Journal of Neuromuscular Diseases - Volume 11, issue 4

Authors: Mohassel, Payam | Abdullah, Meher | Eichler, Florian S. | Dunn, Teresa M.

Article Type: Review Article

Abstract: Motor neuron diseases and peripheral neuropathies are heterogeneous groups of neurodegenerative disorders that manifest with distinct symptoms due to progressive dysfunction or loss of specific neuronal subpopulations during different stages of development. A few monogenic, neurodegenerative diseases associated with primary metabolic disruptions of sphingolipid biosynthesis have been recently discovered. Sphingolipids are a subclass of lipids that form critical building blocks of all cellular and subcellular organelle membranes including the membrane components of the nervous system cells. They are especially abundant within the lipid portion of myelin. In this review, we will focus on our current understanding of disease phenotypes in …three monogenic, neuromuscular diseases associated with pathogenic variants in components of serine palmitoyltransferase, the first step in sphingolipid biosynthesis. These include hereditary sensory and autonomic neuropathy type 1 (HSAN1), a sensory predominant peripheral neuropathy, and two neurodegenerative disorders: juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons, and a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration. We will also review our current understanding of disease pathomechanisms, therapeutic approaches, and the unanswered questions to explore in future studies. Show more

Keywords: Serine palmitoyltransferase, sphingolipid biosynthesis, amyotrophic lateral sclerosis, hereditary sensory and autonomic neuropathy, hereditary spastic paraplegia

DOI: 10.3233/JND-240014

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 735-747, 2024

Authors: Pupillo, Elisabetta | Al-Chalabi, Ammar | Sassi, Serena | Arippol, Emilio | Tinti, Lorenzo | Vitelli, Eugenio | Copetti, Massimiliano | Leone, Maurizio A. | Bianchi, Elisa

Article Type: Systematic Review

Abstract: Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% …were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55–65% in 21.6%, between 70–80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7–36 months in 68, 37–60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%. Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting. Show more

Keywords: Clinical trial, methodology, amyotrophic lateral sclerosis, systematic review, drugs

DOI: 10.3233/JND-230217

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 749-765, 2024

Authors: Olimpio, Catarina | Paramonov, Ida | Matalonga, Leslie | Laurie, Steven | Schon, Katherine | Polavarapu, Kiran | Kirschner, Janbernd | Schara-Schmidt, Ulrike | Lochmüller, Hanns | Chinnery, Patrick F. | Horvath, Rita

Article Type: Research Article

Abstract: Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed. Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders. Methods: The WES data was transferred and processed …by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP. Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n  = 1, MT-TN ), nuclear encoded mitochondrial genes (n  = 2, PDHA1 , and SUCLA2 ) and nuclear genes associated with nonmitochondrial disorders (n  = 5, PNPLA2, CDC40, NBAS and SLC7A7 ). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data. Conclusions: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes. Show more

Keywords: Mitochondrial diseases, respiratory chain deficiencies, next generation sequencing, mitochondrial genes

DOI: 10.3233/JND-240020

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 767-775, 2024

Authors: Decostre, Valérie | De Antonio, Marie | Servais, Laurent | Hogrel, Jean-Yves

Article Type: Research Article

Abstract: Background: Measurement of muscle strength and motor function is recommended in clinical trials of neuromuscular diseases, but the loss of hand strength at which motor function is impacted is not documented. Objectives: To establish the relationship between hand strength and function, and to determine the strength threshold that differentiates normal and abnormal hand function in individuals with Duchenne Muscular Dystrophy (DMD) or Spinal Muscular Atrophy (SMA). Methods: Maximal handgrip and key pinch strength were measured with the MyoGrip and MyoPinch dynamometers, respectively. Hand function was assessed using the MoviPlate, the Motor Function Measure items for distal …upper limb (MFM-D3-UL) and the Cochin Hand Function Scale (CHFS). Results: Data from 168 participants (91 DMD and 77 SMA, age 6–31 years) were analyzed. Relationships between strength and function were significant (P  < 0.001). Hand function was generally preserved when strength was above the strength threshold determined by Receiver-Operating Characteristic (ROC) analysis: For MFM-D3-UL, the calculated handgrip strength thresholds were 41 and 13% of the predicted strength for a healthy subject (% pred) and the key pinch strength thresholds were 42 and 26% pred for DMD and SMA, respectively. For the MoviPlate, handgrip strength thresholds were 11 and 8% pred and key pinch strength thresholds were 21 and 11% pred for DMD and SMA, respectively. For participants with sub-threshold strength, hand function scores decreased with decreasing strength. At equal % pred strength, individuals with SMA had better functional scores than those with DMD. Conclusions: Hand function is strength-dependent for most motor tasks. It declines only when strength falls below a disease-specific threshold. Therefore, therapies capable of maintaining strength above this threshold should preserve hand function. Show more

Keywords: Hand, patient outcome assessment, muscular dystrophy, duchenne, spinal muscular atrophy

DOI: 10.3233/JND-230182

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 777-790, 2024

Authors: Geuens, Sam | Goemans, Nathalie | Lemiere, Jurgen | Doorenweerd, Nathalie | De Waele, Liesbeth

Article Type: Research Article

Abstract: Background: Emerging evidence underscores the high prevalence of neurobehavioral difficulties like ADHD, ASD and OCD, in patients with Duchenne muscular dystrophy (DMD). The substantial impact of these complex behavioral challenges in addition to motor function decline on the well-being of affected individuals and their families is increasingly evident. However, a uniform approach for effective screening, assessment and management of the neurobehavioral symptoms remains elusive. Objective: We explored strategies used by healthcare professionals with clinical expertise in DMD to address neurobehavioral symptoms, in order to uncover diverse practices and to identify potential directions for clinical approaches in managing DMD …neurobehavioral symptoms. Methods and results: Twenty-eight respondents from 16 different countries completed an online survey. Only 35% of the centers systematically screened for neurobehavioral difficulties in their DMD population. Predominant screening methods included history taking and clinical observation. Common neurobehavioral difficulties encompassed learning challenges, dependency from adults, anxiety, concentration difficulties, and social deficits. The participating centers frequently employed parental counseling and liaison with psychosocial healthcare professionals for psychosocial intervention. Conclusion: This study underscores the complex behavioral landscape in DMD, highlighting the need for validated screening, assessment and management strategies and collaborative efforts in implementing these. We advocate for international consensus recommendations for screening, assessment and management of neurobehavioral difficulties in DMD to enhance patient care and communication across healthcare settings. Show more

Keywords: Duchenne muscular dystrophy, behavior, psychology, surveys and questionnaires

DOI: 10.3233/JND-230251

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 791-799, 2024

Authors: Geuens, Sam | Goemans, Nathalie | Lemiere, Jurgen | Doorenweerd, Nathalie | De Waele, Liesbeth

Article Type: Research Article

Abstract: Background: Patients with Duchenne muscular dystrophy (DMD) face a higher risk of neurobehavioral problems, yet an international consensus on screening, assessing, and managing these difficulties is lacking. Objective: This report introduces the term Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND) to comprehensively cover the spectrum of neurobehavioral issues in DMD patients, including behavior, psychiatric disorders, and various cognitive, academic, and psychosocial deficits. To facilitate screening, the DuMAND Checklist, a 43-item tool with five subscales, was developed. Methods and results: DuMAND categories were derived through literature review, parent (48 mothers and 37 fathers), and expert (n  = 28) input …and feedback. The DuMAND Checklist subscales were developed iteratively, incorporating item selection, expert panel (n  = 10) assessment for face validity, comprehensiveness, and a pilot validation study in a DMD sample (n  = 20). DuMAND encompasses five categories: cognition and learning, social responsiveness, emotion regulation, externalizing behavior, and eating and sleeping . Preliminary validation of the DuMAND Checklist indicates acceptable-to-excellent internal consistency and construct validity. Conclusion: By introducing the DuMAND concept, this study seeks to inspire a consensus approach for screening, assessing, and managing neurobehavioral issues in DMD. Incorporating screening, using the DuMAND Checklist, in addition to medical follow-up will facilitate early intervention, addressing a critical gap in identification of neurobehavioral disorders in DMD. Future research is needed to further evaluate psychometric properties of the DuMAND Checklist and investigate the natural course of DuMAND. Show more

Keywords: Duchenne muscular dystrophy, neurobehavioral problems, screening

DOI: 10.3233/JND-240012

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 801-814, 2024

Authors: Lencioni, Tiziana | Bandini, Virginia | Schenone, Cristina | Lagostina, Maria | Aiello, Alessia | Schenone, Angelo | Ferrarin, Maurizio | Trompetto, Carlo | Mori, Laura | Germanotta, Marco | Pazzaglia, Costanza | Massucco, Sara | Marinelli, Lucio | Grandis, Marina

Article Type: Research Article

Abstract: Background: Subjects with Charcot-Marie-Tooth (CMT) disease show hands impairment which is a relevant problem affecting the quality of life. This symptom is related to muscle weakness and reduced motor coordination of the upper limb. However, most studies focus on lower limb impairment, therefore the investigation of upper limb disability is necessary to identify biomarkers able to monitor disease-specific features and to tailor rehabilitation. Objective: This study aimed at characterizing upper limb muscle co-contraction using the co-contraction index (CCI) in CMT population. Methods: Upper limb kinematic and electromyography (EMG) data were collected from fourteen CMT subjects (6-CMT1A …and 8-CMT1X) during motor tasks typical of daily living activities. Rudolph’s CCI was used to quantify muscle co-contraction of four muscle pairs acting on shoulder, elbow and wrist. All CMT subjects underwent clinical examination. Thirteen healthy subjects served as the normative reference (HC). Results: CMT1X and CMT1A showed a significant reduction in CCI for distal and proximal muscle pairs compared to HC. Furthermore, CMT1A showed greater values of CCI compared to CMT1X mainly for the axial and axial-to-proximal muscle pairs. Movement speed and smoothness were not altered compared to HC. In addition, EMG metrics showed moderate-to-strong significant correlations with clinical outcomes. Conclusions: CCI was able to quantify disease-specific deficits with respect to the normative reference, highlighting motor control alterations even before motor output impairment. CCI was also sensitive in detecting CMT subtypes-based differences and adopted compensatory strategies. Our findings suggest that CCI can be an outcome measure for CMT disease monitoring and interventional studies. Show more

Keywords: Charcot-Marie-Tooth disease, surface electromyography, upper extremity, muscle co-contraction, movement analysis

DOI: 10.3233/JND-240006

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 815-828, 2024

Authors: Werlauff, Ulla | Handberg, Charlotte | Kristensen, Bente | Glerup, Sarah | Pharao, Antoniett Vebel | Strøm, Jeanette | Jensen, Bente Thoft

Article Type: Research Article

Abstract: Background: Little is known about the challenges faced by women with a neuromuscular disease (NMD) when having to go to the toilet in other places than home; a topic that is highly important for participation and bladder health. Objective: The aim was to investigate whether women with NMD have problems in going to the toilet when not at home, the problems’ impact on their social activities, education, and working life, which strategies they use to manage the problems, and the prevalence of lower urinary tract symptoms (LUTS). Methods: A national survey containing questions on type of …NMD, mobility, impacts on social activities, education, working life, and bladder health was developed by women with NMD and researchers. LUTS were assessed by the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS). Female patients≥12 years (n  = 1617) registered at the Danish National Rehabilitation Centre for Neuromuscular Diseases were invited. Results: 692 women (43%) accepted the invitation; 21% were non-ambulant. 25% of respondents avoided going to the toilet when not at home. One third of respondents experienced that problems in going to the toilet impacted their social life. 43% of respondents refrained from drinking to avoid voiding when not at home, 61% had a low frequency of urinating, 17% had experienced urinary tract infections, and 35% had experienced urine incontinence. Problems were seldom discussed with professionals, only 5% of participants had been referred to neuro-urological evaluation. Conclusion: The results highlight the difficulties in urinating faced by women with NMD when not at home and how these difficulties impact functioning, participation, and bladder health. The study illustrates a lack of awareness of the problems in the neuro-urological clinic. It is necessary to address this in clinical practice to provide supportive treatment and solutions that will enable participation for women with NMD. Show more

Keywords: Neuromuscular diseases, women’s health, toilet facilities, urinary tract infection, participation, rehabilitation

DOI: 10.3233/JND-230241

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 829-838, 2024

Authors: Colot, Charlotte | Benmechri, Sarah | Everaert, Elke | Muys, Sarah | Van Himme, Linde | Tahon, Valentine | Salmon, Maurine | Van Dyck, Dorine | De Vos, Elke | Deconinck, Nicolas

Article Type: Research Article

Abstract: Background: Spinal muscular atrophy (SMA), a genetic neuromuscular disease caused by lack of survival of motor neuron (SMN) protein, is characterized by muscular atrophy and respiratory and bulbar dysfunction. While swallowing disorders are common, they remain poorly studied. Objectives: Our study aimed to explore 1) intraoral pressure measurements with the Iowa Oral Performance Instrument system and the reliability of a Swallowing Function Assessment Questionnaire (SFAQ) in healthy controls, and 2) evaluate their use as swallowing function biomarkers and the evolution of swallowing function over time in children with SMA. Methods: We recruited 53 healthy children and …27 SMA patients all treated with SMN gene modulator therapy. Participants completed the SFAQ and underwent at least one measurement of maximal oral pressures (lingual, labial, and masseter). Results: Mean oral normalized pressure index were lower (all sites p  < 0.001) and mean SFAQ scores were higher (p  < 0.001) in patients compared with healthy controls. Pressure evolution over 1 year in SMA patients for all three oral sites did not show significant differences. SFAQ scores correlated negatively with oral pressures at all three sites in patients. Conclusions: Both tools provided new insights on the oral and pharyngeal phase of swallowing in SMA patients. In SMA patients, muscle strength in certain crucial anatomical regions during swallowing is weaker than in healthy children. Show more

Keywords: Spinal muscular atrophy, swallowing, oral pressures, outcome measure, neuromuscular disease, muscular atrophy

DOI: 10.3233/JND-240017

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 839-853, 2024

Authors: Meyer, Corentin | Romero, Norma Beatriz | Evangelista, Teresinha | Cadot, Brunot | Laporte, Jocelyn | Jeannin-Girardon, Anne | Collet, Pierre | Ayadi, Ali | Chennen, Kirsley | Poch, Olivier

Article Type: Research Article

Abstract: Medical acts, such as imaging, lead to the production of various medical text reports that describe the relevant findings. This induces multimodality in patient data by combining image data with free-text and consequently, multimodal data have become central to drive research and improve diagnoses. However, the exploitation of patient data is problematic as the ecosystem of analysis tools is fragmented according to the type of data (images, text, genetics), the task (processing, exploration) and domain of interest (clinical phenotype, histology). To address the challenges, we developed IMPatienT (I ntegrated digital M ultimodal P ATIENt daT a), a simple, flexible and …open-source web application to digitize, process and explore multimodal patient data. IMPatienT has a modular architecture allowing to: (i) create a standard vocabulary for a domain, (ii) digitize and process free-text data, (iii) annotate images and perform image segmentation, (iv) generate a visualization dashboard and provide diagnosis decision support. To demonstrate the advantages of IMPatienT, we present a use case on a corpus of 40 simulated muscle biopsy reports of congenital myopathy patients. As IMPatienT provides users with the ability to design their own vocabulary, it can be adapted to any research domain and can be used as a patient registry for exploratory data analysis. A demo instance of the application is available at https://impatient.lbgi.fr/ . Show more

Keywords: Muscular diseases, histology, image processing, computer-assisted, diagnosis, computer-assisted, electronic health records, artificial intelligence

DOI: 10.3233/JND-230085

Citation: Journal of Neuromuscular Diseases, vol. 11, no. 4, pp. 855-870, 2024