Journal of Neuromuscular Diseases - Volume 11, issue 1

Authors: Lochmüller, Hanns | Bönnemann, Carsten G.

Article Type: Editorial

DOI: 10.3233/JND-249000

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 1-3, 2024

Authors: Honda, Masaya | Shimizu, Fumitaka | Sato, Ryota | Nakamori, Masayuki

Article Type: Review Article

Abstract: Purpose of review: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group characterized by muscle weakness and skin symptoms and are categorized into six subtypes: dermatomyositis (DM), polymyositis (PM), anti-synthetase syndrome (ASS), immune-mediated myopathy (IMNM), inclusion body myopathy (IBM), and overlap myositis. Myositis-specific autoantibodies were detected for the diagnosis and classification of IIM. This review highlights the pathogenic contributions of the complement system, microangiopathy, and inflammation in IIM. Recent findings: Deposition of complement around capillaries and/or the sarcolemma was observed in muscle biopsy specimens from patients with DM, ASS, and IMNM, suggesting the pathomechanism of complement-dependent muscle and endothelial …cell injury. A recent study using human muscle microvascular endothelial cells showed that Jo-1 antibodies from ASS induce complement-dependent cellular cytotoxicity in vitro . Based on both clinical and pathological observations, antibody- and complement-mediated microangiopathy may contribute to the development of DM and anti-Jo-1 ASS. Juvenile DM is characterized by the loss of capillaries, perivascular inflammation, and small-vessel angiopathies, which may be related to microinfarction and perifascicular atrophy. Several serum biomarkers that reflect the IFN1 signature and microangiopathy are elevated in patients with DM. The pathological observation of myxovirus resistance protein A (MxA), which suggests a type 1 interferon (IFN1) signature in DM, supports the diagnosis and further understanding of the pathomechanism of IIM. A recent report showed that an increase in triggering receptor expressed on myeloid cells (TREM-1) around perimysial blood vessels and muscles in patients with IIM plays a role in triggering inflammation and promoting the migration of inflammatory cells by secreting proinflammatory cytokines, such as tumor necrosis factor α. Summary: The deposition of complement in muscles and capillaries is a characteristic feature of DM, ASS, and IMNM. Microangiopathy plays a pathogenic role in DM, possibly resulting in perifascicular atrophy. Further understanding of the detailed pathomechanism regarding complement, microangiopathy, and inflammation may lead to novel therapeutic approaches for IIM. Show more

DOI: 10.3233/JND-230168

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 5-16, 2024

Authors: Houwen-van Opstal, Saskia L.S. | van der Holst, Menno | Willemsen, Michel A.A.P. | Niks, Erik H. | De Groot, Imelda. J.M. | Cup, Edith H.C.

Article Type: Review Article

Abstract: BACKGROUND: Shortening of the long finger flexors (Flexor Digitorum Profundus, FDPs) in Duchenne Muscular Dystrophy (DMD) causes reduced hand function. Until now, longitudinal studies on the natural course of the shortening of the FDPs are lacking, which impedes recommendations on timing and evaluation of preventive measures. OBJECTIVE: To investigate the longitudinal course of the FDP length during different disease stages focusing on symmetry, timing, and decline of the FDP length. METHODS: A retrospective, longitudinal multicenter study was conducted in the Radboud university medical center and the Leiden university medical center. The FDP outcome was measured using …goniometry and gross motor function was assessed using the Brooke score. Longitudinal mixed model analyses were used to describe the course of the FDP outcome, and to investigate symmetry in both hands. RESULTS: Data on 534 visits of 197 males (age ranged 4–48 years) showed that in the ambulatory stages the FDP outcome was within a normal range. The mean decline in FDP outcome is 3.5 degrees per year, the biggest decline was seen in Brooke 5 (>15 degrees per year). In Brooke 4, 41% of the FDP outcome was < 40 degrees. No significant differences were found between right and left. CONCLUSIONS: This study supports the consideration of preventive measures to delay shortening of the FDPs in DMD patients transitioning to a Brooke scale of 4 or higher. Besides, natural history of FDP outcome has been established, which provides a base to evaluate (preventive) interventions. Show more

Keywords: Duchenne muscular dystrophy, long finger flexors, goniometry, brooke score, longitudinal course

DOI: 10.3233/JND-221653

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 17-23, 2024

Authors: Landfeldt, E. | Aleman, A. | Abner, S. | Zhang, R. | Werner, C. | Tomazos, I. | Lochmüller, H. | Quinlivan, R.M.

Article Type: Systematic Review

Abstract: Background: Despite advances in the medical management of the disease, respiratory involvement remains a significant source of morbidity and mortality in children and adults with Duchenne muscular dystrophy (DMD). Objective: The objective of this systematic literature review was to synthesize and grade published evidence of factors associated with respiratory health and function in DMD. Methods: We searched MEDLINE, Embase, and the Cochrane Library for records of studies published from January 1, 2000 (to ensure relevance to current care practices), up until and including December 31, 2022, reporting evidence of prognostic indicators and predictors of disease progression …in DMD. The quality of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. Results: The bibliographic search strategy resulted in the inclusion of 29 articles. In total, evidence of 10 factors associated with respiratory health and function in patients with DMD was identified: glucocorticoid exposure (high- to very low-quality evidence), DMD mutations (low-quality evidence), DMD genetic modifiers (low-quality evidence), other pharmacological interventions (i.e., ataluren, eteplirsen, idebenone, and tamoxifen) (moderate- to very low-quality evidence), body mass index and weight (low-quality evidence), and functional ability (low-quality evidence). Conclusions: In conclusion, we identified a total of 10 factors associated with respiratory health in function in DMD, encompassing both pharmacological therapies, genetic mutations and modifiers, and patient clinical characteristics. Yet, more research is needed to further delineate sources of respiratory heterogeneity, in particular the genotype-phenotype association and the impact of novel DMD therapies in a real-world setting. Our synthesis and grading should be helpful to inform clinical practice and future research of this heavily burdened patient population. Show more

Keywords: Muscular dystrophy, Duchenne, lung diseases, pulmonary ventilation, practice guideline, GRADE approach

DOI: 10.3233/JND-230094

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 25-57, 2024

Authors: Jensen, Synnøve M. | Friborg, Oddgeir | Mellgren, Svein Ivar | Müller, Kai Ivar | Bergvik, Svein | Arntzen, Kjell Arne

Article Type: Research Article

Abstract: Background: Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. Objective: To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. Methods: Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, …and 14 months and measures of fatigue and sleep quality at 9 months. Results: HRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p ≤0.006) except mental health in males (p  = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively. Conclusions: The 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9. Show more

Keywords: Muscular dystrophies, Limb-girdle, quality of life, sleep quality, fatigue

DOI: 10.3233/JND-221629

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 59-74, 2024

Authors: Sitas, Barbara | Hancevic, Mirea | Bilic, Katarina | Bilic, Hrvoje | Bilic, Ervina

Article Type: Research Article

Abstract: Background: Risdiplam is an orally administered treatment for spinal muscular atrophy which leads to an improvement in motor function as measured by functional motor scales compared with placebo. Although risdiplam has been registered since 2020, real-world data in adults is still scarce. There have been no new safety signals so far, with some results pointing that risdiplam may be effective Objective: The objective was to present real-world data of 31 adult patients with spinal muscular atrophy type 2 and type 3 treated with risdiplam in the Republic of Croatia Methods: Treatment effects were assessed with motor …function tests and patient reported outcome measures, including Individualized Neuromuscular Quality of Life questionnaire, and Jaw Functional Limitation Scale. Side effects, as well as subjective improvements and symptoms, were noted. Results: Majority of patients did not report any side effects. During treatment, we have observed clinically meaningful improvements in some patients, with stabilization of motor functions in the remaining patients. The majority of patients with bulbar function impairment experienced bulbar function improvement, all patients reported an increased quality of life with treatment. An unexpected observed treatment effect was weight gain in a third of all patients with some patients reporting an increase in appetite and subjective improvement in digestion. Conclusions: Risdiplam treatment was well tolerated with subjective and objective positive outcomes registered as measured by functional motor scales and patient-reported outcomes. Since risdiplam is administered orally and acts as a systemic therapy for a multisystemic disorder, effects in systems other than neuromuscular can be expected and should be monitored. Due to systemic nature of the disease patients need multidisciplinary monitoring. Show more

Keywords: Risdiplam, SMA, patient reported outcome measures

DOI: 10.3233/JND-230197

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 75-84, 2024

Authors: Cutrona, Costanza | de Sanctis, Roberto | Coratti, Giorgia | Capasso, Anna | Ricci, Martina | Stanca, Giulia | Carnicella, Sara | Utlulig, Meric | Bersani, Giulia | lazzareschi, Ilaria | Leoni, Chiara | Buonsenso, Danilo | Luciano, Rita | Vento, Giovanni | Finkel, Richard S. | Pane, Marika | Mercuri, Eugenio

Article Type: Research Article

Abstract: Background: The CHOP-INTEND is an established outcome measure used to assess motor function in young and weak SMA patients previously validated in type I infants older than 3 months. Objective: The aim of our study was to assess the maturation of the CHOP-INTEND scores in a group of healthy infants, establishing which items of the scale can be reliably used in individuals younger than 3 months. Methods: This is a prospective observational study. The whole cohort was divided into 5 age groups. Each of the 16 CHOP-INTEND items was analyzed looking at the frequency distribution of …the scores in each age subgroup. An item was considered developmentally appropriate when > 85% of the infants achieved a full score. Results: our study includes 61 assessments collected < 2 weeks, 25 at 2–4 weeks, 20 at 5–8 weeks, 25 at 9–12 weeks and 20 at 13–17 weeks. Eight of the 16 items were developmentally appropriate already in the first week and another by the end of the first month. The remaining 7 items had more variable responses in the first three months and full scores were consistently achieved only after the third month. Conclusions: Our findings suggest that the CHOP-INTEND can be used before the age of 3 months, but the results should be interpreted with caution, considering which items are developmentally appropriate at the time of testing. This will also help to establish whether the changes observed following early treatments are a sign of efficacy or at least partly reflect maturational aspects. Show more

Keywords: CHOP-INTEND, outcome measure, SMA, motor function, maturation, early treatment

DOI: 10.3233/JND-221644

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 85-90, 2024

Authors: Otto, Louise A.M. | Froeling, M. | van Eijk, Ruben P.A. | Wadman, Renske I. | Cuppen, Inge | van der Woude, Danny R. | Bartels, Bart | Asselman, Fay-Lynn | Hendrikse, Jeroen | van der Pol, W. Ludo

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA. Objective: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect. Methods: We used a quantitative MRI protocol before start of treatment and following the 4th and 6th injection of nusinersen in 8 children with SMA type 2 and 3 during the first …year of treatment. The MR protocol allowed DIXON, T2 mapping and diffusion tensor imaging acquisitions. We also assessed muscle strength and motor function scores. Results: Fat fraction of all thigh muscles with the exception of the m. adductor longus increased in all patients during treatment (+3.2%, p  = 0.02). WaterT2 showed no significant changes over time (–0.7 ms, p  = 0.3). DTI parameters MD and AD demonstrate a significant decrease in the hamstrings towards values observed in healthy muscle. Conclusions: Thigh muscles of children with SMA treated with nusinersen showed ongoing fatty infiltration and possible normalization of thigh muscle microstructure during the first year of nusinersen treatment. Quantitative muscle MRI shows potential as biomarker for the effects of SMA treatment strategies. Show more

Keywords: Muscular atrophy, spinal, magnetic resonance imaging, diffusion tensor imaging, therapeutics

DOI: 10.3233/JND-221671

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 91-101, 2024

Authors: Karazi, Walaa | Coppers, Jacqueline | Maas, Daphne | Cup, Edith | Bloemen, Bart | Voet, Nicole | Groothuis, Jan T. | Pinós, Tomàs | Marti Seves, Ramon | Quinlivan, Ros | Løkken, Nicoline | Vissing, John | Bhai, Salman | Wakelin, Andrew | Reason, Stacey | Voermans, Nicol C.

Article Type: Research Article

Abstract: Background: Glycogen storage disease type 5 (GSD) is an autosomal recessive inherited metabolic myopathy caused by a deficiency of the enzyme muscle glycogen phosphorylase. Individuals with GSD5 experience physical activity intolerance. Objective: This patient-led study aimed to capture the daily life experiences of GSD5, with a focus on adapting to and coping with their physical activity intolerance. Methods: An online survey was composed in close collaboration with patient organizations. It consisted of customized and validated questionnaires on demographics, general health and comorbidities, physical activity, psychosocial well-being and functioning, pain, fatigue and adapting to and coping with …GSD5. Results: One hundred sixty-two participants (16 countries) participated. The majority, n  = 86 (69%) were from the Netherlands, USA or UK. We observed a high rate of misdiagnosis prior to GSD5 diagnosis (49%), surprisingly a relatively high proportion had not been diagnosed by DNA testing which is the gold standard. Being diagnosed had a strong impact on emotional status, daily life activities and important life choices. A large proportion had not received any rehabilitation (41%) nor medical treatment (57%) before diagnosis. Engagement in vigorous and moderate physical activity was reduced. Health related quality of life was low, most likely related to low physical health. The median Fatigue Severity Score was 4.3, indicating moderate to severe fatigue. Participants themselves had found various ways to adapt to and cope with their disability. The adaptations concerned all aspect of their life, including household chores, social and physical activities, and work. In addition to lack of support, participants reported limited availability of information sources. Conclusion: Participants have provided guidance for newly diagnosed people, including the advice to accept one’s limited abilities and maintain an active lifestyle. We conclude that adequate counseling on ways of adapting and coping is expected to increase both health-related quality of life and physical activity. Show more

Keywords: McArdle disease, GSD5, quality of life, adaptations, adjustments, physical activity, international survey

DOI: 10.3233/JND-230027

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 103-116, 2024

Authors: Landfeldt, Erik | Leibrock, Berenike | Hussong, Justine | Thiele, Simone | Abner, Sophia | Walter, Maggie C. | Moehler, Eva | Zemlin, Michael | Dillmann, Ulrich | Flotats-Bastardas, Marina

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness. Objectives: The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA. Methods: Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., …non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). Results: In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5–16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between –0.02 and 0.96. Conclusions: The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population. Show more

Keywords: Quality of Life, muscular atrophy, spinal, burden of illness, activities of daily living, therapy

DOI: 10.3233/JND-230071

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 1, pp. 117-128, 2024