Edited by: Tim Hagenacker, Essen University Hospital, Germany
Reviewed by: Valeria Ada Sansone, Nemo Clinical Center, Italy; Ewout J. N. Groen, UMC Utrecht Brain Center, Netherlands
This article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology
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5q-associated spinal muscular atrophy (SMA) is one of the most common neuromuscular diseases in childhood and is caused by homozygous deletion or less frequently other mutations in the survival motor neuron 1 gene (
To our knowledge, a systematic evaluation of the prevalence and significance of non-motor symptoms (NMS) in adult SMA has not yet been reported. The aim of this study was therefore to assess the NMS burden in adult patients with SMAII and SMAIII with the NMS questionnaire (NMSQuest).
We analyzed data from 70 genetically confirmed SMAII and SMAIII as well as 59 healthy controls (for details see
Demographic and clinical characteristics of the study populations.
Number | 59 | 70 |
Ratio of female (%) | 57.9 | 45.7 |
Age (yr) | 35.3 ± 9.2 | 35.9 ± 10.9 |
Subtypes (n) | – | SMAII (27) SMAIII (43) |
Nusinersen treatment (yes/no) | 0/59 | 40/30 |
Wheelchair-bound/ambulatory | 0/59 | 49/21 |
HFMSE | – | 19.7 ± 21.7 |
RULM | – | 19.5 ± 13.2 |
ALSFRS-R | – | 31.1 ± 8.6 |
The NMSQuest is a 30-item self-completed questionnaire featuring responses as “yes” and “no” to each item and was originally designed and validated for Parkinson's disease patients (
As the samples were not normally distributed according to the Kolmogorov-Smirnov test, the statistical comparisons of data between groups were performed using the non-parametric Mann–Whitney
NMSQuest data from 70 adult SMAII and SMAIII patients and 59 age/sex matched controls were analyzed and compared. Demographic and clinical characteristics of study populations are shown in
Total NMS were not significantly different between SMA and controls (
Patient-reported prevalence of non-motor symptoms (NMS) in adult 5q spinal muscular atrophy (SMA). Total NMS score
Comparison of NMS between controls and SMA patients.
Dribbling | 0 | 4.3 | 0.114 |
Taste/smelling difficulties | 1.8 | 0 | 0.266 |
Swallowing difficulties |
1.8 | 24.3 | 0.000 |
Vomiting | 19.3 | 10.0 | 0.135 |
Constipation | 14.0 | 12.9 | 0.846 |
Bowel incontinence | 0 | 0 | n.c. |
Bowel emptying | 12.3 | 18.6 | 0.333 |
Urgency | 17.5 | 8.6 | 0.130 |
Nocturia |
14.0 | 1.4 | 0.006 |
Pains | 5.3 | 10 | 0.324 |
Weight loss | 1.8 | 7.1 | 0.155 |
Difficulties of remembering | 17.5 | 17.1 | 0.953 |
Loss of interest | 8.8 | 8.6 | 0.968 |
Hallucinations | 1.8 | 0.0 | 0.266 |
Concentration difficulties | 22.8 | 20.0 | 0.701 |
Sad, blues | 28.1 | 35.7 | 0.359 |
Anxiety | 7.0 | 17.1 | 0.087 |
Changes of sex drive | 10.5 | 11.4 | 0.872 |
Sex difficulty | 1.8 | 5.7 | 0.262 |
Felling dizzy | 15.8 | 15.7 | 0.991 |
Falling |
0 | 17.1 | 0.001 |
Daytime sleepiness | 7.0 | 2.9 | 0.272 |
Insomnia | 40.4 | 31.4 | 0.296 |
Intense vivid dreams | 15.8 | 18.6 | 0.680 |
Acting out during dreams | 8.8 | 14.5 | 0.324 |
Restless legs | 14.0 | 21.4 | 0.282 |
Swelling legs |
3.5 | 37.1 | 0.000 |
Excessive Sweating | 7.0 | 17.1 | 0.087 |
Diplopia | 0 | 2.9 | 0.198 |
Delusions | 1.8 | 1.4 | 0.883 |
Comparison of SMAII and SMAIII revealed no significant differences in total NMS score (
Comparison of NMS between SMAII and SMAIII.
Dribbling | 7.4 | 2.3 | 0.307 |
Taste/smelling difficulties | 0 | 0 | n.c. |
Swallowing difficulties | 29.6 | 20.9 | 0.409 |
Vomiting | 11.1 | 9.3 | 0.806 |
Constipation | 11.1 | 14.0 | 0.729 |
Bowel incontinence | 0 | 0 | n.c. |
Bowel emptying | 22.2 | 16.3 | 0.534 |
Urgency | 7.4 | 9.3 | 0.783 |
Nocturia | 0 | 2.3 | 0.425 |
Pains | 11.1 | 9.3 | 0.806 |
Weight loss | 7.4 | 7.0 | 0.946 |
Difficulties of remembering | 18.5 | 16.3 | 0.809 |
Loss of interest | 7.4 | 9.3 | 0.783 |
Hallucinations | 0 | 0 | n.c. |
Concentration difficulties | 22.2 | 18.6 | 0.713 |
Sad, blues | 40.7 | 32.6 | 0.487 |
Anxiety | 25.9 | 11.6 | 0.122 |
Changes of sex drive | 18.5 | 7.0 | 0.140 |
Sex difficulty | 7.4 | 4.7 | 0.629 |
Felling dizzy | 22.2 | 11.6 | 0.236 |
Falling |
3.7 | 25.6 | 0.018 |
Daytime sleepiness | 0 | 4.7 | 0.256 |
Insomnia | 25.9 | 34.9 | 0.432 |
Intense vivid dreams | 26.0 | 14.0 | 0.210 |
Acting out during dreams |
25.9 | 7.1 | 0.031 |
Restless legs | 14.8 | 25.6 | 0.285 |
Swelling legs | 37.0 | 37.2 | 0.988 |
Excessive Sweating | 14.8 | 18.6 | 0.682 |
Diplopia | 0 | 4.7 | 0.256 |
Delusions | 0 | 2.3 | 0.425 |
SMA pathophysiology is caused by homozygous deletion or mutations in the
Patient-reported prevalence of NMS was generally low and, did not—in total—differ significantly from healthy controls and also did not correlate with the severity scores ALSFRS-R, HFMSE and RULM. However, patients in the SMA group complained significantly more frequently about the items “swallowing difficulties,” “falling,” and “swelling legs.” “Swallowing difficulties” were reported by patients who were more severely affected, as indicated by the specific severity scores, as compared to those who were less affected, which may be explained by more prominent bulbar involvement in more severe disease stages. “Falling” was significantly more often complained by patients who were less severely affected by the disease and ambulatory which is explained by the fact that more severely disabled patients are unable to walk and wheelchair-bound and therefore have a lower risk to fall. “Swelling legs” was reported from patients who had lower HFMSE scores. “Swallowing difficulties” and “falling” can be attributed to motor symptoms, but “swelling legs” is highly prevalent and might be a real NMS in SMA. Several reasons could explain this NMS in SMA. It might be a consequence of venous insufficiency due to abnormal posture and/or immobility, as many of the adult patients are fully wheelchair-bound and/or due to decreased muscle strength of the lower limbs with reduced venous muscle pump. Fitting to this hypothesis, patients in this study who complained for “swelling legs” were significantly more frequently full-day wheelchair-bound. On the other hand, it may be related to cardiac insufficiency. Disease involvement of the cardiac muscle has been demonstrated in animal models and patients with severe forms of SMA (
Neuropsychiatric related complaints like “anxiety,” “loss of interest,” “concentration difficulties,” “feeling dizzy” and “insomnia” were reported in a frequency comparable to healthy controls and were not significantly increased in SMA patients. This may appear surprising, because the disease reduces self-reliance and mobility and often leads to dependency on medical aids and comprehensive medical support. However, it fits to the general impression that most adult SMA patients show a high degree of resilience and no signs of adaptive disorders or depression. This observation is confirmed by a recent published study, where Fischer et al. showed that psychological well-being in adult SMA patients was comparable to that of healthy controls and was unrelated to sociodemographic variables or illness characteristics (
Urinary symptoms, including “bowel incontinence,” “bowel emptying incomplete,” “urgency,” and “nocturia,” were only rarely reported by SMA patients. Only a few SMA patients reported “nocturia,” and this was significantly less frequent compared to controls. It could be concluded, that urinary symptoms are not present in these patients. The reason why the item “nocturia” was significantly less frequently reported might be that patients have learned to cope with their motor disabilities, which do not allow them to reach the bathroom in an acceptable time during night.
Comparing groups of patients with SMAII and SMAIII revealed no significant differences in total NMS score. As expected, the item “falling” was significantly more frequent in SMAIII, because all SMAII patients were wheelchair-bound and had therefore a lower risk to fall. The item “acting out during dreams” was more frequent in SMAII, however still not significantly different from controls.
Taken together, patient-reported prevalence of NMS in adult patients with SMA was generally low, arguing for a low perceived burden of other than the motor system. However, “swelling legs” might be a relevant NMS in SMA and its etiology has to be investigated in further studies. Further studies including structured interviews and detailed instrument-based measurements of NMS are warranted to unravel the amount of actual and subclinical NMS in adult SMA.
There are several limitations of this study. First, the screening for NMS was based on a self-rating questionnaire, which was originally designed for Parkinson's disease patients and was not validated for SMA. Previous studies revealed normal quality of life and well-being in adult SMA patients even though these patients were physically severely disabled (
The datasets generated for this study are available on request to the corresponding author.
The studies involving human participants were reviewed and approved by by the local ethics committees of the participating centers. The patients/participants provided their written informed consent to participate in this study.
RG, CW, and AH designed and conceptualized the study. RG and AH drafted and wrote the manuscript. RG, CW, IC, JK, CK, DP, and EA had a major role in the acquisition of data. RG, EA, and AH analyzed the data and performed statistical analysis. All authors interpreted the data and critically revised the manuscript.
RG has received honoraria for presentations/advisory boards from Biogen. CW has received honoraria from Biogen as an advisory board member, for lectures and as a consultant from Hoffmann-La Roche. DP and EA report no disclosures. IC received a travel grant from Biogen. JK has received financial research support form TEVA Pharmaceuticals and honoraria as speaker/consultant for AbbVie, Ipsen, and AveXis/Novartis. CK has received honoraria from Biogen for presentations and as an advisory board member and for presentations from Merz Pharmaceuticals and Ipsen Pharmaceuticals. MD received a travel grant from Biogen and speaker honoraria from Desitin and Genzyme. PL has received financial research support from TEVA Pharmaceuticals and honoraria as speaker/consultant for AbbVie, BIAL, Desitin, Licher MT, Medtronic, Novartis. AL received financial research support from AB Science, Biogen Idec, Cytokinetics, GSK, Orion Pharam, Novartis, TauRx Therapeutics Ltd. and TEVA Pharmaceuticals. He also has received honoraria as a consultant from Mitsubishi, Orion Pharma, Novartis, Teva and as an advisory board member of Biogen, Treeway, and Hoffmann-La Roche. AH has received honoraria for presentations/advisory boards from Desitin and Biogen.
We are deeply grateful to all study participants, their relatives and friends who contributed to this study.