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Seminars in Neurology Aug 2015The dystrophinopathies fall along a spectrum of muscular dystrophy phenotypes, with variable involvement of skeletal and cardiac muscle. The diagnosis of... (Review)
Review
The dystrophinopathies fall along a spectrum of muscular dystrophy phenotypes, with variable involvement of skeletal and cardiac muscle. The diagnosis of dystrophinopathy should be suspected in any patient with a highly elevated creatine kinase level beyond the context of rhabdomyolysis secondary to toxic or metabolic myopathy. Genetic testing for dystrophinopathy is highly sensitive and specific, and identifying a proband will often lead to implications for several relatives at risk for cardiomyopathy, weakness, or anesthetic reactions. Management of the dystrophinopathies is focused primarily on supportive care, although steroid therapy has changed the natural history of Duchenne muscular dystrophy and it is now standard-of-care internationally. An exciting and ongoing area of investigation of the dystrophinopathies is focused on the potential for altering gene expression, as a way of improving muscle health and slowing the rate of muscle degeneration.
Topics: Disease Management; Dystrophin; Genetic Testing; Humans; Muscles; Muscular Dystrophies; Phenotype
PubMed: 26502761
DOI: 10.1055/s-0035-1558982 -
Handbook of Clinical Neurology 2023Infancy- and childhood-onset muscular dystrophies are associated with a characteristic distribution and progression of motor dysfunction. The underlying causes of... (Review)
Review
Infancy- and childhood-onset muscular dystrophies are associated with a characteristic distribution and progression of motor dysfunction. The underlying causes of progressive childhood muscular dystrophies are heterogeneous involving diverse genetic pathways and genes that encode proteins of the plasma membrane, extracellular matrix, sarcomere, and nuclear membrane components. The prototypical clinicopathological features in an affected child may be adequate to fully distinguish it from other likely diagnoses based on four common features: (1) weakness and wasting of pelvic-femoral and scapular muscles with involvement of heart muscle; (2) elevation of serum muscle enzymes in particular serum creatine kinase; (3) necrosis and regeneration of myofibers; and (4) molecular neurogenetic assessment particularly utilizing next-generation sequencing of the genome of the likeliest candidates genes in an index case or family proband. A number of different animal models of therapeutic strategies have been developed for gene transfer therapy, but so far these techniques have not yet entered clinical practice. Treatment remains for the most part symptomatic with the goal of ameliorating locomotor and cardiorespiratory manifestations of the disease.
Topics: Animals; Child; Humans; Muscular Dystrophies; Proteins
PubMed: 37562882
DOI: 10.1016/B978-0-323-98818-6.00024-8 -
Clinical Genetics Aug 2019In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular...
In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.
Topics: Alleles; Biomarkers; Biopsy; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Muscular Dystrophies, Limb-Girdle; Netherlands; Phenotype; Population Surveillance; Retrospective Studies
PubMed: 30919934
DOI: 10.1111/cge.13544 -
Heart Rhythm Oct 2022This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for...
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.
Topics: Arrhythmias, Cardiac; Humans; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Emery-Dreifuss; Myotonic Dystrophy
PubMed: 35500790
DOI: 10.1016/j.hrthm.2022.04.022 -
Biochimica Et Biophysica Acta Apr 2015Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD,... (Review)
Review
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
Topics: Alleles; Animals; Apoptosis; Chromatin; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Chromosomes, Human, Pair 4; Epigenesis, Genetic; Genetic Diseases, Inborn; Genetic Loci; Homeodomain Proteins; Humans; Muscular Dystrophies; Mutation; Repetitive Sequences, Nucleic Acid
PubMed: 24882751
DOI: 10.1016/j.bbadis.2014.05.021 -
Genes Jan 2023GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose... (Review)
Review
GDP-mannose pyrophosphorylase B (GMPPB) is a cytoplasmic protein that catalyzes the formation of GDP-mannose. Impaired GMPPB function reduces the amount of GDP-mannose available for the O-mannosylation of α-dystroglycan (α-DG) and ultimately leads to disruptions of the link between α-DG and extracellular proteins, hence dystroglycanopathy. GMPPB-related disorders are inherited in an autosomal recessive manner and caused by mutations in either a homozygous or compound heterozygous state. The clinical spectrum of GMPPB-related disorders spans from severe congenital muscular dystrophy (CMD) with brain and eye abnormalities to mild forms of limb-girdle muscular dystrophy (LGMD) to recurrent rhabdomyolysis without overt muscle weakness. mutations can also lead to the defect of neuromuscular transmission and congenital myasthenic syndrome due to altered glycosylation of the acetylcholine receptor subunits and other synaptic proteins. Such impairment of neuromuscular transmission is a unique feature of GMPPB-related disorders among dystroglycanopathies. LGMD is the most common phenotypic presentation, characterized by predominant proximal weakness involving lower more than upper limbs. Facial, ocular, bulbar, and respiratory muscles are largely spared. Some patients demonstrate fluctuating fatigable weakness suggesting neuromuscular junction involvement. Patients with CMD phenotype often also have structural brain defects, intellectual disability, epilepsy, and ophthalmic abnormalities. Creatine kinase levels are typically elevated, ranging from 2 to >50 times the upper limit of normal. Involvement of the neuromuscular junction is demonstrated by the decrement in the compound muscle action potential amplitude on low-frequency (2-3 Hz) repetitive nerve stimulation in proximal muscles but not in facial muscles. Muscle biopsies typically show myopathic changes with variable degrees of reduced α-DG expression. Higher mobility of β-DG on Western blotting represents a specific feature of GMPPB-related disorders, distinguishing it from other α-dystroglycanopathies. Patients with clinical and electrophysiologic features of neuromuscular transmission defect can respond to acetylcholinesterase inhibitors alone or combined with 3,4 diaminopyridine or salbutamol.
Topics: Humans; Acetylcholinesterase; Mannose; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophies; Dystroglycans; Muscle Weakness
PubMed: 36833299
DOI: 10.3390/genes14020372 -
Biomolecules Oct 2023Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as... (Review)
Review
Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue. Anti-inflammatory glucocorticoids represent the standard of care for Duchenne muscular dystrophy, the most common muscular dystrophy worldwide; however, long-term exposure to glucocorticoids results in highly adverse side effects, limiting their use. Thus, it is important to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair. Here, we examine the pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies.
Topics: Humans; Muscular Dystrophy, Duchenne; Heart; Cardiomyopathies; Inflammation; Fibrosis
PubMed: 37892218
DOI: 10.3390/biom13101536 -
Continuum (Minneapolis, Minn.) Dec 2019Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy affecting both pediatric and adult patients. This article reviews the phenotype and... (Review)
Review
PURPOSE OF REVIEW
Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy affecting both pediatric and adult patients. This article reviews the phenotype and pathophysiology of the disease as well as the recent efforts in clinical outcome measures and clinical trials.
RECENT FINDINGS
As the name implies, FSHD involves weakness of facial muscles, muscles that fix the scapula, and muscles overlying the humerus (biceps and triceps). The distinctive phenotype of FSHD occurs secondary to two different genetic mechanisms. FSHD type 1 (FSHD1) is due to a deletion on chromosome 4q, leading to hypomethylation and derepression of DUX4. FSHD type 2 (FSHD2) is due to mutations in SMCHD1 with resulting hypomethylation of the same subtelomeric region of chromosome 4q and derepression of DUX4. Understanding the central role of DUX4 has opened up the possibility of disease-modifying treatments. In preparation for clinical trials of novel agents, researchers are in the process of validating a number of clinical trial outcome measures including MRI, the 6-minute walk test, the FSHD Composite Outcome Measure, reachable workspace, electrical impedance myography, and the FSHD Health Index.
SUMMARY
The treatment of FSHD is currently supportive only. While past clinical trials in FSHD have been largely disappointing, novel agents in development, including antisense oligonucleotides, gene therapy, and small molecules, hold promise for future meaningful therapies.
Topics: Child; Female; Humans; Male; Middle Aged; Muscular Dystrophy, Facioscapulohumeral
PubMed: 31794465
DOI: 10.1212/CON.0000000000000801 -
Journal of Biochemistry Jan 2015Most proteins are modified by glycans, which can modulate the biological properties and functions of glycoproteins. The major glycans can be classified into N-glycans... (Review)
Review
Most proteins are modified by glycans, which can modulate the biological properties and functions of glycoproteins. The major glycans can be classified into N-glycans and O-glycans according to their glycan-peptide linkage. This review will provide an overview of the O-mannosyl glycans, one subtype of O-glycans. Originally, O-mannosyl glycan was only known to be present on a limited number of glycoproteins, especially α-dystroglycan (α-DG). However, once a clear relationship was established between O-mannosyl glycan and the pathological mechanisms of some congenital muscular dystrophies in humans, research on the biochemistry and pathology of O-mannosyl glycans has been expanding. Because α-DG glycosylation is defective in congenital muscular dystrophies, which also feature abnormal neuronal migration, these disorders are collectively called α-dystroglycanopathies. In this article, I will describe the structure, biosynthesis and pathology of O-mannosyl glycans.
Topics: Dystroglycans; Glycomics; Glycosylation; Humans; Muscular Dystrophies; Mutation; Polysaccharides
PubMed: 25381372
DOI: 10.1093/jb/mvu066 -
Trends in Cell Biology Mar 2021Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the... (Review)
Review
Fukutin-related protein (FKRP) is a glycosyltransferase involved in the functional glycosylation of α-dystroglycan (DG), a key component in the link between the cytoskeleton and the extracellular matrix (ECM). Mutations in FKRP lead to dystroglycanopathies with broad severity, including limb-girdle and congenital muscular dystrophy. Studies over the past 5 years have elucidated the function of FKRP, which has expanded the number of therapeutic opportunities for patients carrying FKRP mutations. These include small molecules, gene delivery, and cell therapy. Here we summarize recent findings on the function of FKRP and describe available models for studying diseases and testing therapeutics. Lastly, we highlight preclinical studies that hold potential for the treatment of FKRP-associated dystroglycanopathies.
Topics: Dystroglycans; Glycosylation; Glycosyltransferases; Humans; Muscular Dystrophies; Pentosyltransferases
PubMed: 33272829
DOI: 10.1016/j.tcb.2020.11.003