‘Limb-girdle muscular dystrophies’ are group of emerging dissimilar diseases that made some investigators dispute the term rationality, the mutual feature is limb-girdle affection. Herein, we reviewed the disease from historical, nosological, pathophysiological, diagnostic, preventive, therapeutic and future perspectives; with specific attentions to newly evolving trials to bring these hereditary diseases from research counter to clinical zone, and energies that made the incredible recovery from such group of diseases, now part of reality at least in preclinical sector. In conclusion, rapid progress was made in LGMD field in the foregoing decades, yet more cohorts, patient registry, regular follow up, improvement of diagnostic criteria for LGMD subtypes and more understanding pathophysiology of LGMD forms will feasibly improve disease outcome in subsequent years. We also added special chapter for LGMD in China and progression of molecular diagnosis and pathophysiological understanding.
Historically ,Walton and Nattrass (1954) first devised name ‘limb-girdle muscular dystrophies’ to comprise cases of both sexes, beginning usually within the first three decades, with major involvement of scapular, pelvic girdle and trunk muscles and sparing of facial muscles, infrequent pseudo hypertrophy, moderately severe progression and usually an autosomal recessive mode of inheritance.
In1995, the European Neuromuscular Centre Workshop established more precise criteria for diagnosis and classification of LGMD, grouping the different subtypes according to their genetic characteristics.
As it is explicit from long nosological history of LGMD; it is not homogeneous disease, we can just consider LGMD like an ‘umbrella’ term under which more than two dozens of gene defects were recognized.
Each LGMD form has different mechanism; in general we can classify LGMD subtypes according to site of their affected proteins into: sarcolemmal, sarcoplasmic or cytosolic proteins, sarcomeric or myofibrillar proteins and nuclear membrane proteins or according to their functions to: scaffolds, patch up, remodeling, assembling, glycosylating, preventing protein from irreversible aggregation or unknown function.
Treatment-directed pathophysiology signifies the most important type of pathophysiology that studies the pathways that the researchers release through reversal of etiological agents instigating the disease or through disrupting some steps believed to be downstream pathology of missing gene.
To evaluate clinical outcome of pharmacological, cell or gene therapies, authors considered some markers that could reflect disease activity, regression and treatment efficacy without need to do multiple muscle biopsies e.g., contrast agent-enhanced MRI, secreted alkaline phosphatase level (Se AP) in blood, circulating monocyte, luciferase levels, neutralizing antibodies and INF-γ to r AAV and expression proteins.
The relative proportion of each LGMD form varied considerably among different populations. In general LGMD2A represents the most common type in different populations followed either by dysferlinopathies in some areas or by dystroglycanopathies in others or by sarcoglycanopathies in the third. LGMD made the second most common dystrophy after dystrophinopathies in several countries.
Genotype –phenotype correlation is yet difficult to predict and this sector of genetic disorders represents the most obscure and confusing field for investigators and may interpret why most types of gene therapies nowadays attained suboptimal level of recovery.
Clinical, electrophysiological, imaging, biochemical and genetic testing all should be recruited and tailored according to specific case not only to reach diagnosis and provide genetic counseling to probands and relatives but also to understand pathophysiology and to target therapy to precise pathway.
MRI, perioral skin biopsies, blood assay, reverse- protein array, gene expression profiling, proteomic analysis, gene chips, exome and wide genome next generation sequencing are the most important emerging methods to facilitate LGMD diagnosis, whereas gene, cell and pharmaceutical therapies are the most important presumed therapies for this hereditary group of diseases.
Genetic counseling is encouraged to reduce the burden of the disease in the community, especially in areas where founder mutation has been determined.
Like other inherited disorders, no available therapy provided to LGMD patients to date. Management is mainly supportive emotionally and physically.
China contributed greatly to development of molecular genetic biology field; still many hurdles to be passed in neuromuscular research area in general and LGMD especially. Rarity, heterogeneity, non-curability of LGMD made neuromuscular research committee in China pay less attention to this growing field of medicine. There still some obstacles in the way of LGMD project in China need to be paved in near future concerning national registry of patients, clinical outcomes measures and readiness to future clinical trials. We propose collaborative network between neuromuscular disease centers that help manage LGMD problem according to agreed national standards.
Changing nosology, heterogeneous phenotype, variable protein expression, genetic multiplicity and fluctuating preclinical therapeutic responsiveness, taken together all fashioned LGMD nature.
Study 1
Background:
Some hereditary myopathies can mimic acquired polymyositis (PM) in particular when they first present in adulthood with a limb-girdle distribution of weakness. The diagnosis is made yet more complex when inflammatory infiltrates attend muscle biopsy. This is common in certain dystrophies in particular limb-girdle muscular dystrophies.
The clinical picture of LGMD and PM is rather similar, e.g., muscle weakness and atrophy, and often confuses clinicians. Muscle biopsy from both patients, as aforementioned, may demonstrate inflammatory infiltrates. Dramatic progress in biochemical and molecular biology in the last decade had made pathologist somewhat entirely dependent on immunohistochemical, immunoblot and genetic screening results in differentiating the two diseases. However, in some undeveloped areas in the world where such advanced approaches are unobtainable, muscle biopsy and routine histochemical stain are often used to help diagnose muscle diseases. Present literature focuses little on morphological findings of muscular diseases, hence a comprehensive study including various parameters of myopathy and dystrophy, comparing between the most confusing myopathic diseases represents necessity.
Methods:
For better distinction between the two diseases, we performed histochemical morphometric analysis for twenty LGMD biopsies confirmed by protein testing and eight PM biopsies met Dalakas and Hohlfeld 2003 definite criteria for polymyositis. Each parameter of myopathy was evaluated in five or ten randomly selected fields, using Image –Pro plus bio-analytical software. Comparison between groups was tested using independent samples Student’s t-test analysis.
Twenty LGMD patients with inflammatory components were ascertained through Department of Neurology, First Hospital of Jilin University Changchun. Eleven were diagnosed as dysferlinopathy where dysferlin is absent or severely reduced. Four cases diagnosed as sarcoglycanopathy where sarcoglycan -α is deficient. The remaining five cases remained unclassified LGMD where calpain-3, caveolin-3and sarcoglycan-α were normal on immunoblot but showed reduction and abnormal localization of dysferlin staining. We further examined muscle biopsies from eight patients with PM.
Results:
The muscle of LGMD patients revealed more splitting fibers and larger connective tissue surface area in comparison to PM patients (p=0.02, 0.01 respectively). On the opposite the number of regenerating fibers was higher in myositis biopsies (p=0 .04) .Other parameters were akin to those of PM patients.  We also described different patterns MHC - I up regulation on LGMD biopsies.
Conclusion:
We reported some tips of difference between LGMD biopsies and polymyositis. The results attained in the present study have a considerable diagnostic application: wide area of connective tissue combined with high number of splitting fibers and less regenerating fibers should alarm pathologist about dystrophic process. This quantitation study presents the first, involving many parameters of dystrophy comparing them with those of inflammatory myopathy.
Study 2:
Background:
The relative frequency of different limb-girdle muscular dystrophies (LGMD) subtypes varies widely among different populations. While the most common LGMD subtype in Italy, Spain, Turkey, Russia, Brazil and Australia is calpainopathy (LGMD2A), the prevalence of Dystroglycanopathy (LGMD2I) in Norway, Denmark and North England ranks the first among LGMD. In India, sarcoglycanopthies (LGMD2C-2F) quoted the highest figures. Yet USA, Mexico and Japan reported dysferlinopathy as the most frequent type.
Though much is known about clinical features discerning calpainopathy from dysferlinopathy, little is known concerning their pathological findings. Many reports described clinical features and pathological findings of each disease separately and correlated genotype to phenotype in order to outline each subtype in a well characterized fashion, nevertheless comparable pathological consequences of most dystrophic diseases made the field of morphology vacant except for unique findings. Though, wide array of disease activities ranging from slowly progressive to malignant LGMD may possibly be reflected on morphological features. A rigorous comparison between both LGMD2A and LGMD2B biopsy sections was warranted.
In China to date, to our acquaintance, only two cohorts were separately published regarding LGMD; each considered only one LGMD form. Low incidence rate, rarity of consanguineous marriage and one child policy, all hampered wide statistics of this group of diseases. To our knowledge, no cohort has been conducted in China, rating the relative frequency of different LGMD subtypes.
Purpose and material and methods:
For better description of clinical features, biochemical findings, disease frequency, for genetic and prognostic counseling of LGMD patients and for well adjustment of forthcoming therapeutic promises, authors ascertained 68 patients with LGMD phenotype from the Muscle Center of First Hospital of Jilin University. Subtyping was proved by protein analysis.  Here in, we also made pathological correlations between the most common subtypes and reported some odd clinical and pathological features. Besides, we utilized acid phosphatase reaction to label macrophages on biopsies with cellular infiltrates.
Results:
Whilst the diagnosis of calpainopathy was mounded to twelve cases (17%), dysferlin deficit was detected in ten (15%). Two biopsies revealed α-sarcoglycan deficiency (3%) and other two showed caveolin3 lack (3%). The remaining patients stayed with the diagnosis of unclassified LGMD (62%). In general, our results coincide with those in Italy, Turkey, Russia, Brazil and Australia with parallel percentages of various LGMD forms. Now it is accepted that calpainopathy is the most frequent LGMD subtypes worldwide followed by dysferlinopathy whereas LGMD1C represents 2-3% in most conducted cohorts. Whether our sample is representative of Chinese population, still needs to be elucidated by collaborated multicenter LGMD research project throughout China.
We made use of acid phosphatase stain as an alternate of anti- macrophage antibodies to quantify and scan distribution of macrophages on DYSF mutant muscles. Authors could benefit from this easy and cost-effective method with comparable specificity to monoclonal antibodies.
Many studies delivered inflammatory infiltrates in various LGMD subtypes, yet to our information, inflammatory cells in adhalin deficient cases, had never been hitherto described. We identified extensive infiltrates in LGMD2D biopsies, mainly macrophages (stained by acid phosphatase reaction) with little eosinophils. Calpain3 deficient biopsies were insignificantly different from dysferlinopathics (Chi square test, P>0.05).
CK level was highest in LGMD2B>LGMD2D>LGMD1C>LGMD2A in decreasing order of their values.  The results quite indicate that dysferlinopathies are the most active disease followed by sarcoglycanopthies and these data were parallel to figures depicted from other geographic areas.
Relationship between defective membrane healing in dysferlin deficient muscle and immunological attack was verified recently. It was hypothesized that there should be some molecules were released from dysferlinopathic muscles that activated complement system. Uric acid was one of elected molecules that proposed to play role in initiating inflammatory cascade. Our results of normal serum level of uric acid might suggest that there still some unknown molecules, other than uric acid, would trigger the aforementioned pathway.
Conclusions:
We concluded that the distribution of LGMD subtypes in Han Chinese ethnicity was similar to what reported in the West. Less necrotic, regenerating and inflammatory burden but more lobulated fibers noticed in LGMD2A confirms the notion that calpainopathy is less active but more chronic disease compared to dysferlinopathy. Unusual features extended LGMD disease spectrum. Acid phosphatase stain should be considered in suspected dysferlinopathics.
The study represents the first in China, giving clear picture about the ranking of different LGMD subtypes and answered the question ‘which is the most common subtype in China ?’ whereas previous two studies in East and Middle China coped with only one type of limb-girdle muscular dystrophies in each cohort. Comparison of wide range of pathological parameters between LGMD2A and LGMD2B had never been preceded elsewhere. Overall impression about LGMDs in northeastern China was drawn embodied by high occurrence of calpainopathy followed by dysferlinopathy. Wide range and generally late age of disease onset, preeminent proximal myopathy and high CK level along with mostly sporadic cases, male preponderance and preservation of mobility status in most patients fashioned the present cohort.  Upcoming etiologically based treatment opportunities would emphasize the importance of well-categorizing statistical, clinical, biochemical and genetic continuum of LGMD subtypes.
Study 3:
Background:
Limb girdle muscular dystrophy type 2B and Miyoshi myopathy are two common allelic disorders result from defect in DYSF gene. The latter has been mapped to chromosome 2p13, whose protein product is called dysferlin. It had been proposed that dysferlin play role in membrane repair and vesicle trafficking. Pelvic or calf muscle weakness with slow progression, milder involvement of shoulder girdle muscles and marked elevation of serum CK level are the key features of dysferlinopathies.
Morphologically, biopsy from dysferlinopathics shows dystrophic, myopathic changes varying in severity. In advanced stage of the disease, fatty replacement is the rule. Cellular infiltrates are quite common. They differed from those of acquired polymyositis cytologically and in patterns of distribution. Mononuclear inflammatory infiltrates of non-necrotic fibers (MNN) were frequently reported in polymyositis (PM) and might indicate CD8 + T cells population rather than macrophages. However, to our information they had not been reported in dysferlinopathy before. Rimmed vacuoles were reported in Miyoshi myopathy but, to our knowledge, never in LGMD2B. Pyknotic nuclear clumps represent ‘denervation like’ pattern, seen in neurogenic muscular diseases and myotonic dystrophy. Yet, they have not been determined in LGMD biopsies.
Immunohistochemistry in combination with Western blot seemed to be efficient assays to offer diagnosis of dysferlinopathy with high specificity. Cacciottolo and others reliably verified that dysferlin expression of less than twenty percent normal firmly established primary DYSF defect.
To date, few reports have been published of genetically confirmed dysferlinopathy in China.  In this report, we described three LGMD2B and one MM patients with their clinical, physiological, biochemical and molecular findings.
Material and methods:
We followed four northeastern Han Chinese individuals clinically, biochemically, physiologically and genetically using histochemical, immunohistochemical, western blot and gene sequencing.
Results:
Herein, we reported genetically confirmed dysferlinopathic patients with their clinical, biochemical and molecular features. Three unrelated patients were presented with pelvic muscles weakness and wasting while calf atrophy brought the fourth for medical attention. Asymptomatic cardiac problem was discovered incidentally in one patient. Biopsy specimens showed variable dystrophic, myopathic and inflammatory patterns. Rimmed vacuoles were identified in another patient’s biopsy and mononuclear inflammatory infiltrates of non –necrotic fibers (MNN) usually seen in polymyositis were detected in the third, whereas the fourth expressed pyknotic nuclear clumps. Seven different mutations were recognized, four were novel. One mutation shared the hot -spot mutation seen in Japanese and Koreans.
Conclusions:
Our findings emphasize dysferlinopathy should be considered in differential diagnosis of dystrophy with cardiac disorders, rimmed vacuoles-myopathy, mononuclear inflammatory infiltrates of non-necrotic fibers or pyknotic nuclear clumps. These features might enhance our present knowledge of pathophysiology of dysferlin and might have influence on future therapeutic promises. The study might also point out that the hot -spot mutation seen in northeastern Chinese and other eastern Asians could feasibly and cost-effectively be screened before running whole gene sequencing. To our information, this is the first report of genetically confirmed LGMD2B from northeastern China.
In our view, inflammosome up-regulation and complement activation mechanisms are not working on cardiomyocytes given no detected infiltrates and normal gene expression of complement inhibitor decay-accelerating factor/ CD55 in cardiac muscles. Understanding the protective mechanism working against dysferlin deficiency in heart muscles may have impact on future therapeutic choice.
We documented mononuclear inflammatory infiltrates of non –necrotic fibers (MNN) in a genetically confirmed Miyoshi myopathy (MM) patient. The case might emphasize that mechanism involved in polymyositis could also be active in dysferlin deficient muscles. The hypothesis gained some credit, especially after recent work by Cohen et al that revealed the pro-inflammatory NFκB was up-regulated in dysferlin deficient myoblasts and anti-inflammatory drug ‘celastrol’ reduced the NFκB triggering and improved myoblasts myogenesis.
Pathological significance of rimmed vacuoles is yet unresolved, however, LGMD2B must be added to the list of ‘proximal myopathy with rimmed vacuoles’ and DYSF should be one of candidate genes tested if vacuoles were challenged histologically.
Protein –genotype correlation is hard to be drawn given small number of cases, nevertheless patients with only missense mutations showed marked dysferlin reduction, but not complete absence, while entire protein paucity was obtained in the null-mutation verified biopsy.
Based on our current knowledge, it is arbitrary to call the novel missense mutations in cardiac affected patient as ‘cardiopathic’. Yet, more understanding of dysferlin physiology in health and disease and its interactions with other proteins and with external stressor would feasibly solve the mystery of dysferlin gene defect.
It is priori that child born to indigenous marriage, theoretically should have mutation in homozygous state given common ancestor confers the same mutation. Though, this is not always the case and the child might be affected with two heterozygous mutations inherited separately from uncommon ancestors. Or denovo mutations ensued in that child. We described MM patient with two heterozygous mutations born to consanguineous marriage. Unfortunately, parents of our patient were not assessed genetically to see which mechanism was working in that specific case. Nonetheless, many papers described heterozygous mutations in children born to related parents.
The detected missense mutation c. 2997 G> T (P. T999C) was frequently reported in Japanese and Koreans. The age of onset, the severity of symptoms and protein expression was in accordance to what have been previously described by Tagawa et al. It was surprising that the mutation was associated with different phenotypes (LGMD2B, MM and rigid spine syndrome) in Japanese population. This confirms the view that no genotype –phenotype relationship can be outlined in dysferlinopathies and rather some epigenetic influences and other modulating genes, still to be detected, may perhaps decide the final form of distribution of weakness.  The case was considered as one of few reported symptomatic DYSF mutation carriers.
Key words:
LGMD;LGMD2A;LGMD2B;miyoshi myopathy;LGMD2D,LGMD1C; calpain 3; α-sarcoglycan; dysferlin; caveolin3; acid phosphatase stain; polymyositis (PM); major histocompatibility complex class I (MHC-I); morphometric.
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