Measuring Outcomes in Adults with Spinal Muscular Atrophy – Challenges and Future Directions – Meeting Report

Abstract

Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease which affects 1 in 6,000–10,000 live births, caused by loss of the survival motor neuron 1 gene (SMN1). A major focus of therapeutic developments has been on increasing the full-length SMN protein by increasing the inclusion of exon 7 in SMN2 transcripts, enhancing SMN2 gene expression, stabilizing the SMN protein or replacing the SMN1 gene. In June 2017, FDA and EMA have approved the antisense oligonucleotide Nusinersen as the first treatment for all SMA subtypes without age restriction. While prominent treatment effects have been observed in the earlier stages of the disease and in patients up to 15 years of age, there is only limited data from clinical trials in adult SMA patients. First real-world data from neuromuscular clinical centers suggest a therapeutic benefit of nusinersen with a favourable safety profile also in adult SMA patients: in several cases, relevant improvements of motor function is achieved, which might lead to enhanced autonomy in daily life activities and improved quality of life. Systematic follow-up of the motor status with validated instruments is crucial for an adequate monitoring of the therapeutic effects but most of the widely used scales and scores have been developed and evaluated for the pediatric population only. International neuromuscular experts have met in Frankfurt/Main, Germany in May 2019 to discuss relevant aspects of the diagnostic pathway and patient management in adult SMA. The recommendations and challenges in this patient population are discussed.

Muscle MRI in two SMA patients on nusinersen treatment: A two years follow-up

“…Recent studies have demonstrated the role of DTI in the detection and quantification of muscle fibers fat replacement [ 20 , Table 1 ]; FA is a parameter used to quantify the directional orientation of water molecules within the fibers; FA values are ranged between 0 and 1: in principle, when [ [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , [24] , [25] ] tissues are intact, water is forced to move in a specific direction and the FA value is close to 1; unexpectedly patients with severe fat replacement show positive correlation with FA values and negative correlation with Apparent Diffusion Coefficient (ADC); a possible explanation is the artificial increase of FA values in patients with more than 40–45% fat muscle infiltration [ 25 ]. In our cases DTI showed that nusinersen treatment may have a positive effect on size, length and organization of fiber tracts raising the potential neurogenic rescue even in long-standing chronic SMA patients.…”

“…The results from the pivotal [4] and more recent trials [5] with intrathecal nusinersen treatment, as well as the results from real world data [6], have created great expectations in older patients having long-lasting muscular atrophy and weakness; in fact there is growing evidence that treatment is at the very least stabilizing or providing some degree of improvement in motor function [7]. However, there are still some critical issues in understanding results in adults, including the lack of natural history data and outcome measures to monitor disease progression [8]. Furthermore limited data are available on muscle degeneration and neurophysiology over time, and this is often a limiting factor in interpreting the impact of any treatment in these patients.…”

A Canadian Adult Spinal Muscular Atrophy Outcome Measures Toolkit: Results of a National Consensus using a Modified Delphi Method

“…The national OM toolkit can lead to improved monitoring and larger, robust datasets which are of great importance in the adult SMA population [1,2]. Operationalizing a national toolkit with a patient registry such as the Canadian Neuromuscular Disease Registry (CNDR) [11] provides a valuable data resource for clinicians and researchers to facilitate further insight into SMA [13].…”

“…Due to the heterogenous nature of disease progression and multi-system involvement, this toolkit shall include a diverse set of OM which capture, but are not limited to, patient reported outcome measures (PROM), and domains of gross motor function, fine motor function, quality of life, and respiratory function. McGraw et al and Sansone et al both advocate for the inclusion of OM, which assess a wide range of activities and capture meaningful clinical changes [12,13]. To date, few efforts have been made to derive consensus on which OM should be used to assess adult SMA.…”

Design of a Non-Interventional Study to Validate a Set of Patient- and Caregiver-Oriented Measurements to Assess Health Outcomes in Spinal Muscular Atrophy (SMA-TOOL Study)

“…Different therapeutic approaches such as antisense oligonucleotides, small molecules or gene therapy show increased life expectancy and motor and respiratory improvements [7]. However, it has become increasingly apparent that outcome measures used in clinical trials are inadequate to assess the full range of disease severity in real life, both from the patients' and caregivers' perspective and from the clinicians' perspective [8][9][10][11][12][13][14][15][16].…”