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Current Topics in Membranes 2015Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix... (Review)
Review
Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the α2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-α2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-α2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment.
Topics: Animals; Humans; Laminin; Muscular Dystrophies; Phenotype; Receptors, Cell Surface
PubMed: 26610911
DOI: 10.1016/bs.ctm.2015.05.002 -
Italian Journal of Pediatrics Aug 2016Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe... (Review)
Review
Congenital muscular dystrophies (CMDs) are a wide group of muscular disorders that manifest with very early onset of muscular weakness, sometime associated to severe brain involvement.The histologic pattern of muscle anomalies is typical of dystrophic lesions but quite variable depending on the different stages and on the severity of the disorder.Recent classification of CMDs have been reported most of which based on the combination of clinical, biochemical, molecular and genetic findings, but genotype/phenotype correlation are in constant progression due to more diffuse utilization of the molecular analysis.In this article, the Authors report on CMDs belonging to the group of dystroglycanopathies and in particular on the most severe forms represented by the Fukuyama CMD, Muscle-Eye-Brain disease and Walker Walburg syndrome.Clinical diagnosis of infantile hypotonia is particularly difficult considering the different etiologic factors causing the lesions, the difficulty in localizing the involved CNS area (central vs. peripheral) and the limited role of the diagnostic procedures at this early age.The diagnostic evaluation is not easy mainly in differentiating the various types of CMDs, and represents a challenge for the neonatologists and pediatricians. Suggestions are reported on the way to reach a correct diagnosis with the appropriate use of the diagnostic means.
Topics: Brain; Diagnosis, Differential; Humans; Infant, Newborn; Muscular Dystrophies; Severity of Illness Index
PubMed: 27576556
DOI: 10.1186/s13052-016-0289-9 -
Muscle & Nerve Jan 2018Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has... (Review)
Review
Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018.
Topics: Animals; Disease Models, Animal; Disease Progression; Genetic Therapy; High-Throughput Nucleotide Sequencing; Humans; Muscular Dystrophy, Duchenne; Muscular Dystrophy, Facioscapulohumeral
PubMed: 28877560
DOI: 10.1002/mus.25953 -
The Journal of Clinical Investigation Jun 2020Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical... (Review)
Review
Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.
Topics: Animals; CRISPR-Cas Systems; Dystrophin; Gene Editing; Humans; Muscular Dystrophy, Duchenne; Mutation
PubMed: 32478678
DOI: 10.1172/JCI136873 -
International Journal of Molecular... May 2021Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1... (Review)
Review
Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.
Topics: Annexin A1; Annexins; Cell Membrane; Humans; Membrane Proteins; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies
PubMed: 34067866
DOI: 10.3390/ijms22105276 -
Journal of the Neurological Sciences Feb 2016Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in...
BACKGROUND
Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice.
OBJECTIVE
To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature.
METHODS
We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation.
RESULTS
Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600).
CONCLUSION
Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Muscular Dystrophies; Pentosyltransferases; Proteins; Retrospective Studies; Rhabdomyolysis; Young Adult
PubMed: 26810512
DOI: 10.1016/j.jns.2015.12.013 -
Mutation Research. Reviews in Mutation... 2018Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been... (Review)
Review
Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been described to be related to a series of autosomal recessive disorders associated with defective alpha-dystroglycan glycosylation, later termed muscular dystrophy-dystroglycanopathies (MDDGs). MDDGs are characterized by a broad phenotypic spectrum of congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy, accompanied by variable degrees of intellectual disability, brain defects, and ocular abnormalities. To date, at least 76 disease-associated mutations in the POMT1 gene, including missense, nonsense, splicing, deletion, insertion/duplication, and insertion-deletion mutations, have been reported in the literature. In this review, we highlight the present knowledge of the identified disease-associated POMT1 gene mutations and genetic animal models related to the POMT1 gene. This review may help further normative classification of phenotypes, assist in definite clinical and genetic diagnoses, and genetic counseling, and may comprehensively improve our understanding of the basis of complex phenotypes and possible pathogenic mechanisms involved.
Topics: Alternative Splicing; Codon, Nonsense; Humans; INDEL Mutation; Mannosyltransferases; Muscular Dystrophies; Mutation, Missense; Walker-Warburg Syndrome
PubMed: 30454682
DOI: 10.1016/j.mrrev.2018.09.002 -
Clinical Transplantation Jun 2022Cardiac involvement may occur in many forms of muscular dystrophy (MD). While cardiac disease may progress to warrant heart transplantation (HTx), there may be...
INTRODUCTION
Cardiac involvement may occur in many forms of muscular dystrophy (MD). While cardiac disease may progress to warrant heart transplantation (HTx), there may be contraindications related to extra-cardiac disease including pulmonary and skeletal muscle involvement that limit overall survival and impairs post-transplant rehabilitation efforts. This study describes the MD HTx experience at a single high-volume center.
METHODS
We examined the clinical characteristics and outcomes of patients with MD with heart failure (HF) (n = 28), patients with MD status post HTx (n = 20) and non-MD HTx control group (n = 40) matched 2:1 for age at transplant, sex, listing status, and antibody sensitization.
RESULTS
Patients with MD who underwent HTx had increased ventilator days (2 vs. 1 days, p = .013), increased hospital length of stay (20 vs. 12 days, p = .022), and increased discharge to inpatient rehab (60% vs. 8%, p < .001). By 1 year post HTx, patients with MD more often required assistive devices for walking (55% vs. 10%, p = .01). Nonetheless, post-HTx survival was similar at 1 year (100% vs. 97.5%, p = .48) and 5 years (95.0% vs. 87.5%, p = .36). Of the HTx recipients with MD, 95% were followed by a neurologist, 60% by a neuromuscular specialist as part of the Muscular Dystrophy Association Clinic at our center.
CONCLUSION
Transplantation is a feasible option for patients with MD and advanced HF. MD patients who undergo transplantation may benefit from multidisciplinary specialized care to optimize MD-related morbidity.
Topics: Heart Diseases; Heart Failure; Heart Transplantation; Humans; Muscular Dystrophies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 35293038
DOI: 10.1111/ctr.14645 -
The Canadian Journal of Neurological... Jan 2016The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The muscular dystrophies are a heterogeneous group of genetic muscle diseases with variable distribution of weakness and mode of inheritance.
METHODS
We previously performed a systematic review of worldwide population-based studies on Duchenne and Becker muscular dystrophies; the current study focused on the epidemiology of other muscular dystrophies using Medline and EMBASE databases. Two reviewers independently reviewed all abstracts, full-text articles, and abstracted data from 1985 to 2011. Pooling of prevalence estimates was performed using random-effect models.
RESULTS
A total of 1104 abstracts and 167 full-text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The overall pooled prevalence of combined muscular dystrophies was 16.14 (confidence interval [CI], 11.21-23.23) per 100,000. The prevalence estimates per 100,000 were 8.26 (CI, 4.99-13.68) for myotonic dystrophy, 3.95 (CI, 2.89-5.40) for facioscapulohumeral dystrophy, 1.63 (CI, 0.94-2.81) for limb girdle muscular dystrophy, and 0.99 (CI, 0.62-1.57) for congenital muscular dystrophies.
CONCLUSIONS
The studies differed widely in their approaches to case ascertainment, and substantial gaps remain in the global estimates of many other types of muscular dystrophies. Additional epidemiological studies using standardized diagnostic criteria as well as multiple sources of case ascertainment will help address the economic impact and health care burden of muscular dystrophies worldwide.
Topics: Humans; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Facioscapulohumeral; Myotonic Dystrophy
PubMed: 26786644
DOI: 10.1017/cjn.2015.311 -
International Journal of Experimental... Dec 2014There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the... (Review)
Review
There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated.
Topics: Animals; Disease Models, Animal; Dystroglycans; Dystrophin; Humans; Mice, Inbred mdx; Mice, Knockout; Multiprotein Complexes; Muscular Dystrophies
PubMed: 25270874
DOI: 10.1111/iep.12095