Assessment of Bulbar Function in Adult Patients with 5q-SMA Type 2 and 3 under Treatment with Nusinersen.

Svenja Brakemeier,Andreas Thimm,Tim Hagenacker,Juan Munoz-Rosales,Andreas Totzeck,Christoph Kleinschnitz,Kathrin Kizina,Benjamin Stolte

doi:10.3390/brainsci11091244

Abstract

The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

Highlights

The hereditary autosomal recessive neuromuscular disorder, 5q-associated spinal muscular atrophy (SMA), causes progressive weakness of the trunk, limb, ventilatory and bulbar muscles
The most important disease modifier is the SMN2 gene, which differs in only five base pairs from survival motor neuron 1 (SMN1), leading to the expression of a truncated
Feeding disability is prevalent in approximately one-third of SMA patients [5]

Summary

Introduction

The hereditary autosomal recessive neuromuscular disorder, 5q-associated spinal muscular atrophy (SMA), causes progressive weakness of the trunk, limb, ventilatory and bulbar muscles. The most common cause is a homozygous deletion or compound heterozygosity with deletion and point mutation in the survival motor neuron 1 (SMN1) gene [1], resulting in reduced expression of the corresponding SMN protein and consequent degeneration of spinal motor neurons [2]. Onset age and the best motor milestone achieved characterize different historical disease phenotypes, with types 0–4 corresponding to decreasing motor function [4]. In the “pretherapeutic” era, SMA type 1 patients suffered from symptoms during early infancy and most often died before the age of two without mechanical ventilation due to severe bulbar and respiratory impairment, type 2 patients typically achieved the ability to sit, and type 3 patients achieved the ability to walk independently and had a normal life expectancy [6]. The natural course of the disease is chronic and progressive with a loss of motor milestones over time [7]

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