identified the underlying genetic defect in the PLIN4 gene, encoding for perilipin-4 63. (GNE) gene causes DMRV/hIBM. Myopathy is a general term used to describe a number of conditions affecting the muscles. Core-rod myopathy caused by mutations in the nebulin gene. Muller TJ, Kraya T, Stoltenburg-Didinger G, et al. CAV3 expression can be reduced. A missense variant (p.E384K) in TIA1 gene causing the disease was identified in 2013 10. Bitoun M, Bevilacqua JA, Prudhon B, et al. Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: first report from the GNE myopathy Disease Monitoring Program, registry portion. Lehtokari VL, Kiiski K, Sandaradura SA, et al. Another missense change, p.C203Y, has been recently found to cause an upper limb distal myopathy with nemaline bodies 183. More advanced histopathological techniques and refined cell and molecular biology studies have resulted in a better understanding of the pathophysiology of distal myopathies. . Griffin DA, Johnson RW, Whitlock JM, et al. With myopathy, these muscles work less effectively than they should, causing weakness and other symptoms. Schneider I, Stoltenburg G, Deschauer M, et al. MRI studies shows fatty infiltration of the calf muscles 302. Kimonis VE, Mehta SG, Fulchiero EC, et al. A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy, Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies, Eight new mutations and the expanding phenotype variability in muscular dystrophy caused by ANO5. Kazamel M, Sorenson EJ, McEvoy KM, et al. Perilipin-4 is a member of the perilipin family, a group of proteins that coat the surface of lipid droplets 64. Silva AMS, Coimbra-Neto AR, Souza PVS, et al. Although two patients with weakness in hands and in legs or feet were first described as distal myopathy by Gowers over 100 years ago 1, only in 1998 the first genetic defect underlying a distal myopathy was identified 2. Further gene panel sequencing in these patients showed the presence of SQSTM1 mutations previously known to cause the Pagets disease of the bone, a dominant disease with reduced penetrance 15. . Girolami F, Iascone M, Tomberli B, et al. Vazquez J, Lefeuvre C, Escobar RE, et al. The myofibrillar myopathy with aggregates and rimmed vacuoles mimics the histopathological changes seen in myopathies caused by defects in BAG3 and DNAJB6 However, one patient, homozygous for a missense variant, shows a proximal myopathy with contractures and muscle atrophy, expanding the ADSSL-related spectrum of phenotypes 274. Claeys KG, Zuchner S, Kennerson M, et al. Dysferlinopathy in Iran: clinical and genetic report, The limb-girdle muscular dystrophies-multiple genes, multiple mechanisms, Genetic basis of limb-girdle muscular dystrophies: the 2014 update, Late onset in dysferlinopathy widens the clinical spectrum, Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy, Atypical phenotypes in titinopathies explained by second titin mutations. Entry - #604454 - WELANDER DISTAL MYOPATHY; WDM - OMIM GNE is susceptible to Alu-mediated recombination, and copy number variants (CNV) have been reported suggesting the utility of second-tier tests in case of an uninformative sequencing analysis aiming at the identification of single nucleotide variants 164-167. Mutations in DNAJB6, specifically in the G/F domain, cause more often a proximal myopathy (LGMD1D) 187-193. Muscle MRI shows a predominant involvement of the lower legs both anterior and posterior compartment and hamstrings in thighs 39. Expanding the boundaries of RNA sequencing as a diagnostic tool for rare mendelian disease. Laing distal myopathy is a rare autosomal dominant inherited distal myopathy caused by mutations of the MYH7 gene affecting mainly the rod region. Tajsharghi H, Oldfors A, Macleod DP, et al. Molecular and muscle pathology in a series of caveolinopathy patients, Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia, Phenotypic variability in rippling muscle disease. Johnson JO, Pioro EP, Boehringer A, et al. A large Italian family with an autosomal dominant adult-onset distal myopathy and histopathological features of rimmed vacuoles was first described in 2004 62. Despite extensive later studies, this gene has not been confirmed in any other myopathy families. Five distinct predominant distal myopathies have been identified with discrete clinical and genetic patterns. Three different RYR1 mutations were identified in different parts of the gene, which encodes ryanodine receptor 1, a calcium release channel of the sarcoplasmic reticulum that, together with sarcolemmal voltage-gated calcium channels (DHPR), is responsible for the excitation-contraction coupling. Manage a case of inflammatory myopathy. although the distal muscles . Typically, the first symptom of distal muscular dystrophy (DD) is weakness in the distal muscles those farthest away from the hips and shoulders such as those in the hands, feet, lower arms or lower legs. Myopathic changes with rimmed vacuoles are observed in the muscle biopsy. Rusmini P, Cristofani R, Galbiati M, et al. CK levels are normal or mildly elevated. Most commonly, missing or defective proteins in the muscles prevent muscle cells from working properly, leading to symptoms of muscular dystrophy, including muscle weakness and wasting over time. Currently, almost 20 genes (ACTN2, CAV3, CRYAB, DNAJB6, DNM2, FLNC, HNRNPA1, HSPB8, KHLH9, LDB3, MATR3, MB, MYOT, PLIN4, TIA1, VCP, NOTCH2NLC, LRP12, GIPS1) have been associated with an autosomal dominant form of distal myopathy. Olive M, Engvall M, Ravenscroft G, et al. Dynamin-2 mutations linked to centronuclear myopathy impair actin-dependent trafficking in muscle cells, A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice. Distal myopathies In this article, distal myopathy syndromes are discussed. Myopathy Causes, Symptoms, and Treatment - Verywell Health Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Feit H, Silbergleit A, Schneider LB, et al. Clinical spectrum of valosin containing protein (VCP)-opathy. The FLNC gene encodes filamin, an actin ligand that plays an important role in mechanical stabilization, mechanosensation and intracellular signalling through a large network of interactors 174,175. Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture, Common pathogenic mechanism in patients with dropped head syndrome caused by different mutations in the MYH7 gene, Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment, Variant interpretation for dilated cardiomyopathy: refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study, Clinical utility of a phenotype-enhanced MYH7-specific variant classification framework in hypertrophic cardiomyopathy genetic testing, MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy, Laing early-onset distal myopathy with subsarcolemmal hyaline bodies caused by a novel variant in the MYH7 gene. Codependent functions of RSK2 and the apoptosis-promoting factor TIA-1 in stress granule assembly and cell survival, The apoptosis-promoting factor TIA-1 is a regulator of alternative pre-mRNA splicing, TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations, Tibial muscular dystrophy: late adult-onset distal myopathy in 66 Finnish patients, Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. The ADSSL gene encodes the muscle isozyme of adenylosuccinate synthase, the enzyme catalysing the initial reaction in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP) 271,272. Most of the disorders causing distal myopathic weakness are genetically based. 2023, Muscular Dystrophy Association Inc. All rights reserved. The term distal myopathy refers to a long list of genetic muscle diseases presenting at the onset with weakness of distal extremities, usually combined with progressive atrophy of the corresponding distal muscles. Central core disease due to recessive mutations in RYR1 gene: is it more common than described? In 2019, ACTN2 gene was firstly identified to be a cause of a new adult-onset distal muscular dystrophy calling actininopathy and another distinctly different myopathy, named multiple structured core disease (MsCD). Our genes are made of DNA and reside in our chromosomes. Linkage analysis suggested that the causative gene could have been localized in the 19p13.3 locus 62. Distal Myopathies Types of Distal MD The distal dystrophies, or DDs, are caused by many different genetic defects, not all of which are yet known. Myotilinopathy in a family with late onset myopathy, Mutations in myotilin cause myofibrillar myopathy, Different early pathogenesis in myotilinopathy compared to primary desminopathy, New insights into the protein aggregation pathology in myotilinopathy by combined proteomic and immunolocalization analyses, Distinct muscle imaging patterns in myofibrillar myopathies, The diagnostic value of MRI pattern recognition in distal myopathies. Pogoryelova O, Cammish P, Mansbach H, et al. Pollazzon M, Suominen T, Penttila S, et al. adj., adj myopathic. Phenotype of matrin-3-related distal myopathy in 16 German patients, The first French case of MATR3-related distal myopathy: clinical, radiological and histopathological characterization, Impairment of respiratory function in late-onset distal myopathy due to MATR3 Mutation, Whole-body muscle MRI of patients with MATR3-associated distal myopathy reveals a distinct pattern of muscular involvement and highlights the value of whole-body examination, Molecular cloning of matrin 3. Following the FINmaj identification, missense variants in the same exon (364) were also identified in non-Finnish patients 17-19. DNM2-related myopathy is an autosomal dominant slowly progressive centronuclear myopathy characterized by the presence of centrally located nuclei in a several muscle fibres 289. EMG shows myopathic changes and rimmed vacuoles are present in the biopsy. Serum CK is normal or mildly elevated and muscle imaging shows fatty degeneration in anterior tibial muscles and at later stage in all long toe extensors, hamstring and medial gastrocnemius muscles. HMERF titinopathy (i.e. Nemaline myopathy caused by mutations in the nebulin gene may present as a distal myopathy. 49-53. WDM was first described in several Swedish families in 1951 as an autosomal dominant late adult-onset (usually over 50 years) disease with a prominent early involvement of fingers and wrist extensors 9. The term spheroid body myopathy was also used since the protein aggregates in some cases have the corresponding shape 89,90. Many times muscular dystrophy appears to have occurred out of the blue, but in reality, one or both parents may be carriers, silently harboring the genetic mutation. Ishiguro K, Nakayama T, Yoshioka M, et al. Inflammatory Myopathies | National Institute of Neurological Disorders GNE Myopathy - Symptoms, Causes, Treatment | NORD Mroczek M, Durmus H, Bijarnia-Mahay S, et al. Welander distal myopathy, Swedish type - About the Disease - Genetic Characteristic findings of skeletal muscle MRI in caveolinopathies, CAV3 mutation in a patient with transient hyperCKemia and myalgia. Feinstein-Linial M, Buvoli M, Buvoli A, et al. None of the patients had signs of Paget disease of the bone. Through a large number of alternative splicing events, TTN encodes for a large number of different transcripts, developmental-stage or tissue specific 23,24. Typically, the cardiac muscle is spared. Myositis is the term used to describe a group of conditions that cause chronic muscle inflammation, damage, weakness, and (sometimes) pain. Gonzlez-Jamett AM, Baez-Matus X, Olivares MJ, et al. A long range of other myopathies needs to be considered in the differential diagnostics since they may show prominent distal weakness and/or atrophy: Despite the huge developments in the last 20 years to uncover the genetic cause of distal myopathy, some families and patients still remain without a final diagnosis. Causes Diagnosis Treatment Distal muscular dystrophy (DD), also called distal myopathy, is not one disorder, but a group of genetic disorders under the larger umbrella of muscular dystrophy. Abath Neto O, Martins Cde A, Carvalho M, et al. centronuclear myopathy myotubular myopathy . [1] Signs and symptoms CRYAB-related distal myopathy mainly involves the anterior part of the distal leg at the early stage and progresses with a milder proximal weakness. Histopathological features are consistent with myofibrillar myopathy and include rimmed and non-rimmed vacuoles, and myofibrillar disorganization with myotilin accumulations 79-81. Myopathies may be passed on in families (inherited) or they may develop later in life (acquired). After 25 years of disease, the patients became affected by a progressive frontotemporal dementia. Valosin-containing protein-related myopathy and Meige syndrome: Just a coincidence or not? The causative gene (GNE) was identified in 2001 155 and, since then, patients have been reported worldwide. A novel MYH7 founder mutation causing Laing distal myopathy in Southern Spain, Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report. Boland-Freitas R, Graham J, Davis M, et al. Marcos AT, Amoros D, Munoz-Cabello B, et al. . Gonorazky HD, Naumenko S, Ramani AK, et al. Panorama of the distal myopathies - PMC - National Center for GNE genotype explains 20% of phenotypic variability in GNE myopathy, GNE myopathy with novel mutations and pronounced paraspinal muscle atrophy, Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme. Wallgren-Pettersson C, Lehtokari VL, Kalimo H, et al. A large in-frame deletion, dominantly inherited in a three-generation family with a distal nemaline rod/cap myopathy, was recently described 260. Lethal multiple pterygium syndrome: a severe phenotype associated with a novel mutation in the nebulin gene. CAV3 mutations causing exercise intolerance, myalgia and rhabdomyolysis: expanding the phenotypic spectrum of caveolinopathies, Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome, Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy, Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy, Mutations in dynamin 2 cause dominant centronuclear myopathy. A 125-kilodalton protein of the nuclear matrix contains an extensive acidic domain, Nuclear matrins: identification of the major nuclear matrix proteins. The second has onset in adulthood . This is an open access article distributed in accordance with the. The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases. government site. Myofibrillar Myopathy - Symptoms, Causes, Treatment | NORD Definition Myopathy is a general term referring to a disease of skeletal muscle. Muscles farther from the center of the body, like the muscles of the lower legs and forearms, are known as distal muscles. As suggested by a recent study, desmin forms seeding-competent amyloid that is toxic to myofibers and disease-causing mutations enhance the amyloid formation 105. The first has onset in infancy, does not progress past adolescence, and is not incapacitating. Phenotypic spectrum of myopathies with recessive anoctamin-5 mutations. The presence of second causative variants in trans explains the novel entity of early/juvenile onset recessive distal titinopathy, a more severe condition than the late onset TMD 141-143. Reinstein E, Gutierrez-Fernandez A, Tzur S, et al. Servidei S, Capon F, Spinazzola A, et al. DNM2 mutations in a cohort of sporadic patients with centronuclear myopathy. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. It is both dominant and recessive in its nature. First described in a large North American family 34 and later in a large Bulgarian pedigree 35, vocal cord and pharyngeal distal myopathy (VCPDM) is characterized by adult-onset (between 35 and 60 years) distal weakness and weakness of vocal cord and pharyngeal muscles. Chakravorty S, Berger K, Arafat D, et al. Careers, Unable to load your collection due to an error. Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C, Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia. Sialuria is an allelic dominant metabolic disease characterized by the accumulation of N-acetylneuraminic acid (NeuAc) due to missense variants in GNE 171. In adulthood, patients complain of exercise myalgia in the calves, and show 5-10 fold elevated CK. Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy, Diagnostic anoctamin-5 protein defect in patients with ANO5-mutated muscular dystrophy. LGMD patients have a more proximal involvement at the onset but, after 20 years of disease progression, the two phenotypes usually merge as dysferlinopathies 138-140. DD usually appears between ages 40 and 60. At a later stage, proximal muscle weakness and wasting is observed. Non-specific myopathic changes with scattered necrotic fibers are observed in the muscle biopsy. The early stage hypertrophy of calf muscles progresses into muscle atrophy 208. CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy. Often parents have no idea theyre carriers of a disease until they have a child who has the disease. A mutation in myotilin causes spheroid body myopathy, Autosomal dominant spheroid body myopathy, Zaspopathy in a large classic late-onset distal myopathy family, When myopathy breaks the rules: a late-onset distal presentation, A novel mutation in the PDZ-like motif of ZASP causes distal ZASP-related myofibrillar myopathy, ZASPopathy with childhood-onset distal myopathy. Glycoproteins and glycolipids located in the membrane often undergo a sialic acid modification that seems to be crucial for their function 156. Gonzalez-Morales N, Holenka TK, Schock F. Filamin actin-binding and titin-binding fulfill distinct functions in Z-disc cohesion. In 2004 the causative variant was identified in the MYH7 gene encoding the beta heavy chain of myosin 243. Independently described by Nonaka et al. Del Bigio MR, Chudley AE, Sarnat HB, et al. Second tier tests, such as copy number variant (CNV) analysis and RNA sequencing, contribute to identify unrecognized pathogenic variants 148-152. We described the clinical features, muscle MRI and pathological changes as well as genetic mutations in a group of Chinese patients with Laing distal myopathy. Mutations in other parts of the gene may cause late onset myofibrillar myopathy with generalized weakness and cardiomyopathy 176-178. Miyoshi myopathy (MM; early adult-onset, type 2) is a subtype of dysferlinopathy. Distal myopathy 2: MedlinePlus Genetics Recently, a form of DNAJB6-related distal calf-predominant myopathy has been reported in patients with particular mutations in the N-terminal J-domain 194. A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13. An unusual phenotype of late-onset desminopathy, Recessive DES cardio/myopathy without myofibrillar aggregates: intronic splice variant silences one allele leaving only missense L190P-desmin, Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease, Intermediate filament diseases: desminopathy, Identification of a desmin gene mutation in scapuloperoneal syndrome type Kaeser, Desmin mutation responsible for idiopathic dilated cardiomyopathy, Prevalence of desmin mutations in dilated cardiomyopathy, A missense mutation in the b-crystallin chaperone gene causes a desmin-related myopathy, Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations, The p.G154S mutation of the alpha-B crystallin gene (CRYAB) causes late-onset distal myopathy, A novel CRYAB mutation resulting in multisystemic disease. Muscular dystrophy with marked dysferlin deficiency is consistently caused by primary dysferlin gene mutations, A simple and rapid immunoassay predicts dysferlinopathies in peripheral blood film, The Italian limb girdle muscular dystrophy registry: Relative frequency, clinical features, and differential diagnosis, The clinical spectrum and genetic variability of limb-girdle muscular dystrophy in a cohort of Chinese patients, The genetic profile of dysferlinopathy in a cohort of 209 cases: genotype-phenotype relationship and a hotspot on the inner DysF domain. Distal Muscular Dystrophy | Saint Luke's Health System A childhood-onset distal myopathy presenting with hand stiffness and facial weakness has been associated to bi-allelic RYR1 variants 236. Differential Diagnosis of Distal Myopathies - Practical Neurology
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