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Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy: Seventeen cases in eight families including an autopsied case
Abstract
A new type of progressive muscular dystrophy, autosomal recessive distal muscular dystrophy, is described, based on observations on 17 cases (8 males and 9 females) in 8 families, including an autopsied case. The disease developed in young adults. Muscle weakness and atrophy were most marked in the distal parts of the legs, especially in the gastrocnemius and soleus muscles, and then spread to the thighs and gluteal muscles. Early impairment of standing on tip-toe with retention of the ability to stand on the heels was conspicuous. Difficulty in climbing stairs, standing up and walking subsequently appeared, but rarely progressed to confinement to bed. The forearms became mildly atrophic, with decrease in grip strength, but the small hand muscles were spared. The EMG showed myopathic changes and nerve conduction was normal. Serum creatine kinase activity was characteristically increased up to 100-fold in the early stages of the disease. It was also markedly increased in subjects in the preclinical stage and mildly in some heterozygotes. Muscle biopsies revealed myopathic changes with severe segmental necrosis accompanied by regeneration. The changes were similar to those of Duchenne muscular dystrophy. An autopsied case, aged 68 years, showed generalized muscle abnormalities with a distal predominance. The muscles in the lower legs, especially those of the calves, were severely affected. No lesions were found in the brain, spinal cord or peripheral nerves.
... Seither wurde diese Krankheitsentität nach der Erstbeschreiberin als "Distale Myopathie Typ Welander" bezeichnet. In der Folge wurden unter anderem durch N. G. Laing, W. R. Markesbery und R. C. Griggs, K. Miyoshi sowie I. Nonaka weitere distale Myopathien mit differentem klinischem Phänotyp dargestellt und unter Verwendung entsprechender Eponyme klassifiziert [4,[6][7][8]. Mit der zunehmenden Verfeinerung und Erweiterung genetischer Methoden gelang die Identifikation des zugrundeliegenden Genotyps für eine Reihe der vorgenannten Krankheitsbilder. ...
... Lebensjahr. Häufig steht eine Schwäche der Plantarflexion im Vordergrund, der gelegentlich Mylagien voraus gehen [7]. Der Genotyp wurde erstmals 1998 identifiziert, seither sind eine Reihe verschiedener Mutationen im Dysferlin-Gen identifiziert worden [11]. ...
... Auffällig im Vergleich zu anderen distalen Myopathien ist eine deutlich erhöhte CK, teils bis zum 100-fachen über der Norm [7]. Das EMG zeigt neben chronisch-myopathischen Schädigungszeichen häufig auch eine ausgeprägte Spontanaktivität. ...
ZUSAMMENFASSUNG
Distale Myopathien stellen eine heteroge Gruppe von Erkrankungen dar, die sich durch einen prädominanten Befall körperferner Muskelgruppen auszeichnen und zunächst innerhalb weniger klinischer Phänotypen unter Verwendung von Eponymen klassifiziert worden sind. Genetische Hochdurchsatzverfahren haben das genotypische Spektrum der distalen Myopathien in den letzten Jahren erheblich erweitert. Ausgehend vom historischen Kontext wird die aktuelle Klassifikation distaler Myopathien vorgestellt, häufige Krankheitsbilder diskutiert und das diagnostische Vorgehen anhand eines strukturierten Handlungspfades erörtert.
... Dysferlinopathies are autosomal recessive inherited muscle wasting diseases. The first phenotype was described in 1967 (Miyoshi, Saijo et al. 1967) and in 1986 (Miyoshi, Kawai et al. 1986) by Miyoshi. Subsequently this disorder was called Miyoshi Myopathy (MM). ...
... Miyoshi Myopathy (MM) (Miyoshi, Kawai et al. 1986;Bejaoui, Hirabayashi et al. 1995;Liu, Aoki et al. 1998), the distal onset muscular dystrophy; (ii) Limb-Girdle Muscular ...
... • Miyoshi Myopathy: MM or Miyoshi Muscular Dystrophy 1 (MMD1) (OMIM # 254130) (Miyoshi, Kawai et al. 1986;Bejaoui, Hirabayashi et al. 1995;Liu, Aoki et al. 1998) is the most common autosomal recessive myopathy with distal onset and is also the most known type of dysferlinopathy. MM progress is typically slow (decades) and around 15% of the patients will become non-ambulatory. ...
The aim of this project was to build and apply tools for the analysis of muscle omics data, with a focus on Dysferlin deficiency. This protein is expressed mainly in skeletal and cardiac muscles, and its loss due to mutation (autosomal-recessive) of the DYSF gene, results in a progressive muscular dystrophy (Limb Girdle Muscular Dystrophy type 2B (LGMD2B), Miyoshi myopathy and distal myopathy with tibialis anterior onset (DMAT)). We have developed various tools and pipelines that can be applied towards a bioinformatics functional analysis of omics data in muscular dystrophies and neuromuscular disorders. These include: tests for enrichment of gene sets derived from previously published muscle microarray data and networking analysis of functional associations between altered transcripts/proteins. To accomplish this, we analyzed hundreds of published omics data from public repositories. The tools we developed are called CellWhere and MyoMiner. CellWhere is a user-friendly tool that combines protein-protein interactions and protein subcellular localizations on an interactive graphical display (https://cellwhere-myo.rhcloud.com). MyoMiner is a muscle cell- and tissue-specific database that provides co-expression analyses in both normal and pathological tissues. Many gene co-expression databases already exist and are used broadly by researchers, but MyoMiner is the first muscle-specific tool of its kind (https://myominer-myo.rhcloud.com). These tools will be used in the analysis and interpretation of transcriptomics data from dysferlinopathic muscle and other neuromuscular conditions and will be important to understand the molecular mechanisms underlying these pathologies.
... The frequency of MM and LGMD2B phenotype in the present cohort Neurology India / July 2015 / Volume 63 / Issue 4 are similar to those reported previously. [38,39] In the original description by Miyoshi et al., in 1986, all patients had onset at or before 30 years of age, and majority had onset before 20 years of age. [40] In another report from Japan, the mean age of onset for MM was 22 years and for LGMD2B, it was 26 years. ...
... [38,39] In the original description by Miyoshi et al., in 1986, all patients had onset at or before 30 years of age, and majority had onset before 20 years of age. [40] In another report from Japan, the mean age of onset for MM was 22 years and for LGMD2B, it was 26 years. [41] In the present series, majority (85.7%) of patients with MM had onset before 25 years of age. ...
... In the Dutch series also, 54% of the patients had deltoid and biceps atrophy at an early stage of the illness. [39] Miyoshi et al., have described pectoral girdle involvement only in advanced stages of the disease; [40] however, the age at onset and gender had no bearing on the progression of illness. CK was markedly elevated in all our cases except in one. ...
In this prospective study conducted over 2 years, 300 nonconsecutive cases of autosomal recessive limb girdle muscular dystrophies (AR-LGMD) were characterized, based on phenotypic features, biochemical findings, electrophysiological studies, muscle immunohistochemistry (IHC), and western blot (WB) analysis.
Muscle biopsy was performed in 280 index cases. 226 biopsies were subjected for IHC, and, 176 of these for WB analysis.
A total of 246 patients were finally analyzed. This figure included 20 affected siblings. LGMD2B was the most common form and comprised of 33.3% (n = 82) of the entire cohort. This was followed by alpha-dystroglycanopathies with 61 (24.79%) patients (LGMD2I in 15, 2K in 10 and combined deficiency of both in the remaining). LGMD 2C-F was present in 35 (14.23%) cases and LGMD2A in 22 (10.2%) cases, and were identified by routine WB, densitometry method and autocatalytic assay. LGMD2G was present in 8 patients (3.25%), and LGMD2H and 2J in 2 cases each, respectively.
For the first time, we have identified patients with LGMD2G, 2H, 2I, and 2K by the WB technique. These may be the common forms of autosomal recessive (AR)-LGMD's among Indian patients and need identification for prognostication and appropriate counseling. Although not a nationwide study, our data is sufficient to provide information about the relative proportions of various LGMD2 subtypes in India. Diagnosing LGMD2 based on classical clinical features, IHC and WB is fairly sensitive and specific; however, further genetic studies are required to confirm the diagnosis.
... Early adult onset distal myopathy (Miyoshi myopathy) was first described in 1967. Thereafter most cases have been reported from Japan (Miyoshi et al., 1967(Miyoshi et al., , 1986. In western countries Miyoshi myopathy has been described only in anecdotal cases (Kuhn and Schroder, 1981;De Visser, 1983;Barohn et al., 1991;Crespo and Codina, 1994). ...
... Onset of Miyoshi myopathy is said to occur between 15 and 25 years (Miyoshi et al., 1986, Barohn et al., 1991. One of the first characteristics is weakness and atrophy of the calf muscles, preventing the patients from standing on tip-toe. ...
... This study of 24 Dutch Miyoshi-type distal muscular dystrophy patients is larger than the original series of 17 patients reported by Miyoshi et al. (1986) and indicates that Miyoshi myopathy is not as rare in Western countries as previously thought. ...
Miyoshi-type distal muscular dystrophy has now been found to be more frequent outside Japan than was previously thought. We studied 24 Dutch patients with Miyoshi-type distal muscular dystrophy and focused on its clinical expression and natural history, muscle CT-scans and muscle biopsy findings. Our study shows that Miyoshi myopathy is a heterogeneous, slowly progressive disorder. The disease starts with weakness and atrophy of the calves and progressively involves the proximal leg and hip muscles and, in a later stage the shoulder and upper arm muscles. After 10 years disease duration, one-third of the patients are dependent on wheelchairs for out-of-door transportation. Disease progression is related to disease duration and not to early age of onset of symptoms. Onset may be at any age and is asymmetrical in roughly half of the cases. Four cases had been initially diagnosed as idiopathic hyper-CK-aemia.
... They can be identified by the following features: Autosomal pattern of genetic inheritance, early or late onset distal muscle atrophy, increased creatine kinase (CK) and abnormal muscle biopsy. [1,3] The Miyoshi myopathy may be distinct among the hereditary distal myopathies, first described in the medical literature in 1967 in Japan by Miyoshi et al. [2,4] We describe a family of distal myopathy where the diagnostic clue towards the underlying diagnosis was pointed out by a physical examination finding of "calf heads on a trophy" sign. ...
... [1,3] The Miyoshi myopathy may be distinct among the hereditary distal myopathies. First described in the medical literature in 1967 in Japan by Miyoshi et al. [4] Onset of the disease is in early adult life with weakness and atrophy of the leg muscles. [1,2] Recently genetic linkage to chromosome 2p12-14 [1] has been established. ...
... In Japan its incidence is approximately 1 in 440,000 inhabitants. [1,4] The AR pattern of inheritance in combination with the clinical features, EMG, serum CK level and muscle biopsy in our patient were suggestive of Miyoshi myopathy. Muscle biopsy done in his twin sister was also suggestive of Miyoshi myopathy. ...
Miyoshi myopathy is an autosomal recessive distal myopathy with predominant involvement of the posterior calf muscles attributed to mutations in the dysferlin gene. We report a 26-year-old male, born of nonconsanginous parentage. He noticed weakness and atrophy of leg muscles with inability to walk on his heels. The creatine kinase concentration was high. The electromyography showed myopathic pattern and the muscle biopsy disclosed dystrophic changes with absence of dysferlin. Miyoshi myopathy may be distinct among the hereditary distal myopathies. There are only few reported cases of Miyoshi myopathy in the world literature. In India only 12 cases were reported who had classical features of Miyoshi myopathy. Our's is a typical case of Miyoshi myopathy, with an affected twin sister as well. He also had "calf heads on a trophy sign" on physical examination, which is considered to be pathognomonic of this disease.
... LGMDR2 describes a phenotype with predominant proximal lower and upper limb weakness at presentation [1] , and was previously called LGMD2B before recent consensus review of LGMD nomenclature [2] . MMD1 describes a phenotype with predominantly distal lower limb weakness at presentation [3] . ...
... We speculate that this may be explained by a geographical preference for diagnosis. Japanese sites may be more likely to diagnose MMD1 as the default, unless presentation is strikingly different, due to site experience, as MMD1 was first described in a Japanese cohort [3] . ...
This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments.
... These symptoms are usually accompanied by marked increase in plasma creatine kinase levels (CK) (Galassi et al., 1987;Barohn et al., 1991Barohn et al., , 1998Linssen et al., 1997;Rosales et al., 2010). Three main clinical phenotypes and some other variants of dysferlinopathy have been described (Miyoshi et al., 1967(Miyoshi et al., , 1986Liu et al., 1998;Bashir et al., 1998;Illa et al., 2001;Nguyen et al., 2005Nguyen et al., , 2007Laval and Bushby, 2004;Okahashi et al., 2008;Paradas et al., 2009;Klinge et al., 2008). There is also a marked inter-and intrafamiliar phenotypical variability (Miyoshi et al., 1986;Illarioshkin et al., 1996;Ueyama et al., 2002;Guglieri et al., 2008;Rosales et al., 2010. ...
... Three main clinical phenotypes and some other variants of dysferlinopathy have been described (Miyoshi et al., 1967(Miyoshi et al., , 1986Liu et al., 1998;Bashir et al., 1998;Illa et al., 2001;Nguyen et al., 2005Nguyen et al., , 2007Laval and Bushby, 2004;Okahashi et al., 2008;Paradas et al., 2009;Klinge et al., 2008). There is also a marked inter-and intrafamiliar phenotypical variability (Miyoshi et al., 1986;Illarioshkin et al., 1996;Ueyama et al., 2002;Guglieri et al., 2008;Rosales et al., 2010. However systematic muscle magnetic resonance imaging and functional assessment of patients with these different phenotypes do not show substantial differences in terms of distribution and severity of muscle compromise (Paradas et al., 2010;Díaz et al., 2016). ...
Mutations in the dysferlin gene are linked to a group of muscular dystrophies known as dysferlinopathies. These myopathies are characterized by progressive atrophy. Studies in muscle tissue from dysferlinopathy patients or dysferlin-deficient mice point out its importance in membrane repair. However, expression of dysferlin homologous proteins that restore sarcolemma repair function in dysferlinopathy animal models fail to arrest muscle wasting, therefore suggesting that dysferlin plays other critical roles in muscle function. In the present review, we discuss dysferlin functions in the skeletal muscle, as well as pathological mechanisms related to dysferlin mutations. Particular focus is presented related the effect of dysferlin on cell membrane related function, which affect its repair, vesicle trafficking, as well as Ca2 + homeostasis.Such mechanisms could provide accessible targets for pharmacological therapies.
... Се годня выделяется более 30 генетических вариантов ПКМД, для 27 из которых идентифицированы гены [4]. К редким вариантам ПКМД 2-го типа относятся дисферлинопатии (ДП) (частота 1:200 000) со специфическим клиническим паттерном и течением болезни [3,5]. Описаны 3 аллельных варианта: дистальная миопатия Миоши (ММ, Miyoshi myopathy OMIM # 254130), поясно-конечностная миопатия (LGMD, 2BOMIM # 253601) и дистальная миопатия с дебютом в разгибателях стоп (DMAT, OMIM # 606768) [6]. ...
... Клинический разбор изменения с многочисленными воспалительными очагами [5]. При ПКМД типа 2В (ПКМД 2В ) клиническая картина имеет большое сходство с ММ. ...
Miyoshi myopathy (MM) is a rare distal form of limb-girdle muscular dystrophies characterized by weakness primarily affecting the calves in adolescence or young adulthood, with slow progression, the ascending pattern of involvement of muscle groups in an atrophic process, and with obvious clinical polymorphism at onset (3 allelic variants are described). In MM, hypercreatine phosphatemia is noted to be 20– 50 times the normal blood concentrations. MM is referred to the dysferlinopathies with different mutations in the DYSF gene. In that manuscript we describe a 20-year familial case of 2 brothers with MM, including changes in their clinical manifestations, biochemical, CT and EMG parameters. The diagnosis was verified by whole exome sequencing of the DYSF gene to identify a homozygous missense mutations (c. 5302C>T) leading to replacement in the polypeptide chain of DYSF p.Arg1768Trp. The differential diagnosis of MM with clinically similar hereditary neuromuscular diseases is discussed.
... The dysferlin (DYSF) gene was mapped to chromosome 2p13 (2,3) . Mutations in the DYSF gene are associated with autosomal recessive muscle disorders, with known distinct phenotypes, where Miyoshi myopathy (MM) (4) and limb girdle muscular dystrophy 2B (LGMD2B) (2) were the first to be recognized. Recently, a new phenotype, with proximodistal weakness (PD) was recognized (5) and seems to be a common clinical presentation. ...
... After the original clinical description by Miyoshi (4) and the mapping of the disease to chromosome 2p13 (2,3) , a general clinical and laboratory consensus was established about dysferlinopathies (3) : onset in mid to late childhood or early adulthood, slowly progressive, autosomal recessive inheritance, high CK levels, a dystrophic pattern on muscle histology and a myopathic picture in the EMG evaluation. ...
Introduction: Mutations in the dysferlin (DYSF) gene are responsible for autosomal recessive muscle disorders, known as dysferlinopathies. The clinical expression is variable, with several phenotypes recognized. The two most common are the Miyoshi myopathy (MM) and the limb-girdle muscular dystrophy 2B (LGMD2B). A third phenotype, the distal anterior compartment myopathy (DACM) is rare and recently, a proximodistal (PD) phenotype was included in the classic clinical repertoire of dysferlinopathies. Characteristically they have their onset in mid to late childhood or early adulthood and are associated with high levels of CK. Commonly there is a symmetrical clinical onset and they very rarely become clinically manifest in old age. Clinical Case: The patient is a 64 year old Caucasian male, the only child of a non consanguineous marriage. He has a two year history of walking difficulties, with a prominent instability of the left foot, which caused him inability to run and tendency to fall. Neurological examination revealed atrophy of the antero-lateral compartment of the left leg and the tibialis anterior and peroneus left muscles were weak [3/5 on the Medical Research Council (MRC) scale]. He had a left steppage gait. The muscles of the posterior compartment of the legs looked normal, as well as the intrinsic foot muscles. Deep tendon reflexes were abolished throughout. CK values were slightly elevated and EMG examination showed myopathic changes in the muscles of the lower limbs. Legs muscle MRI evidenced generalized muscle atrophy and fat infiltration, more significant on the left side and in the posterior compartment of the legs. Histological muscle examination revealed fibre size variability, with atrophied fibre groups, rare rimmed vacuoles and scarce necrotic fibres; dysferlin was irregularly labelled at the sarcolemmal level, with some fibres not expressing dysferlin. Genetic testing detected the causal mutation c.5626G<A (p.Asp1876Asn). Conclusion: This clinical case is unique because of its very late onset and clinical presentation (unilateral distal anterior compartment myopathy), whose features were not until now reported in literature. Clinical presentation of dysferlinopathies is becoming more heterogeneous than initially suspected and immunohistochemistry and genetic studies are the last resources to diagnose these unusual cases.
... Dans notre réponse à cet article [36], nous soulignions que ce taux d'acceptation spontanée (d'une pratique nouvelle, non encore intégrée, ni par les médecins ni par leurs patientes) nous semblait au contraire extrêmement élevé et encourageant. Alors que des données canadiennes estiment que moins de 25 % des femmes victimes osent parler spontanément de ce sujet à leur médecin [3] et que, selon d'autres auteurs, la prévalence de la violence conjugale dans leur clientèle serait 10 fois plus élevée que ne le perçoivent les médecins [37], un tel dépistage actif nous semble relever d'une bonne pratique de la médecine de premier recours et ceci d'autant plus que des études nord-américaines concluent aux bonnes performances ¢ en termes de sensibilité et de spécificité ¢ de ce type de dépistage par un simple interrogatoire [38][39][40]. Quelques questions simples peuvent suffire à entamer une démarche de dépistage actif et systématique : « Vous entendez-vous bien avec votre mari ? Vous disputez-vous avec lui ? ...
... Mais celle-ci a permis d'avancer dans d'autres domaines de la pathologie dystrophique. Par exemple, dans les myopathies distales, dont une forme particulière avait été identifiée au Japon (Miyoshi, 1986 [40]), de transmission autosomique récessive. Celle-ci fut d'abord localisée sur le bras court du chromosome 2 avant que son gène ne soit identifié, codant pour une nouvelle protéine nommée dysferline [41]. ...
... Кроме того, высокие темпы развития анстисмысловой и генной терапии позволяют в последнее время акцентировать внимание на этиотропных подходах в лечении пациентов с миопатиями. DOI: 10.19163/2307-9266-2022-10-5- Первые симптомы возникают в подростковом возрасте [28,29] Дисферлин [30] Дисферлин является линкерным мембрана-ассоциированным белком, функция которого заключается в опосредовании кальций-зависимой регенерации механических повреждений сарколеммы. ...
The aim of the work was to analyze the available therapeutic options for the conventional therapy of hereditary myopathies.
Materials and methods. When searching for the material for writing a review article, such abstract databases as PubMed and Google Scholar were used. The search was carried out on the publications during the period from 1980 to September 2022. The following words and their combinations were selected as parameters for the literature selection: “myopathy”, “Duchenne”, “myodystrophy”, “metabolic”, “mitochondrial”, “congenital”, “symptoms”, “replacement”, “recombinant”, “corticosteroids”, “vitamins”, “tirasemtiv”, “therapy”, “treatment”, “evidence”, “clinical trials”, “patients”, “dichloracetate”.
Results. Congenital myopathies are a heterogeneous group of pathologies that are caused by atrophy and degeneration of muscle fibers due to mutations in genes. Based on a number of clinical and pathogenetic features, hereditary myopathies are divided into: 1) congenital myopathies; 2) muscular dystrophy; 3) mitochondrial and 4) metabolic myopathies. At the same time, treatment approaches vary significantly depending on the type of myopathy and can be based on 1) substitution of the mutant protein; 2) an increase in its expression; 3) stimulation of the internal compensatory pathways expression; 4) restoration of the compounds balance associated with the mutant protein function (for enzymes); 5) impact on the mitochondrial function (with metabolic and mitochondrial myopathies); 6) reduction of inflammation and fibrosis (with muscular dystrophies); as well as 7) an increase in muscle mass and strength. The current review presents current data on each of the listed approaches, as well as specific pharmacological agents with a description of their action mechanisms.
Conclusion. Currently, the following pharmacological groups are used or undergoing clinical trials for the treatment of various myopathies types: inotropic, anti-inflammatory and antifibrotic drugs, antimyostatin therapy and the drugs that promote translation through stop codons (applicable for nonsense mutations). In addition, metabolic drugs, metabolic enzyme cofactors, mitochondrial biogenesis stimulators, and antioxidants can be used to treat myopathies. Finally, the recombinant drugs alglucosidase and avalglucosidase have been clinically approved for the replacement therapy of metabolic myopathies (Pompe’s disease).
... Dysferlinopathy is a form of LGMD, most commonly described as LGMDR2 or Miyoshi myopathy (MMD1). 5,6 In this disease, from the same functional starting point, one patient may remain stable for 3 years, while another deteriorates significantly over only 1 year. 7,8 Being able to predict progression of muscular dystrophies has several advantages. ...
Background:
Water T2 (T2H2O ) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies.
Methods:
Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3-tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function.
Results:
A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6-min walk than those with a lower T2H2O (<40.6 ms). Optimum sensitivity and specificity thresholds for predicting decline were 39.0 ms in adductor magnus and vastus intermedius, 40.0 ms in vastus medialis, and 40.5 ms in vastus lateralis from different sites equipped with different MRI systems.
Conclusions:
In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. This suggests that inter-patient differences in functional decline over time may be, in part, explained by different severities of the active muscle damage, assessed by T2H2O measure at baseline. Significant challenges remain in standardizing T2H2O values across sites to allow determining globally applicable thresholds. The results from the present work are encouraging and suggest that T2H2O could be used to improve prognostication, patient selection, and disease modelling for clinical trials.
... Thus, patients notice that they cannot walk on tiptoe or climb stairs. 42 Patients experience discomfort and pain in the calf area, which is a sign of Miyoshi myopathy, distinguishing it from other distal muscular dystrophies. ...
Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in muscle tissues and is localized in the sarcolemma, where it performs its main function of resealing and maintaining of the integrity of the cell membrane. At least four forms of dysferlinopathies have been described: Miyoshi myopathy, limb‐girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, and isolated hyperCKemia. Here we review the clinical features of different forms of dysferlinopathies and attempt to identify genotype–phenotype correlations. Because of the great clinical variability and rarety of the disease and mutations little is known, how different phenotypes develop as a result of different mutations. However, missense mutations seem to induce more severe disease than LoF, which is typical for many muscle dystrophies. The role of several specific mutations and possible gene modifiers is also discussed in the paper.
... LGMD2B/R2 predominantly affects the lower limb proximal muscles with relative sparing of upper limb involvement. Miyoshi myopathy (MM) was originally described in Japan in 1967 as a distal myopathy affecting the posterior compartment muscles (gastrocnemius and soleus) [16]. Mapping LGMD2B/R2 and MM to the same chromosome was unexpected; both phenotypes have been reported in the same family [17][18][19][20]. ...
Limb-girdle muscular dystrophies (LGMDs) represent a major group of muscle disorders. Treatment is sorely needed and currently expanding based on safety and efficacy adopting principles of single-dosing gene therapy for monogenic autosomal recessive disorders. Gene therapy has made in-roads for LGMD and this review describes progress that has been achieved for these conditions. This review first provides a background on the definition and classification of LGMDs. The major effort focuses on progress in LGMD gene therapy, from experimental studies to clinical trials. The disorders discussed include the LGMDs where the most work has been done including calpainopathies (LGMD2A/R1), dysferlinopathies (LGMD2B/R2) and sarcoglycanopathies (LGMD2C/R5, LGMD2D/R3, LGMD2E/R4). Early success in clinical trials provides a template to move the field forward and potentially apply emerging technology like CRISPR/Cas9 that may enhance the scope and efficacy of gene therapy applied to patient care.
... 2) MM is a distal dysferlinopathy that was first described in Japan by Miyoshi, et al. in 1967 and subsequently in 1986. 3,4) The incidence and prevalence of dysferlinopathies worldwide are unknown. However, it has been reported in other geographical regions including It-aly, Spain, India, and Middle Eastern countries. ...
Dysferlin is a sarcolemmal protein present in muscle cells. It is responsible for muscle membrane repair. Dysferlin gene (DYSF) mutation, resulting in deficiency in this protein, is termed dysferlinopathy. Clinically, it manifests as early adulthood onset of muscle weakness with markedly elevated creatine kinase levels. The main phenotypes are limb-girdle muscular dystrophy type 2B (LGMD2B), affecting proximal muscles, and Miyoshi myopathy (MM), affecting distal muscles. Dysferlin is also present in cardiomyocytes, and case reports have emerged of cardiac abnormalities in dysferlinopathy. While routine methods of cardiac screening, namely, electrocardiography or echocardiography, are convenient and noninvasive, they often exhibit insufficient diagnostic sensitivity for detecting subclinical cardiac remodeling during early stages of cardiomyopathy. Cardiac magnetic resonance imaging though can provide accurate assessment of cardiac chamber sizes and function. With gadolinium administration, it can also detect areas of myocardial scarring and fibrosis. Early diagnosis of neuromuscular disease-related cardiomyopathy is of clinical significance, as appropriate treatment can retard myocardial fibrosis, delaying cardiomyopathy progression. We present a case of a patient with MM incidentally diagnosed with concomitant cardiomyopathy.
... Miyoshi myopathy was first reported in 1986 by K. Miyoshi in Japan [1]. Dysferlinopathy is an autosomal recessive disease seen in adolescence or young adulthood [2]. ...
Background: Dysferlinopathy is an autosomal recessive disease seen in adolescence or young adulthood. Miyoshi Myopathy is characterized by weakness and wasting of posterior compartment leg muscles rather than the anterior compartment and distal upper limb muscles. Still, the intrinsic muscles of the foot and hands are spared. There are several undiagnosed cases in India and also around the world with dysferlinopathy. Diagnosis for the same requires advanced biological laboratories along with high economic funding for diagnostic purposes.
Case Summary: This case report presents a 22-year-old male diagnosed with Miyoshi myopathy/LGMD2b
(dysferlinopathy). The subject complained about a loss of balance, strength, and difficulty in performing activities of daily living. The patient was given Aquatic Therapy along with conventional physical therapy for a duration of 6weeks, which included three days of supervised therapy along with 3days home protocol and a rest day kept at the end of every week.
Outcome Measures: Standardized scales like the Barthel Index and the Berg Balance Scale were used for the assessment of pre and post the progress of the subject for Quality of Life and Balance, respectively. Manual Muscle testing was used for assessments for pre and post muscle strength of the subject.
Conclusion: The timely diagnosis of a rare condition before the advancement of the disorder and thus the use of appropriate intervention of physiotherapy, which consisted of progressive muscle-strengthening exercises along with balance training proved to be promising in preventing falls, muscle atrophy and thus making the patient independent for doing daily activities.
... Mutations in DYSF have been associated with Miyoshi muscular dystrophy (MMD, OMIM #254130) [160], limb-girdle muscular dystrophy 2B (LGMDR2, formerly LGMD2D, OMIM #253601) [160], and distal myopathy with anterior tibial onset (OMIM #606768) [160]. Miyoshi muscular dystrophy is an early-adult-onset disorder involving distal muscle weakness of the upper and lower limbs with sparing of the intrinsic hand muscles [161]. Serum creatine kinase levels are increased, and biopsies show a dystrophic pattern with necrosis. ...
Muscle contraction requires specialized membrane structures with precise geometry and relies on the concerted interplay of electrical stimulation and Ca2 + release, known as excitation-contraction coupling (ECC). The membrane structure hosting ECC is called triad in skeletal muscle and dyad in cardiac muscle, and structural or functional defects of triads and dyads have been observed in a variety of myopathies and cardiomyopathies. Based on their function, the proteins localized at the triad/dyad can be classified into three molecular pathways: the Ca2 + release complex (CRC), store-operated Ca2 + entry (SOCE), and membrane remodeling. All three are mechanistically linked, and consequently, aberrations in any of these pathways cause similar disease entities. This review provides an overview of the clinical and genetic spectrum of triad and dyad defects with a main focus of attention on the underlying pathomechanisms.
... The soleus muscle from mice is reported to be similar to human skeletal muscle, due to the higher proportion of slow twitch myofibres [54], thus our murine results may have strong implications for understanding the dysferlinopathy pathology. Indeed, in the human disease, the soleus is one of the first muscles affected [55], with recent detailed MRI analyses of many muscles in human dysferlinopathy patients showing pathological changes in the soleus, due to adipocyte replacement, early in the disease progression [16]. The differences in severity of dystropathology progression in the soleus between the human disease and the mouse model may be due (in part) to the very different loading patterns present between large bipedal humans and very small quadrupedal mice, combined with impact of the far longer growth phase (~16-20 years depending on gender) and longevity of humans compared with mice. ...
Dysferlinopathies are a form of muscular dystrophy caused by gene mutations resulting in deficiency of the protein dysferlin. Symptoms manifest later in life in a muscle specific manner, although the pathomechanism is not well understood. This study compared the impact of dysferlin-deficiency on in vivo and ex vivo muscle function, and myofibre type composition in slow (soleus) and fast type (extensor digitorum longus; EDL) muscles using male dysferlin-deficient (dysf-/-) BLAJ mice aged 10 months, compared with wild type (WT) C57Bl/6J mice. There was a striking increase in muscle mass of BLAJ soleus (+25%) (p<0.001), with no strain differences in EDL mass, compared with WT. In vivo measures of forelimb grip strength and wheel running capacity showed no strain differences. Ex vivo measures showed the BLAJ soleus had faster twitch contraction (-21%) and relaxation (-20%) times, and delayed post fatigue recovery (ps<0.05); whereas the BLAJ EDL had a slower relaxation time (+11%) and higher maximum rate of force production (+25%) (ps<0.05). Similar proportions of MHC isoforms were evident in the soleus muscles of both strains (ps>0.05); however, for the BLAJ EDL, there was an increased proportion of type IIx MHC isoform (+5.5%) and decreased type IIb isoform (-5.5%) (ps<0.01). This identification of novel differences in the impact of dysferlin-deficiency on slow and fast twitch muscles emphasises the importance of evaluating myofibre type specific effects to provide crucial insight into the mechanisms responsible for loss of function in dysferlinopathies; this is critical for the development of targeted future clinical therapies.
... Dysferlin is important in the wound healing of membranous microlesions in a calcium-depen- dent manner. [2][3][4] Mutations in the dysferlin gene (DYSF) cause limb girdle muscular dystrophy 2B (LGMD2B) 5 or the more distal forms, Miyoshi myopathy 6 and anterior tibial muscular dystrophy. 7 Currently, dysferlinopathies cannot be treated. ...
Limb girdle muscular dystrophy 2B (LGMD2B) is without treatment and caused by mutations in the dysferlin gene (DYSF). One-third is missense mutations leading to dysferlin aggregation and amyloid formation, in addition to defects in sarcolemmal repair and progressive muscle wasting. Dysferlin-null mouse models do not allow study of the consequences of missense mutations. We generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. We chose U7 small nuclear RNA (snRNA)-based splice switching to demonstrate a possible exon-skipping strategy in this new animal model. We show that Dysf exons 37 and 38 can successfully be skipped in vivo. Overall, the MMex38 mouse model provides an ideal tool for preclinical development of treatment strategies for dysferlinopathy.
... [7] LGMD2B and MM are initially characterized by different clinical presentations which include predominant weakness of muscles of the pelvic and shoulder girdle in the LGMD2B presentation [8] and distal weakness in the MM presentation. [9] Collectively, the clinical presentations caused by pathogenic variants in the DYSF gene and dysferlin protein deficiency are termed dysferlinopathy. The onset of dysferlinopathy is usually in late teens or adulthood with slow progression and marked elevation of CK levels. ...
Background
Limb-girdle muscular dystrophy (LGMD) is the most common adult-onset class of muscular dystrophies in India, but a majority of suspected LGMDs in India remain unclassified to the genetic subtype level. The next-generation sequencing (NGS)-based approaches have allowed molecular characterization and subtype diagnosis in a majority of these patients in India.
Materials and Methods
(I) To select probable dysferlinopathy (LGMD2B) cases from other LGMD subtypes using two screening methods (i) to determine the status of dysferlin protein expression in blood (peripheral blood mononuclear cell) by monocyte assay (ii) using a predictive algorithm called automated LGMD diagnostic assistant (ALDA) to obtain possible LGMD subtypes based on clinical symptoms. (II) Identification of gene pathogenic variants by NGS for 34 genes associated with LGMD or LGMD like muscular dystrophies, in cases showing: absence of dysferlin protein by the monocyte assay and/or a typical dysferlinopathy phenotype, with medium to high predictive scores using the ALDA tool.
Results
Out of the 125 patients screened by NGS, 96 were confirmed with two dysferlin variants, of which 84 were homozygous. Single dysferlin pathogenic variants were seen in 4 patients, whereas 25 showed no variants in the dysferlin gene.
Conclusion
In this study, 98.2% of patients with absence of the dysferlin protein showed one or more variants in the dysferlin gene and hence has a high predictive significance in diagnosing dysferlinopathies. However, collection of blood samples from all over India for protein analysis is expensive. Our analysis shows that the use of the “ALDA tool” could be a cost-effective alternative method. Identification of dysferlin pathogenic variants by NGS is the ultimate method for diagnosing dysferlinopathies though follow-up with the monocyte assay can be useful to understand the phenotype in relation to the dysferlin protein expression and also be a useful biomarker for future clinical trials.
... In this phenotype (Fig. 1), which is the most frequent in many populations, weakness is first evident in distal leg muscles, particularly posterior compartment muscles (gastrocnemius, soleus). 20 The onset usually occurs between ages 15 and 30 years (on average at 19 years), and rarely after age 40. [21][22][23] At onset, patients complain of impaired ability to stand or walk on tiptoe and of difficulty in going down stairs. ...
Dysferlin-deficient limb girdle muscular dystrophy type 2B, distal Miyoshi myopathy, and other less frequent phenotypes are a group of recessive disorders called dysferlinopathies. They are characterized by wide clinical heterogeneity. To diagnose dysferlinopathy, a clinical neuromuscular workup, including electrophysiological and muscle imaging investigations, is essential to support subsequent laboratory testing. Increased serum creatine kinase levels, distal or proximal muscle weakness, and myalgia with onset in the second or third decades are the main clinical features of the disease. In muscle biopsies, severe dysferlin deficiency by immunoblot or its abnormal localization by immunohistochemistry are the gold standard, as they have a high diagnostic value. Dysferlin testing on monocytes is a valuable alternative to muscle immunoblotting. Molecular techniques for gene mutation detection, such as next generation sequencing, have improved the genetic diagnosis, which is crucial for treatment and genetic counselling. This article is protected by copyright. All rights reserved.
... Японским исследователем К. Миоши с соавторами в 1967 году впервые была описана дистальная миопатия с рецессивной формой наследования у четырех больных из двух кровнородственных семей, со значительно повышенным уровнем креатинкиназы в сыворотке крови, которая в последующем получила название «миопатия Миоши» [1,2]. Клинические проявления миопатии Миоши имеют сходство с ПКМД 2В. ...
Dysferlinopathies is a group of autosomal-recessive inherited neuromuscular diseases, which are characterized by defect in mRNA expression or in functionioning of dysferlin protein, appearing in about 1/200 000 births. Dysferlin is encoded by DYSF gene (Dystrophy-associated fer-1- like). It's disruption can cause various types of primary dysferlinopathies, which include Miyoshi myopathy (MM), Limb-girdle Muscular Dystrophy type 2B (LGMD2B) and distal myopathy with anterior tibial onset. Also, dysferlin deficiency can be associated with other diseases, such as caveolin- And calpainopathies. Here we discuss dysferlin protein structure and function, it's clinical phenotypes, known animal models and developing treatment strategies for dysferlinopathies.
... We also identified two novel homozygous potentially disease-associated variants, c.4741C>T (p.R1581C) and c.6209A>G (p.Y2070C), in the DYSF gene, which encodes Dysferlin, a calcium-dependent phospholipid binding protein that plays a role in muscle membrane maintenance and repair (Bansal et al., 2003;Bashir et al., 1998). Previously described phenotypes of Dysferlin dysfunction include early onset muscle weakness that manifests in late teens to early twenties (Miyoshi et al., 1986). The dysferlin p.R1581C variant is part of the fifth C2 Ferlin domain, which is involved in vesicle fusion events. ...
Genetic analysis of clinical phenotypes in consanguineous families is complicated by co-inheritance of large DNA regions carrying independent variants. Here we characterized a family with early onset cone-rod dystrophy (CRD) and muscular dystrophy. Homozygosity mapping followed by whole exome sequencing revealed a nonsense mutation, p.R270*, in ALMS1 and two novel potentially disease-causing missense variants, p.R1581C and p.Y2070C, in DYSF. ALMS1 and DYSF are genetically and physically linked on chromosome 2 in a genomic region suggested by homozygosity mapping and associated with Alström syndrome, which includes CRD, and with limb girdle muscular dystrophy, respectively. Affected family members lack additional systemic manifestations of Alström syndrome but exhibit mild muscular dystrophy. RNA-seq data did not reveal any significant variations in ALMS1 transcripts in the human retina. Our study thus implicates ALMS1 as a non-syndromic retinal disease gene and suggests a potential role of variants in interacting cilia genes in modifying clinical phenotypes. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Dysferlinopathies refer to a spectrum of muscular dystrophies that cause progressive muscle weakness and degeneration. They are caused by mutations in the DYSF gene, which encodes the dysferlin protein that is crucial for repairing muscle membranes. This review delves into the clinical spectra of dysferlinopathies, their molecular mechanisms, and the spectrum of emerging therapeutic strategies. We examine the phenotypic heterogeneity of dysferlinopathies, highlighting the incomplete understanding of genotype-phenotype correlations and discussing the implications of various DYSF mutations. In addition, we explore the potential of symptomatic, pharmacological, molecular, and genetic therapies in mitigating the disease’s progression. We also consider the roles of diet and metabolism in managing dysferlinopathies, as well as the impact of clinical trials on treatment paradigms. Furthermore, we examine the utility of animal models in elucidating disease mechanisms. By culminating the complexities inherent in dysferlinopathies, this write up emphasizes the need for multidisciplinary approaches, precision medicine, and extensive collaboration in research and clinical trial design to advance our understanding and treatment of these challenging disorders.
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.
Distal myopathies are a group of genetic, primary muscle diseases. Patients develop progressive weakness and atrophy of the muscles of forearm, hands, lower leg, or feet. Currently, over 20 different forms, presenting a variable age of onset, clinical presentation, disease progression, muscle involvement, and histological findings, are known. Some of them are dominant and some recessive. Different variants in the same gene are often associated with either dominant or recessive forms, although there is a lack of a comprehensive understanding of the genotype-phenotype correlations. This chapter provides a description of the clinicopathologic and genetic aspects of distal myopathies emphasizing known etiologic and pathophysiologic mechanisms.
For inherited diseases, obtaining a definitive diagnosis is critical for proper disease management, family planning, and participation in clinical trials. This can be challenging for dysferlinopathy due to the significant clinical overlap between the 30+ subtypes of limb–girdle muscular dystrophy (LGMD) and the large number of variants of unknown significance (VUSs) that are identified in the dysferlin gene, DYSF. We performed targeted RNA-Seq using a custom gene-panel in 77 individuals with a clinical/genetic suspicion of dysferlinopathy and evaluated all 111 identified DYSF variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. This evaluation identified 11 novel DYSF variants and allowed for the classification of 87 DYSF variants as pathogenic/likely pathogenic, 8 likely benign, while 16 variants remained VUSs. By the end of the study, 60 of the 77 cases had a definitive diagnosis of dysferlinopathy, which was a 47% increase in diagnostic yield over the rate at study onset. This data shows the ability of RNA-Seq to assist in variant pathogenicity classification and diagnosis of dysferlinopathy and is, therefore, a type of analysis that should be considered when DNA-based genetic analysis is not sufficient to provide a definitive diagnosis.
Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT, OMIM #606768). We report the first Korean MMD1 misdiagnosed as Becker muscular dystrophy (BMD), which was caused by a combination of compound heterozygous c.663 + 1G > C and p.Trp992Arg of the DYSF gene. A 70-year-old male previously diagnosed with BMD was admitted for genetic counseling. Since he was clinically suspected to have dysferlinopathy but not BMD, targeted panel sequencing was performed to discover the potential hereditary cause of the suspected muscular dystrophy in the proband. Consequently, two pathogenic single nucleotide variants of the DYSF gene, c.663 + 1G > C (rs398123800) and p.Trp992Arg (rs750028300), associated with dysferlinopathy were identified. These variants were previously reported with variant allele frequencies of 0.000455 (c.663 + 1G > C) and 0.000455 (c.2974T > C; p.Trp992Arg) in the Korean population. This report emphasizes the need for common variant screening in the diagnostic algorithms of certain muscle disorders or gene panels with potential pathogenic effects and high rates of recurrent variants.
Riassunto
Una miopatia distale deve essere ipotizzata in presenza di un deficit motorio puro che inizia con un coinvolgimento dei muscoli distali degli arti inferiori e/o superiori. Negli ultimi anni sono stati identificati molti geni che possono essere rivelatori di una miopatia distale. Va tuttavia sottolineato che questi geni possono spesso essere responsabili anche di altre forme di miopatia, come la distrofia dei cingoli, le miopatie congenite o anche le neuropatie motorie. L’esame clinico e l’anamnesi specificano la topografia del deficit, l’età di insorgenza e la modalità di trasmissione. L’attenta ricerca di un aumento delle creatinfosfokinasi (CPK), di una cardiopatia, di un coinvolgimento faringeo e di una cataratta può fornire preziosi indizi per l’identificazione di queste miopatie distali. In un certo numero di casi, la biopsia muscolare resta indispensabile perché permette di precisare le caratteristiche istologiche della miopatia, in particolare la presenza o meno di vacuoli orlati e l’alterazione della rete miofibrillare, nonché di effettuare studi immunoistochimici sull’espressione di varie proteine il cui difetto o il cui accumulo possono essere responsabili di miopatie distali. Inoltre, la risonanza magnetica (RM) muscolare è divenuta uno strumento indispensabile per caratterizzare la topografia della lesione, a volte subclinica. Con l’arrivo delle tecniche di sequenziamento ad alto rendimento, il cui corollario è l’identificazione di numerose varianti di significato incerto, una precisa caratterizzazione fenotipica resta indispensabile per l’interpretazione dei risultati genetici.
Zusammenfassung
Die Distalen Myopathien umfassen eine Gruppe von genetisch determinierten Muskelerkrankungen bei denen Paresen und eine fortschreitende Atrophie der distalen Muskelgruppen im Vordergrund stehen. Der klinische Phänotyp, der Erkrankungsbeginn, der Vererbungsmodus sowie histologische Veränderungen helfen die einzelnen Formen zu differenzieren. Das klinische und genetische Spektrum ist allerdings heterogen. In den letzten Jahren hat durch die erweiterte genetische Diagnostik die Anzahl der nachgewiesenen Mutationen exponentiell zugenommen. Im folgenden Beitrag werden die Klassifikation, die klinischen Besonderheiten und die relevanten genetischen Aspekte dargestellt.
Background
To characterize the phenotypic, neurophysiological, radiological, pathological, and genetic profile of 33 Saudi Arabian families with dysferlinopathy.
Methods
A descriptive observational study was done on a cohort of 112 Saudi Arabian families with LGMD. Screening for the Dysferlin (DYSF) gene was done in a tertiary care referral hospital in Saudi Arabia. Clinical, Neurophysiological, Radiological, Pathological, and Genetic findings in subjects with dysferlin mutation were the primary outcome variables. Statistical analysis was done by Epi-info.
Results
33 out of 112 families (29.46%) registered in the LGMD cohort had Dysferlinopathy. 53 subjects (28 males, 52.83%) from 33 families were followed up for various periods ranging from 1 to 28 years. The mean age of onset was 17.79 ± 3.48 years (Range 10 to 25 years). Miyoshi Myopathy phenotype was observed in 50.94% (27 out of 53), LGMDR2 phenotype in 30.19% (16 out of 53), and proximodistal phenotype in 15.09% (8 out of 53) of the subjects. Loss of ambulation was observed in 39.62% (21 out of 53 subjects). Electrophysiological, Radiological, and histopathological changes were compatible with the diagnosis. Mean serum Creatinine Kinase was 6,464.45 ± 4,149.24 with a range from 302 to 21,483 IU/L. In addition, 13 dysferlin mutations were identified two of them were compound heterozygous. One founder mutation was observed c.164_165insA in 19 unrelated families.
Conclusion
The prevalence of Dysferlinopathy was 29.46% in the native Saudi LGMD cohort. It is the most prevalent subtype seconded by calpainopathy. The clinical course varied among the study subjects and was consistent with those reported from different ethnic groups. One founder mutation was identified. Initial screening of the founder mutations in new families is highly recommended.
Miyoshi myopathy (MM) is a rare autosomal recessive disorder caused by dysferlin (DYSF) gene mutation. Miyoshi myopathy-inducing mutation sites in the DYSF gene have been discovered worldwide. In the present study, a patient with progressive lower extremity weakness is reported, for which MM was diagnosed according to clinical manifestations, muscle biopsy, and immunohistochemistry. In addition, the DYSF gene of the patient and his parents was sequenced and analyzed and two heterozygous mutations of the DYSF gene (c.4756C> T and c.5316dupC) were discovered. The first mutation correlated with MM while the second was a new mutation. The patient was diagnosed with a compound heterozygous mutation. The mutation site is a new member of pathogenic MM gene mutations.
Skeletal muscle is the most abundant type of tissue in human body, being involved in diverse activities and maintaining a finely tuned metabolic balance. Autophagy, characterized by the autophagosome–lysosome system with the involvement of evolutionarily conserved autophagy-related genes, is an important catabolic process and plays an essential role in energy generation and consumption, as well as substance turnover processes in skeletal muscles. Autophagy in skeletal muscles is finely tuned under the tight regulation of diverse signaling pathways, and the autophagy pathway has cross-talk with other pathways to form feedback loops under physiological conditions and metabolic stress. Altered autophagy activity characterized by either increased formation of autophagosomes or inhibition of lysosome-autophagosome fusion can lead to pathological cascades, and mutations in autophagy genes and deregulation of autophagy pathways have been identified as one of the major causes for a variety of skeleton muscle disorders. The advancement of multi-omics techniques enables further understanding of the molecular and biochemical mechanisms underlying the role of autophagy in skeletal muscle disorders, which may yield novel therapeutic targets for these disorders.
Dysferlinopathy is a group of autosomal recessive muscular dystrophies caused by variants in the dysferlin gene (DYSF), with variable proximal and distal muscle involvement. We performed DYSF gene analyses of 200 cases suspected of having dysferlinopathy (cohort 1), and identified diagnostic variants in 129/200 cases, including 19 novel variants. To achieve a comprehensive genetic profile of dysferlinopathy, we analyzed the variant data from 209 affected cases from unrelated 209 families including 80 previously diagnosed and 129 newly diagnosed cases (cohort 2). Among the 90 types of variants identified in 209 cases, the NM_003494.3: c.2997 G>T; p.Trp999Cys, was the most frequent (96/420; 22.9%), followed by c.1566 C>G; p.Tyr522* (45/420; 10.7%) on an allele base. p.Trp999Cys was found in 70/209 cases (33.5%) including 20/104 cases (19.2%) with the Miyoshi muscular phenotype and 43/82 cases (52.4%) with the limb‐girdle phenotype. In the analysis of missense variants, p.Trp992Arg, p.Trp999Arg, p.Trp999Cys, p.Ser1000Phe, p.Arg1040Trp and p.Arg1046His were located in the inner DysF domain, representing in 113/160 missense variants (70.6%). This large cohort highlighted the frequent missense variants located in the inner DysF domain as a hotspot for missense variants among our cohort of 209 cases (>95%, Japanese) and hinted at their potential as targets for future therapeutic strategies.
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The term dystrophy is derived from the Greek word “dus” meaning “bad” and “trophia” meaning “nourishment” as it was initially thought of muscle disease due to disordered nutritional factors. Muscular dystrophies are a group of heterogeneous genetic disorders that have in common irreversible loss of muscle fibers resulting from repetitive cycles of degeneration, necrosis, regeneration, and eventually fibrosis and fat replacement [1]. The worldwide prevalence of muscular dystrophies is 16.14 per 100,000 [2]. The most common muscular dystrophy is the Duchenne muscular dystrophy (DMD), first described by Edward Meryon in 1851 at the Royal Medical and Chirurgical Society meeting. The same was published a year later [3, 4]. In the ensuing years 1861 and 1868, Guillaume-Benjamin-Amand Duchenne described the same disease in greater detail [5]. The term “muscular dystrophy”, however, was first coined by Erb in 1891 [6]. Over the years, scientists gradually realized that muscular dystrophies were inherited and most had a characteristic pattern of muscle involvement. The myopathological features common to most muscular dystrophies are variation in muscle fiber size and shape, myonecrosis, myophagocytosis and eventually replacement of myoarchitecture by fibroadipose connective tissue. The first clinical classification for muscular dystrophies was proposed by Walton and Nattrass based on the pattern of muscle involvement [7]. The clinical classification although simple has many limitations because of considerable overlap between the subgroups and at times between nondystrophic myopathies. For example, limb-girdle muscular dystrophy 2A (LGMD2A) can clinically mimic facioscapulohumeral muscular dystrophy (FSHD). Dysferlinopathy (LGMD2B), LGMD2A, and FSHD are common mimics of inflammatory myopathy [8]. Histopathological features in such cases may at times provide a clue to the subtype of muscular dystrophy under question. FSHD and LGMD2B may have endomysial mononuclear infiltrate as the dominant finding. In oculopharyngeal muscular dystrophy (OPMD), rimmed vacuoles and nuclear tubulofilamentous inclusions are quite characteristic. Lobulated fibers and eosinophils are commonly encountered in LGMD2A. However, these findings can be a double-edged sword and misleading at times. In LGMD2B, infiltration of the endomysium by mononuclear cells associated with MHC-I upregulation and elevated serum CK levels may mimic inflammatory myopathy. Lobulated fibers are known to occur in a variety of conditions such as normal myotendinous junctions, LGMD2A, α-sarcoglycanopathy, dysferlinopathy, carriers of dystrophin gene mutation, Bethlem myopathy, LGMD2G, scapuloperoneal muscular dystrophy, nemaline myopathy, etc. [9–15]. Similarly, rimmed inclusions can be observed in Becker muscular dystrophy, Miyoshi myopathy, LGMD2I, LGMD2G, FSHD, titinopathy, oculopharyngeal muscular dystrophy, scapuloperoneal muscular dystrophy, congenital muscular dystrophy with merosin deficiency, GNE myopathy, etc. [9, 11, 16–23]. One of the most significant breakthroughs in the history of myopathology is the discovery of DMD gene locus by Monaco et al. [24]. Thereafter, the amassing wealth of molecular genetic data with respect to the muscle diseases has been phenomenal. Recent classifications have focused on the molecular genetic mechanisms that underlie muscular dystrophies especially the genes encoding proteins directly or indirectly associated with muscle contraction and repair. The data is likely to increase exponentially as new state-of-the-art techniques evolve in the future. In this chapter, we will follow the molecular pathology-based classification with emphasis on clinical and myopathological features. Although there is an interplay of other factors, this classification is being adopted because of its lucidity. The onset of dystrophies may be at birth or may be delayed until late adulthood. The key aspect in the assessment of a suspected muscular dystrophy is defining the pattern of muscle weakness. Most of the adult muscular dystrophies have a “limb-girdle” pattern of weakness with proximal limb muscles being weaker than distal muscle groups. It is important to look for additional features such as facial weakness, scapular winging, calf hypertrophy/atrophy, asymmetry in strength, and rippling of muscles to narrow down the list of differential diagnosis. Dystrophies affect not only skeletal muscles. Cardiomyopathy may be the presenting feature. The primary reason for demise in most cases of dystrophy can be attributed to respiratory muscle failure. Smooth muscles may also be affected, leading to abnormal gastrointestinal motility. Serum creatine kinase (CK) levels are usually raised (sometimes up to 20 times normal or greater) in most of the dystrophies. However, this is not always true especially in some of the more indolent disorders and in end-stage muscle disease where the muscle does not have enough CK. Levels of other enzymes, including aldolase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), may be elevated as well. Electromyography (EMG) may be helpful in sporadic cases and in patients with normal or modest elevation CK levels. Muscle imaging, especially the magnetic resonance imaging (MRI), is helpful to assess selective muscle involvement and to guide biopsy sites. In most patients with muscular dystrophy, genetic studies are the first line of investigations to circumvent the need for a muscle biopsy. However, muscle biopsy may be indicated under special circumstances such as ambiguous clinical manifestations, non-contributory genetic testing, and unknown prevalence of the suspected dystrophy. Diagnostic accuracy increases when light microscopic morphology is complemented by ancillary techniques. Development of diagnostic antibodies against proteins implicated in dystrophy permits us in drafting appropriate protocols to guide genetic testing.
Educational objectives:
To discuss a case of adult-onset asymmetric distal leg weakness in a patient who presented with weakness and atrophy of the posterior compartment of the left leg.
Key questions:
1. What is the differential diagnosis of asymmetric distal leg weakness?2. How would a clinician approach diagnostic testing for such a patient?3. What is the final diagnosis for this patient?4. How to treat this patient?
Die Diagnostik der Skelettmuskelerkrankungen hat in den letzten 10-20 Jahren außerordentliche Fortschritte erfahren, die vor all em auf die Entwicklung neuer Methoden in der Histochemie. Immunhistochemie, Zytochemie, Biochemie und Elektronenmikroskopie zurückzuführen sind.
Five distinct predominant distal myopathies have been identified with discrete clinical and genetic patterns. Miyoshi myopathy (MM; early adult-onset, type 2) is a subtype of dysferlinopathy. Furthermore, MM is the most common form of autosomal recessive distal myopathy. MM is typically characterized by muscular weakness, initially affecting the gastrocnemius or soleus muscle from the late teens or early adulthood. The present study reports a case of MM that was confirmed by pathological and immunohistochemical methods, in addition to a review of the relevant literature. A 37-year-old male patient presented with muscular weakness in the left foot. This clinical manifestation was not typical of MM, and the patient was initially diagnosed with inflammatory myopathy. He was treated with dexamethasone at a dose of 10 mg for 5 days followed by gradual tapering, following which the symptoms were alleviated; however, the pathology, immunohistochemistry and electromyography eventually confirmed the diagnosis of MM. The treatment was then terminated and the patient was discharged. The present study further supports the underlying heterogeneity in atypical MM-like phenotypes. Dysferlin protein deficiency can be identified by pathological examination. The pathology of dysferlinopathy is characterized by changes of muscular dystrophy. Inflammatory cellular infiltration is a relatively common finding in the muscle biopsies from numerous patients with dysferlinopathy. Therefore, the detection of dysferlin deficiency or marked reduction on the sarcolemma using immunohistochemical staining is important for the diagnosis of dysferlinopathy.
Objective:
To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.
Methods:
The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.
Results:
There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.
Conclusions:
These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.
This study reports on a detailed clinical, electrophysiological, muscle computed tomography (CT) and laboratory investigation carried out on five families with definite linkage to chromosome 2p. Some clinical and laboratory features were common to most of the patients, such as the very high serum creatine kinase (CK) levels (mean 43.70 times the normal). The onset was most frequently in the late teens or early twenties with weakness and wasting of the pelvic girdle muscles. All patients had normal motor milestones and had not complained of any symptoms of muscle disease in early childhood. The clinical course was variable both between and within some families, but was most often slowly progressive. Some variability in the pattern of muscle involvement between the different families has also been observed.
Nucleic acid therapies have gained significant traction in recent years as a promising new approach to treating various genetic diseases. Such therapies employ synthetic, small molecules called antisense oligonucleotides (AOs) which are capable of modulating the transfer of genetic information from nucleic acid to protein through various mechanisms, including the augmentation of pre-mRNA splicing and downregulation of expression. Thus, AOs can prevent the incorporation of genetic mutations causing disease into final protein transcripts as well as reduce levels of mutant transcripts, potentially ameliorating disease phenotype. This process, also known as antisense therapy, has recently been the subject of several preclinical and clinical trials aimed at treating muscular dystrophies. Thanks to recent advancements in antisense drug chemistries, numerous studies have demonstrated the safety, tolerability, and efficacy of AOs administered to patients with Duchenne muscular dystrophy, the most common form of muscular dystrophy. In the wake of promising clinical trial data, it may well be that the first federally approved marketable antisense drug for treating muscular dystrophy could be on the horizon.
Introduction:
We report a patient in whom the diagnosis of a treatable disease was delayed for 30 years.
Methods:
Recent discoveries of next generation sequencing (NGS) have allowed us to reconsider the diagnosis of limb girdle muscular dystrophy (LGMD) cases of unknown etiology.
Results:
A 36-year old man appeared to have LGMD with onset in shoulder girdle muscles, but all sarcolemmal and cytoskeletal proteins tested by immunoblotting and immunohistochemistry gave normal results. He developed respiratory insufficiency and became dependent on overnight ventilation at age 44. By NGS technology, 2 mutations in the GAA gene (IVS1 and a missense mutation in exon 11) allowed us to make a definite diagnosis of glycogenosis type II (Pompe disease) and start enzyme replacement therapy at age 71.
Discussion:
Mild non-dystrophic features on muscle biopsy and respiratory muscle involvement should suggest late-onset Pompe disease in patients with an unclassified LGMD phenotype. NGS may help make the diagnosis. This article is protected by copyright. All rights reserved.
Introduction: Dysferlin is an ubiquitarious transmembranar protein, with major expression in the skeletal muscle. The dysferlin gene was mapped to chromosome 2p13. Three distinct phenotypes have been described as secondary to its absence or reduced expression, namely, Limb-Girdle Muscular Dystrophy type 2B (LGMD 2B), Miyoshi Myopathy (MM) and Distal Anterior Compartment Myopathy (DAMT). Clinical asymptomatic patients with elevated CK have also been described. Objectives: To present both clinical and laboratory characteristics as well as the clinical evolution of eight patients, with a deficiency of the dysferlin protein. Patients and methods: Analysis of the clinical files of eight patients with signs and/or clinical symptoms secondary to a deficiency of the dysferlin protein, confirmed by immunohistochemical analysis and/or genetic studies of the dysferlin gene. Results: The eight patients are divided in equal number by each sex. The mean time since the first symptoms until now is 10,2 ± 6,5 years (2-24 years) and actual mean age is 29,5 ± 9,1 years (20-49 years). In the first clinical examination, one patient presented only complaints of easy fatigability (FM), the LGMD 2B phenotype was identified in five patients and the MM phenotype in two patients. Nowadays, four patients present generalization of muscle weakness (3 LGMD 2B, 1 MM) and the others keep the same clinical picture (2 LGMD 2B, 1 MM, 1 FM). Elevatio n of serum CK levels was present in all patients. A muscular dystrophic pattern was identified in the biopsies of 7 patients, with absence of dysferlin in the sarcolemma of the fibers of five tested patients. Pathogenic mutations of the dysferlin gene were confirmed in 7 patients, being the same mutation in 3 patients, 2 with LGMD 2B phenotype and the other with MM phenotype. Conclusions: This group of p atients is elucidative about the recognized clinical and genetic heterogeneity of muscle diseases related to dysferlin deficiency. It's also noteworthy the variability in the initial clinical picture and evolution.
The limb-girdle muscular dystrophies are a genetically heterogeneous and phenotypically diverse group of hereditary muscle diseases characterized by progressive proximal lower and upper extremity muscle weakness with relative sparing of extraocular, facial, and distal extremity muscles. Over the past few decades, several of the genes and proteins underlying this group of disorders have been identified, providing a window of opportunity to study pathophysiologic mechanisms of muscle disease and regeneration. While specific therapeutic interventions for these diseases are scarce, better understanding of the mechanisms and modifiers of disease hold the promise for better treatments in the future. Linking pathophysiology with clinical phenotypes when appropriate, the goal of this chapter is to characterize these various disorders in a way that is useful for clinical practice and provide a rational approach to the workup of patients with limb-girdle muscular dystrophy.
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