Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report.

BACKGROUND: Dysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once. CASE PRESENTATION: We describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers. CONCLUSIONS: This case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

Insomnia and sleep-disordered breathing in FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020).

Limb-girdle muscular dystrophy R9 (LGMDR9) is a progressive and disabling genetic muscle disease. Sleep is relevant in the patient care as it impacts on health, functioning, and well-being. LGMDR9 may potentially affect sleep by physical or emotional symptoms, myalgia, or sleep-disordered breathing (SDB) through cardiorespiratory involvement. The objective was to investigate the occurrence of insomnia and unrecognized or untreated SDB in LGMDR9, associated factors, and relationships with fatigue and health-related quality of life (HRQoL). All 90 adults in a Norwegian LGMDR9 cohort received questionnaires on sleep, fatigue, and HRQoL. Forty-nine of them underwent clinical assessments and 26 without mask-based therapy for respiration disorders additionally underwent polysomnography (PSG) and capnometry. Among 77 questionnaire respondents, 31% received mask-based therapy. The prevalence of insomnia was 32% of both those with and without such therapy but was significantly increased in fatigued respondents (54% vs 21%). Insomnia levels correlated inversely with mental HRQoL. Among 26 PSG candidates, an apnea-hypopnea index (AHI) ≥ 5/h was observed in 16/26 subjects (≥ 15/h in 8/26) with median 6.8 obstructive apneas and 0.2 central apneas per hour of sleep. The AHI was related to advancing age and an ejection fraction < 50%. Sleep-related hypoventilation was detected in one subject. Fatigue severity did not correlate with motor function or nocturnal metrics of respiration or sleep but with Maximal Inspiratory Pressure (r = - 0.46). The results indicate that insomnia and SDB are underrecognized comorbidities in LGMDR9 and associated with HRQoL impairment and heart failure, respectively. We propose an increased attention to insomnia and SDB in the interdisciplinary care of LGMDR9. Insomnia and pulmonary function should be examined in fatigued patients.

RETINAL VASCULAR DISEASE IN LIMB-GIRDLE MUSCULAR DYSTROPHY.

PURPOSE: To report bilateral retinal vascular occlusive disease in limb-girdle muscular dystrophy (LGMD). METHODS: Case report. RESULTS: A 34-year-old Asian woman was referred for evaluation and management of central retinal vein occlusion. Ultra-wide-field fluorescein angiography showed resolving initial peripheral retinal vein occlusion in one eye and peripheral venular segmental staining in the fellow asymmetric eye. Genetic testing established the diagnosis of LGMD. CONCLUSION: Similar to other forms of muscular dystrophy, LGMD is caused by genetic abnormalities in sarcolemma proteins, a key structural component that connects the intracellular cytoskeleton of a myofiber to the extracellular matrix. Like other muscular dystrophies, LGMD may be associated with retinal vascular abnormalities noted. In this case, retinal vascular smooth muscle dysfunction was seen in LGMD, analogous to reported vascular abnormalities in other muscular dystrophies such as facioscapulohumeral dystrophy and Duchenne muscular dystrophy.

Pain interference and fatigue in limb-girdle muscular dystrophy R9.

Pain is prevalent in individuals with limb-girdle muscular dystrophy (LGMD) R9, but impact on daily living and correlation with fatigue remain unknown. Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference and fatigue short forms were completed annually by 23 children and 54 adults with biallelic fukutin-related protein (FKRP) variants for up to six years. Concurrent motor and pulmonary function were evaluated. Pain interference T-scores were near the normal mean of 50 by linear mixed model analysis (48.5 in children, 51.6 in adults). 58% of participants experienced pain interference levels greater than the general population on at least one assessment. Fatigue T-scores were elevated in adults but not children (49.0 in children, 55.1 in adults), and 75% had at least one elevated fatigue score. Of participants with at least two visits, serial scores were not consistent across visits, without a clear pattern. Pain interference and fatigue were positively correlated (r = 0.55). Both increased with older age (r = 0.21 and 0.41 respectively). Neither differed by sex or ambulation status. Motor (r=-0.32) and pulmonary (r=-0.25) function correlated with fatigue in adults, not children. Results suggest that pain in those with LGMDR9 is variable and episodic, limiting impact on daily life, while fatigue increases over time.

A new era: Speckle tracking echocardiography and cardiomyopathies.

Limb-girdle muscular dystrophy (LGMD) is a heterogeneous inherited disorder affecting the skeletal muscle and frequently also involve the heart and in LGMD; development of dilated cardiomyopathy is common and usually the predominant feature. Arrhythmias and conduction disease can be associated with the development of cardiomyopathy.

Evaluation of cardiomyopathy with two-dimensional speckle tracking echocardiography in limb-girdle muscular dystrophy type 2A and 2B.

PURPOSE: Cardiac involvement in limb-girdle muscular dystrophy (LGMD)2A and LGMD2B, the most common subgroups of LGMD, is controversial. Our study aims to determine whether myocardial dysfunction develops in LGMD2A and LGMD2B patients. METHODS: The study included 16 LGMD2A, 12 LGMD2B patients, and 48 healthy individuals. Comparisons included demographic, clinical, and laboratory parameters of LGMD2A and LGMD2B subgroups and traditional echocardiography and two-dimensional speckle tracking echocardiography (2D-STE) parameters with the normal population. RESULTS: The median age was 33 (22-39 interquartile range [IQR]) in the LGMD2A group, 33 (27-38 IQR) in the LGMD2B group, and 28 (25-35 IQR) in the control group. The left ventricular (LV) ejection fraction of both LGMD2A and LGMD2B groups was similar to the control group (p = 0.296 and p = 0.918). Apical 4-chamber longitudinal strain (LS), Apical 2-chamber LS, Apical 3-chamber LS, left ventricular global longitudinal strain (LVGLS)-mid-myocardial, LVGLS-endocardium, and LVGLS-epicardium were lower (less negative) in the LGMD2B group compared to the control group (p = 0.006, p = 0.001, p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively). CONCLUSION: LV 2D-STE parameters of LGMD2A patients were similar to the control group, while they decreased significantly (less negative) in LGMD2B patients, indicating that LV subclinical myocardial dysfunction may develop in LGMD2B patients.

Slowly Progressive Limb-Girdle Weakness and HyperCKemia - Limb Girdle Muscular Dystrophy or Anti-3-Hydroxy-3-Methylglutaryl-CoA-Reductase-Myopathy?

BACKGROUND: Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)-myopathy is a usually rapidly progressive form of immune-mediated necrotizing myopathy (IMNM). Rarer clinical courses show slow progression and resemble the phenotype of limb-girdle dystrophy (LGMD). OBJECTIVE: We demonstrate the difficulties in differentiating LGMD versus anti-HMGCR-myopathy. METHODS: We report on a 48-year-old patient with slowly progressive tetraparesis and hyperCKemia for more than 20 years. RESULTS: Due to myopathic changes in initial and second muscle biopsy and typical clinical presentation, the patient was diagnosed with LGMD 20 years ago; despite comprehensive genetic testing including exome diagnostics, the genetic cause of disease could not be identified. Finally, HMG-CoA reductase antibodies were detected, confirming the diagnosis of anti-HMGCR-myopathy. By re-work-up of a second muscle biopsy specimen from year 2009, the diagnosis of a IMNM was made in retrospect. Seven cycles of high-dose immunoglobulins were administered; patient reported outcome measures have mildly improved. CONCLUSION: Patients with clinical LGMD phenotype, degenerative changes in muscle biopsy but without genetic confirmation of the disease should be tested for HMG-CoA-myopathy, thereby allowing for an early start of treatment.

2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders.

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by the Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.

Inhibition of autophagy rescues muscle atrophy in a LGMDD2 Drosophila model.

Limb-girdle muscular dystrophy D2 (LGMDD2) is an ultrarare autosomal dominant myopathy caused by mutation of the normal stop codon of the TNPO3 nuclear importin. The mutant protein carries a 15 amino acid C-terminal extension associated with pathogenicity. Here we report the first animal model of the disease by expressing the human mutant TNPO3 gene in Drosophila musculature or motor neurons and concomitantly silencing the endogenous expression of the fly protein ortholog. A similar genotype expressing wildtype TNPO3 served as a control. Phenotypes characterization revealed that mutant TNPO3 expression targeted at muscles or motor neurons caused LGMDD2-like phenotypes such as muscle degeneration and atrophy, and reduced locomotor ability. Notably, LGMDD2 mutation increase TNPO3 at the transcript and protein level in the Drosophila model Upregulated muscle autophagy observed in LGMDD2 patients was also confirmed in the fly model, in which the anti-autophagic drug chloroquine was able to rescue histologic and functional phenotypes. Overall, we provide a proof of concept of autophagy as a target to treat disease phenotypes and propose a neurogenic component to explain mutant TNPO3 pathogenicity in diseased muscles.

Combined high flow nasal cannula and negative pressure ventilation as a novel respiratory approach in a patient with acute respiratory failure and limb-girdle muscular dystrophy.

We describe the case of a 56-year-old-man with limb-girdle muscular dystrophy affected by acute hypercapnic failure secondary to pneumonia treated with high flow nasal cannula, intermittent abdominal ventilation, and negative pressure ventilation. The patient did not tolerate noninvasive positive pressure ventilation and refused invasive ventilation and tracheostomy. We successfully experienced a novel approach combining high flow nasal cannula with cycles of intermittent abdominal pressure ventilation and negative pressure ventilation.

Respiratory muscle involvement in HNRNPDL LGMD D3 muscular dystrophy: an extensive clinical description of the first Italian patient.

Limb girdle muscular dystrophy is a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation. Autosomal dominant LGMD represent 10% of all LGMDs. HNRNPDL-related muscular dystrophy, LGMD1G/LGMD D3 (MIM#609115), is an extremely rare autosomal dominant adult onset myopathy described in a handful of families. Here we fully characterized the muscular and respiratory involvement of a 58 years old Italian woman presenting the previously reported pathogenic variant c.1132G > C p.(Asp378Asn) in the HNRNPDL gene.

Limb girdle muscular dystrophy due to LAMA2 gene mutations: new mutations expand the clinical spectrum of a still challenging diagnosis.

Mutations in LAMA2 gene, encoding merosin, are generally responsible of a severe congenital-onset muscular dystrophy (CMD type 1A) characterized by severe weakness, merosin absence at muscle analysis and white matter alterations at brain Magnetic Resonance Imaging (MRI). Recently, LAMA2 mutations have been acknowledged as responsible of LGMD R23, despite only few cases with slowly progressive adult-onset and partial merosin deficiency have been reported. We describe 5 independent Italian subjects presenting with progressive limb girdle muscular weakness, brain white matter abnormalities, merosin deficiency and LAMA2 gene mutations. We detected 7 different mutations, 6 of which are new. All patients showed normal psicomotor development and slowly progressive weakness with onset spanning from childhood to forties. Creatin-kinase levels were moderately elevated. One patient showed dilated cardiomyopathy. Muscle MRI allowed to evaluate the degree and pattern of muscular involvement in all patients. Brain MRI was fundamental in order to address and/or support the molecular diagnosis, showing typical widespread white matter hyperintensity in T2-weighted sequences. Interestingly these alterations were associated with central nervous system involvement in 3 patients who presented epilepsy and migraine. Muscle biopsy commonly but not necessarily revealed dystrophic features. Western-blot was usually more accurate than immunohystochemical analysis in detecting merosin deficiency. The description of these cases further enlarges the clinical spectrum of LAMA2-related disorders. Moreover, it supports the inclusion of LGMD R23 in the new classification of LGMD. The central nervous system involvement was fundamental to address the diagnosis and should be always included in the diagnostic work-up of undiagnosed LGMD.

Cardiomyopathy in limb girdle muscular dystrophy R9, FKRP related.

INTRODUCTION: Reported frequencies of cardiomyopathy in limb girdle muscular dystrophy R9 (LGMDR9) vary. We describe the frequency and age at onset of cardiomyopathy in an LDMDR9 cohort. METHODS: Echocardiograms from 56 subjects (157 echocardiograms) with LGMDR9 were retrospectively reviewed. The cumulative probability of having an abnormal echocardiogram as a function of age was assessed by survival analysis for interval-censored data by genotype. Correlations between cardiac and clinical function were evaluated. RESULTS: Twenty-five (45%) participants had cardiomyopathy. The median age at first abnormal echocardiogram for subjects homozygous for the c.826C>A variant was 54.2 y compared to 18.1 y for all other fukutin-related protein (FKRP) genotypes (P < .0001). There was a weak correlation between ejection fraction and 10-Meter Walk Test speed (r = 0.25), but no correlation with forced vital capacity (r = 0.08). DISCUSSION: Cardiomyopathy is prevalent among those with LGMDR9 and occurs later in subjects homozygous for the c.826C>A mutation. These data will help to guide surveillance and management.

The use of ivabradine in a patient with inappropriate sinus tachycardia and cardiomyopathy due to limb girdle muscular dystrophy type 2I.

Muscular dystrophies are a heterogeneous group of disorders that commonly involve cardiac and skeletal muscle. Comprehensive guidelines for the management of cardiac failure and arrhythmias are available. However, the studies from which their recommendations are derived did not include any patients with muscular dystrophy. Some medications (eg, betablockers) may have significant side effects in this cohort. In some situations the use of agents with unique mechanisms of action such as ivabradine (a 'funny' channel inhibitor) may be more appropriate. Use of ivabradine has not previously been reported in limb girdle muscular dystrophy (LGMD). We describe the course of a patient with LGMD type 2I, cardiomyopathy and inappropriate sinus tachycardia treated with ivabradine. As advances in respiratory support have improved the outcomes of patients with muscular dystrophy; the prognostic significance of cardiac disease has increased. Ivabradine is tolerated and may reduce symptoms, morbidity and mortality in this cohort.

Cardiac Intervention Improves Heart Disease and Clinical Outcomes in Patients With Muscular Dystrophy in a Multidisciplinary Care Setting.

Background Patients with muscular dystrophy (MD) represent a vulnerable patient population with no clearly defined care model in modern-day clinical practice to manage a high burden of heart disease and comorbidities. We demonstrate the effectiveness of cardiac interventions, namely the initiation and optimization of medical and device therapies, as part of a multidisciplinary care approach to improve clinical outcomes in patients with MD. Methods and Results We conducted a prospective cohort study at the Neuromuscular Multidisciplinary clinic following patients with dystrophinopathies, limb-girdle MD, type 1 myotonic dystrophy, and facioscapulohumeral MD. A negative control group classified as non-MD myopathies without heart disease, was also tracked. Our cohort of 185 patients (median age: 42 years; 79 [42.7%] women), included 145 patients with MD. Cardiomyopathy was present in 65.6% of the patients with dystrophinopathies (21 of 32) and 27.3% of the patients with limb-girdle MD (9 of 33). Conduction abnormalities were common in type 1 myotonic dystrophy (33.3% [20/60] patients). Cardiac intervention reversed systolic dysfunction, with left ventricular ejection fraction improving from 43% to 50.0% over a 3-year period. A sustained reduction in healthcare utilization was also observed. The number of outpatient clinic visits decreased from 3.0 to 1.5 visits per year, the duration of hospitalizations was reduced from 14.2 to 0.9 days per year, and the number of cardiac-related hospitalizations decreased from 0.4 to 0.1 hospitalizations per year associated with low mortality. Conclusions Our study demonstrates that cardiac intervention as part of a comprehensive multidisciplinary care approach to treating patients with MD leads to a sustained improvement in clinical outcomes.

Dilated cardiomyopathy and limb-girdle muscular dystrophy-dystroglycanopathy due to novel pathogenic variants in the DPM3 gene.

Deficiency of Dolichol-P-mannose synthase subunit 3 (DPM3) affects the N-glycosylation and O-mannosylation pathways that are respectively involved in congenital disorders of glycosylation (CDG) and alpha-dystroglycanopathies. Herein, we describe novel pathogenic variants in the DPM3 gene in two unrelated male patients. They developed dilated cardiomyopathy in their late teens, limb-girdle muscular dystrophy - one patient in childhood and the other in adulthood. In both patients, next generation sequencing found in the DPM3 gene a heterozygous deletion and a heterozygous pathogenic missense mutation in exon 2 (c.41T>C, p.Leu14Pro). Electrophoresis of serum transferrin found an abnormal N-glycosylation profile suggestive of CDG type 1 (decreased tetrasialotransferrin, increased disialo- and asialotransferrin). Only two cases of DPM3 gene mutations with limb-girdle muscular dystrophy-dystroglycanopathy have been reported previously. The present study highlights several aspects related to DPM3 gene mutations such as mild to moderately severe limb-girdle muscular dystrophy, dilated cardiomyopathy, and abnormal N-glycosylation profile suggestive of CDG type 1.

An update on diagnostic options and considerations in limb-girdle dystrophies.

INTRODUCTION: Limb-girdle muscular dystrophies (LGMDs) encompass a clinically heterogeneous group of rare, genetic progressive muscle disorders presenting with weakness and atrophy of predominant pelvic and shoulder muscles. The spectrum of disease severity ranges from severe childhood-onset muscular dystrophy to adult-onset dystrophy. Areas covered: The review presents an update of the clinical phenotypes and diagnostic options for LGMD including both dominant and recessive LGMD and consider their differential clinical and histopathological features. An overview of most common phenotypes and of possible complications is given. The management of the main clinical respiratory, cardiac, and central nervous system complications are covered. The instrumental, muscle imaging, and laboratory exams to assess and reach diagnosis are described. The use of recent genetic techniques such as next generation sequencing (NGS), whole-exome sequencing compared to other techniques (e.g. DNA sequencing, protein analysis) is covered. Currently available drugs or gene therapy and rehabilitation management are focused on. Expert commentary: Many LGMD cases, which for a long time previously remained without a molecular diagnosis, can now be investigated by NGS. Gene mutation analysis is always required to obtain a certain molecular diagnosis, fundamental to select homogeneous group of patients for future pharmaceutical and gene trials.