently classified into five different subtypes, from the most severe (type 0) to the mildest (type 4) depending on age at onset, best motor function achieved, and copy number of the SMN2 gene. The two recent approved treatments for SMA patients revolutionized their life quality and perspectives. However, upon treatment with Nusinersen, the most widely administered therapy up to date, a high degree of variability in therapeutic response was observed in adult SMA patients. These data, together with the lack of natural history information and the wide spectrum of disease phenotypes, suggest that further efforts are needed to develop precision medicine approaches for all SMA patients. Here, we compile the current methods for functional evaluation of adult SMA patients treated with Nusinersen. We also present an overview of the known molecular changes underpinning disease heterogeneity. We finally highlight the need for novel techniques, i.e., -omics approaches, to capture phenotypic differences and to understand the biological signature in order to revise the disease classification and device personalized treatments.
Highlights
Spinal muscular atrophy (SMA) is a neurodegenerative disease affecting motoneurons (MN) in the brainstem and spinal cord caused by the homozygous mutation of the Survival of Motor Neuron 1 (SMN1) gene [1]
This section of the review will focus on functional outcomes reported to reliably assess the Nusinersen response in SMA adult patients
The discovery of several disease modifier genes, starting with Survival of Motor Neuron 2 (SMN2) [1], and epigenetic factors [92] has revolutionized the traditional classification and account for a wider complexity. This aspect will further change in light of the recently approved therapies that are modifying the course of the disease and increasing patients’ survival
Summary
Spinal muscular atrophy (SMA) is a neurodegenerative disease affecting motoneurons (MN) in the brainstem and spinal cord caused by the homozygous mutation of the Survival of Motor Neuron 1 (SMN1) gene [1]. Treatment with Nusinersen showed very promising results in young type 1 patients [14,15] and some positive effects in type 2 and 3 patients (no type 4 patients have been enrolled in clinical trials to date) [18,19,20] The latter studies which include adult SMA patients (>18 years old) showed that their response to Nusinersen, evaluated as motor function improvement, was highly variable, with 40–50% of responders at best [18,19,20]. An in-depth analysis of both functional outcomes’ evaluation and molecular biomarkers, would help determine the differences that define the wide spectrum of clinical features among SMA patients and their disparate response to treatment Efforts in this direction could lead to the development of personalized medicine approaches in the future
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