Journal of Neuromuscular Diseases - Volume 9, issue 1

Authors: Theret, Marine | Saclier, Marielle | Messina, Graziella | Rossi, Fabio M.V.

Article Type: Review Article

Abstract: While skeletal muscle remodeling happens throughout life, diseases that result in its dysfunction are accountable for many deaths. Indeed, skeletal muscle is exceptionally capable to respond to stimuli modifying its homeostasis, such as in atrophy, hypertrophy, regeneration and repair. In particular conditions such as genetic diseases (muscular dystrophies), skeletal muscle’s capacity to remodel is strongly affected and undergoes continuous cycles of chronic damage. This induces scarring, fatty infiltration, as well as loss of contractibility and of the ability to generate force. In this context, inflammation, primarily mediated by macrophages, plays a central pathogenic role. Macrophages contribute as the primary regulators …of inflammation during skeletal muscle regeneration, affecting tissue-resident cells such as myogenic cells and endothelial cells, but also fibro-adipogenic progenitors, which are the main source of the fibro fatty scar. During skeletal muscle regeneration their function is tightly orchestrated, while in dystrophies their fate is strongly disturbed, resulting in chronic inflammation. In this review, we will discuss the latest findings on the role of macrophages in skeletal muscle diseases, and how they are regulated. Show more

Keywords: Macrophage, skeletal muscle, muscle dystrophy, repair, inflammation

DOI: 10.3233/JND-210737

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 1-23, 2022

Authors: Querin, Giorgia | Biferi, Maria Grazia | Pradat, Pierre-Francois

Article Type: Review Article

Abstract: The development of new possible treatments for C9orf72 -related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72 -ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72 -ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before …symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18 F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials. Show more

Keywords: ALS, FTD, C9orf72, biomarkers, symptomatic, pre-symptomatic, clinical trials, antisense oligonucleotides, ASO, clinical markers, neuroimaging, MRI, DTI, PET, brain imaging, neurofilaments, DPRs

DOI: 10.3233/JND-210754

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 25-37, 2022

Authors: Mitelman, Olga | Abdel-Hamid, Hoda Z. | Byrne, Barry J. | Connolly, Anne M. | Heydemann, Peter | Proud, Crystal | Shieh, Perry B. | Wagner, Kathryn R. | Dugar, Ashish | Santra, Sourav | Signorovitch, James | Goemans, Nathalie | for the investigators from the LNMRC Natural History study | McDonald, Craig M. | for the investigators from the CINRG Duchenne National History Study | Mercuri, Eugenio | for the investigators from The DMD Italian Group | Mendell, Jerry R.

Article Type: Research Article

Abstract: Background: Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. Objective: To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. Methods: Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls …and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. Results: Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p  < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: –3.3 vs. –6.0 percentage points annually, p  < 0.0001). Conclusions: Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls. Show more

Keywords: Duchenne muscular dystrophy, eteplirsen, dystrophin, loss of ambulation, 6-minute walk test, forced vital capacity

DOI: 10.3233/JND-210665

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 39-52, 2022

Authors: Crowe, Kelly E. | Zygmunt, Deborah A. | Heller, Kristin | Rodino-Klapac, Louise | Noguchi, Satoru | Nishino, Ichizo | Martin, Paul T.

Article Type: Research Article

Abstract: Background: GNE myopathy (GNEM) is a rare, adult-onset, inclusion body myopathy that results from mutations in the GNE gene. GNE encodes UDP-GlcNAc epimerase/ManNAc-6 kinase, a protein with two enzymatic activities that comprise the committed step in biosynthesis of sialic acid (SA), an essential glycan that appears on the terminal positions of many extracellular oligosaccharide chains. These GNE mutations can cause a reduction of SA in many tissues, although pathology is restricted to skeletal muscles through a poorly understood mechanism. Objective: Despite recent advances in the field, it remains unclear which therapeutic avenue is most promising …for the restoration of SA level in skeletal muscle affected by GNEM. Our objective was to assess dietary and gene therapy strategies for GNEM in Cmah -deficient GNED 207V Tg Gne-/- mice, a model that allows for the visualization of orally delivered N-glycolylneuraminic acid (Neu5Gc), one of the two predominant SA forms in muscle. Methods: Methods included in situ physiology studies of the tibialis anterior muscle, studies of ambulation and limb grip strength, and muscle staining using MAA, SNA, and anti-Neu5Gc antibody, along with qPCR, qRT-PCR, western blot, and HPLC studies to assess virally introduced DNA, GNE gene expression, GNE protein expression, and SA expression. Results: We found that a diet enriched in Neu5Gc-containing glycoproteins had no impact on Neu5Gc immunostaining in muscles of GNEM model mice. Delivery of a single high dose oral Neu5Gc therapy, however, did increase Neu5Gc immunostaining, though to levels below those found in wild type mice. Delivery of a single dose of GNE gene therapy using a recombinant Adeno Associated Virus (rAAV) vector with a liver-specific or a muscle-specific promoter both caused increased muscle Neu5Gc immunostaining that exceeded that seen with single dose monosaccharide therapy. Conclusions: Our findings indicate that dietary loading of Neu5Gc-containing glycoproteins is not effective in increasing muscle Neu5Gc expression, while single dose oral Neu5Gc monosaccharide or GNE gene therapy are. Neu5Gc immunostaining, however, showed greater changes than did lectin staining or HPLC analysis. Taken together, these results suggest that Neu5Gc immunostaining may be more sensitive technique to follow SA expression than other more commonly used methods and that liver expression of GNE may contribute overall muscle SA content. Show more

Keywords: Myopathy, sialic acid, gene therapy, AAV, hereditary inclusion body myopathy

DOI: 10.3233/JND-200575

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 53-71, 2022

Authors: Molera, Cristina | Sarishvili, Tinatin | Nascimento, Andrés | Rtskhiladze, Irakli | Muñoz Bartolo, Gema | Fernández Cebrián, Santiago | Valverde Fernández, Justo | Muñoz Cabello, Beatriz | Graham, Robert J. | Miller, Weston | Sepulveda, Bryan | Kamath, Binita M. | Meng, Hui | Lawlor, Michael W.

Article Type: Research Article

Abstract: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound skeletal muscle weakness, respiratory distress, and motor dysfunction. However, pathology is not limited to muscle and can be associated with life-threatening hepatic peliosis. Hepatobiliary disease has been reported in up to 17% of XLMTM patients but has not been extensively characterized. We report on five XLMTM patients who experienced intrahepatic cholestasis in their disease natural history, illustrating the need to further investigate these manifestations. These patients shared presentations that included pruritus, hypertransaminemia, and hyperbilirubinemia with normal gamma-glutamyl transferase, following infection or vaccination. Three patients who had genetic …testing showed no evidence of genetic mutations associated with familial cholestasis. In one patient, progression to cirrhotic, decompensated liver disease occurred. Further investigations into the molecular pathomechanism underpinning these clinical observations in XLMTM patients will be important for informing patient care. Show more

Keywords: X-linked myotubular myopathy, myotubularin, hepatobiliary disease, liver abnormalities, intrahepatic cholestasis

DOI: 10.3233/JND-210712

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 73-82, 2022

Authors: Gros, Marilyn | Nunes, Andreia M. | Daoudlarian, Douglas | Pini, Jonathan | Martinuzzi, Emanuela | Barbosa, Susana | Ramirez, Monique | Puma, Angela | Villa, Luisa | Cavalli, Michele | Grecu, Nicolae | Garcia, Jérémy | Siciliano, Gabriele | Solé, Guilhem | Juntas-Morales, Raul | Jones, Peter L. | Jones, Takako | Glaichenhaus, Nicolas | Sacconi, Sabrina

Article Type: Research Article

Abstract: Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles’ pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics’ efficacy. Objectives: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD. Methods: We retrospectively measured the levels of 20 …pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression. Results: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression. Conclusions: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients. Show more

Keywords: Facioscapulohumeral muscular dystrophy (FSHD), disease biomarkers, Interleukin-6, cytokines

DOI: 10.3233/JND-210711

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 83-93, 2022

Authors: Siddiqui, Shahyan | Polavarapu, Kiran | Bardhan, Mainak | Preethish-Kumar, Veeramani | Joshi, Aditi | Nashi, Saraswati | Vengalil, Seena | Raju, Sanita | Chawla, Tanushree | Leena, Shingavi | Mathur, Aradhana | Nayak, Sushmita | Mohan, Dhaarini | Shamim, Uzma | Prasad, Chandrajit | Lochmüller, Hanns | Faruq, Mohammed | Nalini, Atchayaram

Article Type: Research Article

Abstract: Background and Purpose: Mutations in the GMPPB gene affect glycosylation of α-dystroglycan, leading to varied clinical phenotypes. We attempted to delineate the muscle MR imaging spectrum of GMPPB -related Congenital Myasthenic syndrome (CMS) in a single-center cohort study. Objective: To identify the distinct patterns of muscle involvement in GMPPB gene mutations. Methods: We analyzed the muscle MR images of 7 genetically proven cases of GMPPB dystroglycanopathy belonging to three families and studied the potential qualitative imaging pattern to aid in clinico -radiological diagnosis in neuromuscular practice. All individuals underwent muscle MRI (T1, T2, …STIR/PD Fat sat. sequences in 1.5 T machine) of the lower limbs. Qualitative assessment and scoring were done for muscle changes using Mercuri staging for fibro-fatty replacement on T1 sequence and Borsato score for myoedema on STIR sequence. Results: All patients were of South Indian origin and presented as slowly progressive childhood to adult-onset fatigable limb-girdle muscle weakness, elevated creatine kinase level, and positive decrement response in proximal muscles. Muscle biopsy revealed features of dystrophy. All patients demonstrated identical homozygous mutation c.1000G > A in the GMPPB gene. MRI demonstrated early and severe involvement of paraspinal muscles, gluteus minimus, and relatively less severe involvement of the short head of the biceps femoris. A distinct proximo-distal gradient of affliction was identified in the glutei, vasti, tibialis anterior and peronei. Also, a postero-anterior gradient was observed in the gracilis muscle. Conclusion: Hitherto unreported, the distinctive MR imaging pattern described here, coupled with relatively slowly progressive symptoms of fatigable limb-girdle weakness, would facilitate an early diagnosis of the milder form of GMPPB - dystroglycanopathy associated with homozygous GMPPB gene mutation. Show more

Keywords: GMPPB, congenital myasthenic syndrome, limb-girdle muscular dystrophy, magnetic resonance imaging

DOI: 10.3233/JND-200628

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 95-109, 2022

Authors: Rich, Kelly A. | Fox, Ashley | Yalvac, Mehmet | Heintzman, Sarah | Tellez, Marco | Bartlett, Amy | Severyn, Steven | Linsenmayer, Mathew | Kelly, Kristina | Reynolds, Jerry | Sterling, Gary Brent | Weaver, Tristan | Rajneesh, Kiran | Pino, Megan G. | Arnold, W. David | Elsheikh, Bakri | Kolb, Stephen J.

Article Type: Research Article

Abstract: Objective: To retrospectively evaluate the utility of serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) as biomarkers for spinal muscular atrophy (SMA) progression and response to nusinersen treatment. Methods: NfL and pNfH levels were quantified using single molecular array (SIMOA) in CSF of 33 adult SMA patients (SMN copy number 3–5) before and in response to nusinersen treatment. In 11 of the patients, blood serum samples were also collected. CSF NfL and pNfH from patients were compared to CSF Nfs from age-matched controls without neurological disease (n  = 6). For …patients, pearson correlation coefficients (r) were calculated to investigate associations between Nf levels and other functional outcome measures. Results: Nf levels were similar between SMA and control adults and showed no change in response to nusinersen treatment in CSF or serum. Cross-sectional analyses showed an increase in CSF NfL and pNfH with age in patients (NfL p  = 0.0013; pNfH p  = 0.0035) and an increase in CSF NfL in controls (p  = 0.002). In non-ambulatory patients, baseline serum pNfH showed a negative correlation with multiple strength and functional assessment metrics including Revised Upper Limb Module (r  = –0.822, p  = 0.04), upper extremity strength (r  = –0.828, p  = 0.042), lower extremity strength (r  = –0.860, p  = 0.028), and total strength (r  = –0.870, p  = 0.024). Conclusions: Nf levels did not change in response to nusinersen in adults with SMA and were not different from controls. In patients and controls, we detected an age-related increase in baseline CSF NfL and pNfH levels. Though some associations were identified, our results suggest Nf levels are not preditive or prognostic biomarkers in this population. Show more

Keywords: Adult spinal muscular atrophy, neurofilament protein, biomarker, aging

DOI: 10.3233/JND-210735

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 111-119, 2022

Authors: Blaschek, Astrid | Hesse, Nikolas | Warken, Birgit | Vill, Katharina | Well, Therese | Hodek, Claudia | Heinen, Florian | Müller-Felber, Wolfgang | Schroeder, Andreas Sebastian

Article Type: Research Article

Abstract: Background: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. Objective: Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. Methods: We have developed a system for tracking full-body motion in …infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2–46 months of age; CHOP INTEND score 10–50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. Results: 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3–1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6–10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8–8.5%). Conclusions: Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages. Show more

Keywords: (4–10): Spinal muscle atrophy (SMA), 3D motion tracking, kinect, CHOP

DOI: 10.3233/JND-200619

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 121-128, 2022

Authors: Tankink, Maurits | Horlings, Corinne G.C. | Voermans, Nicol | van der Sluijs, Barbara | Kessels, Roy P.C. | van Engelen, Baziel | Raaphorst, Joost

Article Type: Article Commentary

Abstract: Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD. 24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration. In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. …Correlations were small to medium. Show more

Keywords: Oculopharyngeal muscular dystrophy, frontotemporal dementia, behavioural impairment, neuromuscular disorders, neuropsychiatry

DOI: 10.3233/JND-200592

Citation: Journal of Neuromuscular Diseases, vol. 9, no. 1, pp. 129-135, 2022