Limb-girdle Type Research Articles

Safety and Efficacy of Autologous Bone Marrow Derived Mononuclear Cell Transplant in the Management of Various Neurological Disorders.

Cerebral palsy (CP), traumatic spinal cord injury (SCI), and muscular dystrophy (MD), among the various other neurological disorders, are major global health problems because they are chronic disorders with no curative treatments at present. Current interventions aim to relieve symptoms alone and therefore emphasize the necessity for new approaches. This study aims to assess the safety and efficacy of autologous bone marrow-derived mononuclear cell (BM-MNC) therapy in patients with CP, traumatic SCI, and MD. Functional improvement and safety are the primary outcomes, while secondary outcomes include patient-reported improvement in quality of life. This was a single-arm, open-label prospective study conducted on 100 patients with CP, SCI, and MD at the GSVMMedical College, Kanpur, India. Bone marrow aspirates were processed via centrifugation, and autologous BM-MNCs were administered intrathecally or intramuscularly. Gross motor function classification system (GMFCS) for CP, the American spinal injury association (ASIA) motor score for SCI, and the north star assessment for limb girdle type dystrophies (NSAD) for MD were used for functional outcome assessment at baseline and at post-treatment cycles. Informed consent was obtained, and the study was approved by the ethics committee. Paired t-tests were used to analyze statistical significance (p<0.05). Functional improvements were significant with autologous BM-MNC therapy. Improved motor and cognitive function were shown in CP patients with reduced GMFCS scores (p<0.001). Upper and lower extremity ASIA motor scores improved markedly (p<0.001) in SCI patients. Stabilized muscle strength was seen in MD patients, with increased NSAD and activities of daily living (ADL) scores, suggesting slowing of the disease progression (p<0.019). Side effects were mild and transient. Autologous BM-MNC therapy appears to be a promising, minimally invasive option for patients with CP, SCI, and MD, which appears to markedly improve functional outcomes and quality of life and may therefore be relevant to clinical practice.

A 5-year natural history study in LAMA2-related muscular dystrophy and SELENON-related myopathy: the Extended LAST STRONG study

BackgroundSELENON-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive axial muscle weakness, rigidity of the spine, scoliosis, and respiratory insufficiency. Laminin-a2-related muscular dystrophy (LAMA2-MD) has a similar clinical phenotype, which ranges from severe, early-onset congenital muscular dystrophy type 1A (MDC1A) to milder forms presenting as childhood- or adult-onset limb-girdle type muscular dystrophy. The first 1.5-year natural history follow-up showed that 90% of the patients had low bone quality, respiratory impairments were found in all SELENON-RM and most of the LAMA2-MD patients, and many had cardiac risk factors. However, further extensive knowledge on long-term natural history data, and clinical and functional outcome measures is needed to reach trial readiness. Therefore, we extended the natural history study with 3- and 5-year follow-up visits (Extended LAST STRONG).MethodsThe Extended LAST STRONG is a long-term natural history study in Dutch-speaking patients of all ages diagnosed with genetically confirmed SELENON-RM or LAMA2-MD, starting in September 2023. Patients visit our hospital twice over a period of 2 years to complete a 5-year follow up from the initial LAST-STRONG study. At both visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, muscle ultrasound, respiratory assessments (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years), X-ray of the left hand (age ≤ 17 years), lower extremity MRI (age ≥ 10 years), accelerometry for 8 days (age ≥ 2 years), and questionnaires (patient report and/or parent proxy; age ≥ 2 years). All examinations are adapted to the patient’s age and functional abilities. Disease progression between all subsequent visits and relationships between outcome measures will be assessed.DiscussionThis study will provide valuable insights into the 5-year natural history of patients with SELENON-RM and LAMA2-MD and contribute to further selecting relevant and sensitive to change clinical and functional outcome measures. Furthermore, this data will help optimize natural history data collection in clinical care and help develop clinical care guidelines.Trial registrationThis study protocol including the patient information and consent forms has been approved by medical ethical reviewing committee (‘METC Oost-Nederland’; https://www.ccmo.nl/metcs/erkende-metcs/metc-oost-nederland, file number: 2023–16401). It is registered at ClinicalTrials.gov (NCT06132750; study registration date: 2023-10-05; study first passed date: 2023-11-15).

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

322P Rasch evaluation of North Star Ambulatory Assessment and North Star Assessment for limb-girdle type muscular dystrophies in Becker muscular dystrophy

No beneficial use of the wearable cardioverter defibrillator among patients suffering from inherited and congenital heart disease: data from a European multicenter registry.

Data on the use of the wearable cardioverter defibrillator in patients suffering from inherited and congenital heart disease are limited. Consequently, evidence for guideline recommendations in this patient population is lacking. In total 1,675 patients were included in a multicenter registry of eight European centers. In the present cohort, we included 18 patients suffering from congenital and inherited heart disease. Nine patients (50%) were male with a mean age of 41.3 ± 16.4 years. Four patients suffered from hypertrophic cardiomyopathy (HCM), four patients suffered from non-compaction cardiomyopathy (NCCM), two patients were diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) and one patient suffered from muscular dystrophy of the limb-girdle type with cardiac involvement, secondary cardiomyopathy. Three patients presented with Brugada syndrome (BrS). One patient suffered from long-QT syndrome type 1 (LQTS1). Furthermore, two patients had congenital heart defects and one patient suffered from cardiac sarcoidosis (CS). There were no appropriate/inappropriate shocks with the WCD in this cohort. One patient had recurrent self-limiting sustained ventricular tachycardia during the wear time, but actively inhibited a shock and was hospitalized. The compliance rate in this cohort was 77.8% with a mean wear time of 45.3 ± 26.9 days with a mean follow-up time of 570 ± 734 days. 55.6% (10/18) of the patients received an ICD after WCD wear time. This retrospective study of patients with inherited and congenital heart disease shows that WCD use is not beneficial in the majority of patients with inherited and congenital heart disease.

Limb-Girdle Type Myasthenia Gravis Diagnosed with Invasive Thymic Carcinoma

Limb-Girdle Type Myasthenia Gravis Diagnosed with Invasive Thymic Carcinoma

P.164 Clinical outcome study of dysferlinopathy 2: Characterising involvement of the intrinsic muscles of the hand in LGMDR2

Progressive weakness of the intrinsic muscles of the hand is an under-recognized and -reported in LGMDR2/2B but has significant impact on the functional ability of the hand. The Jain Foundation Clinical Outcome Study of dysferlinopathy (COS2) is an international 2-year natural history study of patients with LGMDR2/2B with the aim to characterise disease progression and determine most appropriate clinical outcome assessments. COS2 includes an assessment of the hand with bilateral manual muscle testing (MMT) and dominant hand only testing of pinch and grip strength using a CITEC hand held dynamometer (HHD). Here we describe the characteristics of hand strength in the COS2 cohort using MMT and HHD. 92 COS2 participants with complete MMT and HHD data at their baseline visit were included in the analysis. HHM grip and pinch strength was performed on the dominant hand and includes the maximum of three trials. MMT scores and HHM values were compared between males and females using a Wilcoxon rank sum test. The correlation between MMT scores and HHM values and age at the study visit were calculated using a Spearman correlation. There were no significant differences between male and female subjects on any hand function test. The flexor digitorum profundus muscle group was most affected with a median MMT grade of 4/5. The flexor digitorum superficialis muscle was less involved with a median MMT of 5-/5. At the thumb, the flexor policis longus was the most affected muscle with a median MMT of 4/5. Dorsal interossei muscles were well preserved. Grip HHD was significantly correlated with age (p=.01). Future work will examine the longitudinal change in the function of the hand and relationship to Performance of Upper limb and motor function as measured by the North Star Assessment for Limb girdle type muscular dystrophies. This is the first study to characterise the function of the hand in LGMDR2 and indicates assessment of the hand should be included as part of the clinical review of patients with LGMDR2.

FP.34 Clinical outcome study of dysferlinopathy: correlation between MRI fat fraction in lower limbs and clinical outcome assessments over a 3-year period

The Jain Foundation COS of dysferlinopathy is an international study in genetically confirmed dysferlinopathy patients, with the aim to identify relevant outcome measures to facilitate trial readiness. Due to its wide range of clinical phenotypes and rates of disease progression, an objective marker to quantify disease progression would be ideal. We assessed the application of quantitative magnetic resonance imaging (MRI) as a prognostic tool for these patients. Our aim is to establish whether there is a correlation between fat fraction (FF) in thigh and/or lower leg muscles and clinical outcome assessments (COA) when comparing baseline (BL) values and changes from BL to year 1 (Y1) and to year 3 (Y3). We selected 84 patients from COS1 who had a Dixon MRI of the lower limbs (LL) and at least one of the following COA: time to rise from floor (RFF), time to climb / descend 4 steps (4SC/4SD), time up and go (TUG), time to walk 10m (10MWT), 6 min walk test (6MWT) and North Star Assessment for limb girdle type muscular dystrophy (NSAD) score. Spearman correlation (rs) was performed using SPSS statistics, p value 0.05. We found a significant correlation at BL between LL FF values and all COA, with the highest rs between thigh FF and NSAD (-.675) and 6MWT (-.665). We didn't find any correlations between changes in FF between BL and Y1 and changes in COA during that same period, but we did observe a significant correlation with changes in TUG (.445) and 4SC (.41) between BL and Y3. We observed a significant correlation between changes in thigh FF between BL and Y3 and changes in TUG (.706), RFF (.607), 4SC (.545) and NSAD[HR1] (-.374). No correlations were found when analysing changes in lower legs FF and COA. Our results show that changes in FF of the thigh muscles over one year could predict functional changes at a later stage, in a three-year period, suggesting that MRI could be used to identify dysferlinopathy patients at risk of more severe disease progression in routine clinical care.

P.167 Clinical outcome study of dysferlinopathy: gait analysis of siblings and phenotype variation

Patients with limb girdle muscular dystrophy (LGMD) R2/2B, caused by mutations in the <i>DYSF</i> gene, have a distinct gait pattern, although this has not been characterised with instrumented gait analysis. In the Jain Foundation Clinical Outcome Study of dysferlinopathy (COS2, http://www.jain-foundation.org/dysferlinoutcomestudy), we are investigating the utility of instrumented gait analysis as a novel clinical biomarker. Patients with LGMDR2 have variability in the presentation of muscle weakness and rate of progression, even within family members. In a pair of siblings with LGMDR2, we conducted gait analysis at two points, six months apart when barefoot and shod. The aim was to quantify gait in siblings with LGMDR2 and evaluate temporospatial parameters changes over six months. Two COSII patients, a male aged 30, and his younger sister aged 27, completed gait analysis at baseline and six-month visits using an instrumented walkway (GAITRite, 240Hz). Patients were asked to walk at a comfortable walking speed when barefoot and shod, and to walk fast when shod only. Temporospatial characteristics including gait velocity, step length, step width, stance and swing duration were extracted. Barefoot gait velocities at baseline were similar between siblings with the male walking at 1.16m/s and his sister at 1.20m/s, however the male sibling walked with a step width double that of his sister. Functionally the male had a more severe disease presentation, with a North Star assessment for limb girdle type muscular dystrophy score of 28/54 at baseline, and the female 42/54. At baseline, both siblings had capacity to increase shod walking speed when asked to walk fast; by 25% for the male and 47% for the female sibling. At six months when shod, gait analysis determined very small changes (<5%) in walking speed, step length, stance time in both siblings. However, step width increased by 12% in the male subject. Gait analysis provides detailed evaluation of temporospatial parameters and captures differences across siblings and walking conditions.

Validation of the North Star Assessment for Limb-Girdle Type Muscular Dystrophies.

ObjectiveThe North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes.MethodsAssessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children’s Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data “fit” with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity.ResultsThe NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981–0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of rs(134) = .92).ConclusionAlthough LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings.ImpactRecent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings.

Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach.

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods.

Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated with symptoms involving the central nervous system. In the 2010s, the structure of sugar chains involved in the onset of dystroglycanopathy and the functions of its causative gene products began to be identified as if they were filling the missing pieces of a jigsaw puzzle. In parallel with these discoveries, various dystroglycanopathy model mice had been created, which led to the elucidation of its pathological mechanisms. Then, treatment strategies based on the molecular basis of glycosylation began to be proposed after the latter half of the 2010s. This review briefly explains the sugar chain structure of dystroglycan and the functions of the causative gene products of dystroglycanopathy, followed by introducing the pathological mechanisms involved as revealed from analyses of dystroglycanopathy model mice. Finally, potential therapeutic approaches based on the pathological mechanisms involved are discussed.

Contraction-Induced Loss of Plasmalemmal Electrophysiological Function Is Dependent on the Dystrophin Glycoprotein Complex.

Weakness and atrophy are key features of Duchenne muscular dystrophy (DMD). Dystrophin is one of the many proteins within the dystrophin glycoprotein complex (DGC) that maintains plasmalemmal integrity and cellular homeostasis. The dystrophin-deficient mdx mouse is also predisposed to weakness, particularly when subjected to eccentric (ECC) contractions due to electrophysiological dysfunction of the plasmalemma. Here, we determined if maintenance of plasmalemmal excitability during and after a bout of ECC contractions is dependent on intact and functional DGCs rather than, solely, dystrophin expression. Wild-type (WT) and dystrophic mice (mdx, mL172H and Sgcb−/− mimicking Duchenne, Becker and Limb-girdle Type 2E muscular dystrophies, respectively) with varying levels of dystrophin and DGC functionality performed 50 maximal ECC contractions with simultaneous torque and electromyographic measurements (M-wave root-mean-square, M-wave RMS). ECC contractions caused all mouse lines to lose torque (p<0.001); however, deficits were greater in dystrophic mouse lines compared to WT mice (p<0.001). Loss of ECC torque did not correspond to a reduction in M-wave RMS in WT mice (p=0.080), while deficits in M-wave RMS exceeded 50% in all dystrophic mouse lines (p≤0.007). Moreover, reductions in ECC torque and M-wave RMS were greater in mdx mice compared to mL172H mice (p≤0.042). No differences were observed between mdx and Sgcb−/− mice (p≥0.337). Regression analysis revealed ≥98% of the variance in ECC torque loss could be explained by the variance in M-wave RMS in dystrophic mouse lines (p<0.001) but not within WT mice (R2=0.211; p=0.155). By comparing mouse lines that had varying amounts and functionality of dystrophin and other DGC proteins, we observed that (1) when all DGCs are intact, plasmalemmal action potential generation and conduction is maintained, (2) deficiency of the DGC protein β-sarcoglycan is as disruptive to plasmalemmal excitability as is dystrophin deficiency and, (3) some functionally intact DGCs are better than none. Our results highlight the significant role of the DGC plays in maintaining plasmalemmal excitability and that a collective synergism (via each DGC protein) is required for this complex to function properly during ECC contractions.

LGMD: EP.188 Elevation of fast but not slow muscle fiber injury biomarkers after exercise in Becker and LGMDR9 muscular dystrophies

Patients with muscular dystrophies (MDs) experience progressive muscle damage. A key approach to understand the nature and dynamics of the muscle damage is to examine the biomarker response to exercise. Type I and II muscle fibers differ in their troponin I (TnI) isoforms. We examined circulating TnI isoform response to exercise in patients with Becker (BMD) and, limb-girdle (LGMD) types R9 (FKRP) and R12 (ANO5) muscular dystrophies, as well as healthy controls. 27 subjects (6 BMD, 3 FKRP, 9 ANO5 and 9 controls) have been studied thus far.

LGMD: EP.182 Quality of life in dysferlinopathy can be good despite poor function

Measuring quality of life (QoL) in chronic conditions is complex. However, it is important for guiding management and may be required for approval of new treatments. Here we evaluate the QoL-gNMD neuromuscular quality of life assessment tool in patients with dysferlinopathy. Methods: Twenty genetically confirmed patients with dysferlinopathy were evaluated by trained physiotherapists during the first year of the Jain clinical outcomes study in dysferlinopathy extension study. Assessments included the QoL-gNMD, the ACTIVLIM and the North Star assessment for limb girdle type muscular dystrophy (NSAD).

CONGENITAL MUSCULAR DYSTROPHIES: EP.69 LAST STRONG: LAMA2 and SELENON to study trial readiness, outcome measures and natural history

SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset rigidity of the spine and respiratory insufficiency. Patients with mutations in LAMA2 gene causing merosin-deficient congenital muscular dystrophy (LAMA2-MD) have a similar clinical phenotype, with a heterogenous disease spectrum ranging from a severe, early-onset congenital (complete laminin α2 deficiency) to a mild, childhood-onset limb-girdle type muscular dystrophy (partial laminin α2 deficiency). For both SELENON-RM and LAMA2-MD, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data. Appropriate clinical and functional outcome measures need to be selected to reach trial readiness. We are performing a natural history study in Dutch-speaking patients diagnosed with SELENON-RM (n=10, mean age=18 (3-50) years, F=3, M=7) and LAMA2-MD (n=20, mean age=19 (3-50) years, F=15; M=5). Patients have four visits over a period of 1.5 year, with an interval of six months. At all visits, they undergo standard neurological examination, hand-held dynamometry (age≥5 years), functional measurements, questionnaires (patient report and/or parent proxy; age≥2 years), muscle ultrasound including ultrasound of the diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age≥5 years), and accelerometry for eight days; at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography), X-ray of the spine (age≥2 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age≥2 years) and full body magnetic resonance imaging (MRI) (age≥10 years). Hereby we aim to describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD and to select outcome measures for future clinical trials. Our natural history study is an essential step to reach trial readiness.

Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale

Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline. The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021.

Expanding the Clinico-Genetic Spectrum of Myofibrillar Myopathy: Experience From a Chinese Neuromuscular Center.

Background: Myofibrillar myopathy is a group of hereditary neuromuscular disorders characterized by dissolution of myofibrils and abnormal intracellular accumulation of Z disc-related proteins. We aimed to characterize the clinical, physiological, pathohistological, and genetic features of Chinese myofibrillar myopathy patients from a single neuromuscular center.Methods: A total of 18 patients were enrolled. Demographic and clinical data were collected. Laboratory investigations, electromyography, and cardiac evaluation was performed. Routine and immunohistochemistry stainings against desmin, αB-crystallin, and BAG3 of muscle specimen were carried out. Finally, next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders were performed.Results: Twelve pathogenic variants in DES, BAG3, FLNC, FHL1, and TTN were identified, of which seven were novel mutations. The novel DES c.1256C>T substitution is a high frequency mutation. The combined recessively/dominantly transmitted c.19993G>T and c.107545delG mutations in TTN gene cause a limb girdle muscular dystrophy phenotype with the classical myofibrillar myopathy histological changes.Conclusions: We report for the first time that hereditary myopathy with early respiratory failure patient can have peripheral nerve and severe spine involvement. The mutation in Ig-like domain 16 of FLNC is associated with the limb girdle type of filaminopathy, and the mutation in Ig-like domain 18 with distal myopathy type. These findings expand the phenotypic and genotypic correlation spectrum of myofibrillar myopathy.

Hereditary neuromuscular diseases. Part 1. Muscular dystrophies: dystrophinopathy emerinopathy and facio-scapulo-humeral forms

Written of history of the description of myopathies, modem classification of muscular dystrophies, clinical-genetic peculiarities of basic types of muscular dystrophies (dystrophinopathy, emerinopathy, facio-scapulo-limb type, limb-girdle types, distal types, ocylopharingeal and oculopharingodistal) and their diagnostic, pathogenesis and methods of treatment.

Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy

Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present an individual with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF)—a member of the Ferlin protein family and close homolog of DYSF—as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859QfsTer8 is supported by functional studies in vitro using the primary patient’s skeletal muscle mesenchymal progenitor cells, including both RNA sequencing and morphological studies, as well as recapitulating the muscle phenotype in vivo in zebrafish. We provide the first evidence supporting a role of MYOF in human muscle disease.

Overexpression of Mutant FKRP Restores Functional Glycosylation and Improves Dystrophic Phenotype in FKRP Mutant Mice

Autosomal recessive homozygous or compound heterozygous mutations in FKRP result in forms of muscular dystrophy-dystroglycanopathy varying in age of onset, clinical presentation, and disease progression, ranging from the severe Walker-Warburg, type A,5 (MDDGA5), muscle-eye-brain (MDDGB5) with or without cognitive deficit, to limb-girdle type 2I (MDDGC5). Phenotypic variation indicates degrees of functionality of individual FKRP mutation, which has been supported by the presence of residual expression of functionally glycosylated α-dystroglycan (DG) in muscles of both animal models and patients. However, direct evidence showing enhancement in glycosylation of α-DG by mutant FKRP is lacking. Using AAV9-mediated overexpression of mutant human FKRP bearing the P448L mutation (mhFKRP-P448L) associated with severe congenital muscular dystrophy (CMD), we demonstrate the restoration of functional glycosylation of α-DG and reduction in markers of disease progression. Expression of mhFKRP-P448L also corrects dystrophic phenotypes in the models of L276I mutation with mild disease phenotype and causes no obvious histological or biomarker alteration in C57BL/6 normal mice. Our results confirm the existing function of mutant FKRP. The results also suggest that mutant FKRP could be an alternative approach for potential gene therapy should normal FKRP gene products be immunogenic.