Natural History of Mandibular Function in Spinal Muscular Atrophy Types 2 and 3

Background: Hereditary proximal spinal muscular atrophy (SMA) is characterized by abnormal alpha motor neuron function in brainstem and spinal cord. Bulbar dysfunction, including limited mouth opening, is present in the majority of patients with SMA but it is unknown if and how these problems change during disease course. Objective: In this prospective, observational, longitudinal natural history study we aimed to study bulbar dysfunction in patients with SMA types 2 and 3. Methods: We included 44 patients with SMA types 2 and 3 (mean age was 33.6 (95% CI 28.4;38.9) and re-examined them after on average 4 years. None were treated with SMN-modulating treatments before or during the course of this study. Longitudinal assessments included a questionnaire on mandibular and bulbar function, the Mandibular Function Impairment Questionnaire (MFIQ), and a clinical examination of masticatory performance, maximum voluntary bite force, and mandibular movements including the active maximal mouth opening. Results: We found significant higher MFIQ scores and a significant decrease of all mandibular movements in patients with SMA type 2 (p < 0.001), but not in SMA type 3. Masticatory performance and maximum voluntary bite force did not change significantly. Mean reduction of active maximal mouth opening at follow-up was 3.5 mm in SMA type 2 (95%CI: 2.3; 4.7, p < 0.001). SMA type 2 was an independent predictor for a more severe reduction of the mouth opening (β = –2.0 mm (95%CI: –3.8; –0.1, p = 0.043)). Conclusions: Bulbar functions such as mandibular mobility and active maximum mouth opening decrease significantly over the course of four years in patients with SMA type 2

Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

Objective To investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity. Methods We performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1-4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood. Results We identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing. Conclusions PLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity

Exploring functional strength changes during nusinersen treatment in symptomatic children with SMA types 2 and 3

The Hammersmith Functional Motor Scale-Expanded (HFMSE) is a validated outcome measure for monitoring changes in functional strength in patients with spinal muscular atrophy (SMA). The objective of this study was to explore changes in HFMSE item-scores in children with SMA types 2 and 3a treated with nusinersen over a period of six to twenty months. We stratified patients according to motor ability (sitting and walking), and calculated numbers and percentages for each specific improvement (positive score change) or decrease (negative score change) for the total group and each subgroup and calculated frequency distributions of specific score changes. Ninety-one percent of the children showed improvement in at least 1 item, twenty-eight percent showed a score decrease in 1 or more items. In the first six to twenty months of nusinersen treatment motor function change was characterized by the acquisition of the ability to perform specific tasks with compensation strategies (score changes from 0 to 1). Children with the ability to sit were most likely to improve in items that assess rolling, whilst children with the ability to walk most likely improved in items that assess half-kneeling. The ability most frequently lost was hip flexion in supine position

Mastication in Patients with Spinal Muscular Atrophy Types 2 and 3 is Characterized by Abnormal Efficiency, Reduced Endurance, and Fatigue

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13–67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = − 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p < 0.001; p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p < 0.001). Muscle ultrasound of the mastication muscles showed an abnormal muscle structure in 90% of both ambulant and non-ambulant patients. This study aims to understand the nature and underlying mechanisms of mastication problems in patients with SMA types 2 and 3 with reported bulbar problems

Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine

Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA). Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements. These sEMG changes over time indicate levels of peripheral muscle fatigue and recruitment of new motor units, respectively. Results: In comparison to a placebo, patients with SMA using pyridostigmine had fourfold smaller decreases in frequency and twofold smaller increases in amplitudes of sEMG signals in some muscles, recorded during ESTs (p < 0.05). We found no effect of pyridostigmine on MVC RMS amplitudes. Conclusions: sEMG parameters indicate enhanced low-threshold (LT) motor unit (MU) function in upper-extremity muscles of patients with SMA treated with pyridostigmine. This may underlie their improved endurance. Significance: Our results suggest that enhancing LT MU function may constitute a therapeutic strategy to reduce fatigability in patients with SMA

Psychological well-being in adults with spinal muscular atrophy: the contribution of participation and psychological needs

PURPOSE: Patients with spinal muscular atrophy (SMA) suffer from slowly progressive weakness of axial, respiratory and proximal muscles, leading to restrictions in activity and participation. This study aims to investigate patients' level of psychological well-being, using the International Classification of Functioning model and self-determination theory as theoretical frameworks. MATERIALS AND METHODS: In this cross-sectional study, adults with SMA were invited to complete a questionnaire. Instruments to assess psychological well-being included the Satisfaction with Life Scale, the Rosenberg Self-Esteem Scale and the Positive and Negative Affect Scale. Hierarchical lineal regression analyses were performed to investigate the contribution of participation (International Classification of Functioning model) and satisfaction of the need for autonomy, competence and relatedness (self-determination theory) to well-being. RESULTS: Ninety-two respondents (67%) returned the questionnaire. Levels of psychological well-being were comparable to that of healthy reference samples. Well-being was unrelated to sociodemographic variables or illness characteristics. By contrast, well-being was closely related to respondents' satisfaction with participation, and their sense of autonomy, competence and relatedness. CONCLUSIONS: This study illustrates the relevance of psychological needs for understanding well-being of individuals with SMA. Supporting patients in meeting their psychological needs should become an objective of person-centred care for this population. Implications for rehabilitation Spinal muscular atrophy is a rare inherited disease, characterized by slowly progressive muscle weakness. Psychological well-being, including satisfaction with life, self-esteem and emotional functioning of adults with spinal muscular atrophy appears very comparable with that of healthy reference samples. In line with the International Classification of Functioning framework, well-being in adults with spinal muscular atrophy may be improved by increasing their (satisfaction with) participation. Moreover, clinical assessment and management should focus on optimizing patients' satisfaction with their basic psychological needs (autonomy, competence, relatedness), as this is strongly related to indices of psychological well-being

Quantitative MRI of skeletal muscle in a cross-sectional cohort of patients with spinal muscular atrophy types 2 and 3

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross-sectional cohort of patients of varying type, disease severity and age. Thirty-one patients with SMA types 2 and 3 (aged 29.6 [7.6-73.9] years) and 20 healthy controls (aged 37.9 [17.7-71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = -0.56 and -0.59; both P < .001) whereas for fat fraction values are τ = -0.50 and -0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle

Characterization of Pseudomonas aeruginosa isolates: Occurrence rates, antimicrobial susceptibility patterns, and molecular typing in the global SENTRY Antimicrobial Surveillance Program, 1997-1999

During 1997–1999, a total of 70,067 isolates (6631 Pseudomonas aeruginosa isolates) were analyzed in the SENTRY program by geographic region and body site of infection. The respiratory tract was the most common source of P. aeruginosa. P. aeruginosa isolation rates increased during the study interval. Europe was the only region to show a significant decline in β-lactam and aminoglycoside susceptibility rates. There was a reduction in the rates of susceptibility of Canadian isolates to imipenem and of Latin American isolates to meropenem. A total of 218 multidrug-resistant P. aeruginosa isolates (MDR-PSA; resistant to piperacillin, ceftazidime, imipenem, and gentamicin) were observed; MDR-PSA occurrence rates (percentages of all isolates) ranged from 8.2% (Latin America) to 0.9% (Canada). No antimicrobial inhibited >50% of MDR-PSA strains. Molecular characterization of selected, generally resistant strains was performed. Isolates showing unique ribogroups were found in Europe, Latin America, and the United States, but clonal spread was documented in several medical centers.A. C. Gales, R. N. Jones, J. Turnidge, R. Rennie, and R. Rampha