I Nishino

..However, we still do not know why hyposialylation leads to the formation of rimmed vacuoles. To further elucidate the pathomechanism and to develop a therapy of DMRV, we need to produce mouse model mouse for this disease...

..The identification of the MNGIE gene has allowed us to classify MNGIE as a disease of nucleoside dysmetabolism. We may be entering a new era of research on mitochondrial nucleoside metabolism...

..To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein...

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..Muscular dystrophy includes many genetically distinct disorders. The list of causative genes for muscular dystrophy has been expanding rapidly, including those for congenital muscular dystrophies...

..Recently, HIBM was shown to be associated with the mutations in the gene encoding the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE)...

..Danon disease, the best-characterized disorder in this group, is caused by primary deficiency of a lysosomal membrane protein, LAMP-2. Therefore, diseases in this category are expected to be primary lysosomal disease...

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..Asymmetrical wasting of muscles in the extremities exhibited uniform and highly selective CT imaging patterns. RNA and DNA analyses confirmed novel compound heterozygous mutations (R147X/L212F) in the human CAPN3 gene...

..Haplotype analysis suggests that this new AVM and XMEA may be allelic despite different clinical presentations...

..Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and laminin-alpha2 supporting the hypothesis that FKRP has a role in the interaction between the extracellular matrix components...

..Only one of the patients had a mutation in the collagen VI gene, suggesting that the primary abnormality in most of the patients involved some other molecules...

..We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase...

..Heart transplantation is the most effective treatment for the otherwise lethal cardiomyopathy. CONCLUSIONS: Danon disease is an X-linked dominant multisystem disorder affecting predominantly cardiac and skeletal muscles...

..Deposition of C5b-9 and multilayered basal lamina in one patient suggest that the infantile disease is pathogenically similar to X-linked myopathy with excessive autophagy...

..To determine the frequency of primary collagen VI deficiency in congenital muscular dystrophy (CMD) in Japan and to establish the genotype-phenotype correlation...

..Increased number and variation in size of myonuclei were detected. More precise observations using electron microscopy is warranted to characterize the detailed nuclear changes in nuclear envelopathy...

..Defined by distinct clinical features, this disease constitutes the fourth entity in the group of autophagic vacuolar myopathy in which the vacuolar membranes have features of sarcolemma...

..With regard to other sarcolemmopathies, we discuss pathological mechanisms based on available data...

..Their patient expressed alpha-dystroglycan (alpha-DG) core protein, but fully glycosylated alpha-DG antibody epitopes were absent, associated with the loss of laminin-binding activity...

..The pathogenic mechanism may be related to aberrant thymidine metabolism, leading to impaired replication or maintenance of mtDNA, or both...

..We previously reported that the majority of patients with UCMD have sarcolemma-specific collagen VI deficiency (SSCD). More recently, we found heterozygous COL6A1 glycine substitutions in patients with UCMD with SSCD...

..Mitochondrial enlargement may represent functional compensation for mitochondrial depletion in the central sarcoplasm, where myofibrillar degeneration occurred...

..MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases...

..This result implies the necessity of other protein(s) for proper membrane localization of dysferlin, or some roles of dysferlin in the cytoplasmic region...

..This is the first patient who had a mutation at the central part of an intron of the dystrophin gene instead of at the exon-intron border...

..We recently reported that almost all patients with central core disease (CCD) with ryanodine receptor 1 gene (RYR1) mutations in the C-terminal domain had type 1 fibers, nearly exclusively, in addition to typical central cores...

..Uncovering the molecular bases of intergenomic communication defects will enhance our understanding of the mechanisms responsible for maintaining mtDNA integrity...

..Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described...

..The nucleotide substitution at nt 15915 disrupts a highly conserved base pair in anticodon stem of the tRNA(Thr). Our data suggest that the 15915 mutation is an additional mtDNA mutation responsible for mitochondrial encephalomyopathies...

..Absence of microfibrils on EM, together with normal collagen fibrils and basal lamina, suggests that loss of a link between interstitium and basal lamina may be a new molecular pathomechanism of muscular dystrophy...

..CONCLUSIONS: The new screening method for the detection of VLCAD deficiency using an immunohistochemical technique identified 13 new Japanese patients with VLCAD deficiency...

..This patient further demonstrated possible clinical heterogeneity of myopathies with mutations in the caveolin-3 gene...

..In this review, we briefly summarize the progress in DMRV research, and highlight efforts of researchers in generating the animal model for this myopathy...

..Analysis of MTM1 knocked-out mice indicates that the characteristic small fibers in XLMTM muscles are due to atrophy rather than hypoplasia...

..The correlation between clinical phenotype and the gene mutations was unclear, which suggested the role of additional genetic and epigenetic factors in modifying clinical symptoms...

..Caveolin-3 was deficient and caveolae were lacking in muscles from both patients. Our data confirm that caveolin-3 deficiency causes LGMD-1C and expand the variability in CAV3 gene mutations...

..Strong expression of dysferlin in TAs suggests the possibility that it is located not only at the sarcolemma but also in the SR, at least in the pathological conditions...

..Our findings underscore the notion that hyposialylation plays an important role in the pathomechanism of DMRV/hIBM...

..As some effective drugs have been widely used and some promising therapies are under certified, comprehensive understanding of these diseases from clinical, pathological and molecular aspects would be of much help for the patients...

..Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven...

..In conclusion, AVSF with acetylcholinesterase activity are autolysosomes surrounded by secondarily generated intracytoplasmic sarcolemma-like structure and delineates a subgroup of AVMs...

..Confocal microscopic observation with marker antibodies confirmed that calpain 3 is localized in the N2 region of myofibrils. Furthermore, using this antibody, we examined the localization of calpain 3 in LGMD2A muscles...

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..There are no specific clinical characteristics distinctive to RBM, thus further studies are necessary to characterize this disorder both clinically and pathologically...

..This mutation in the second immunoglobulin-like domain impairs myotilin dimerization and alters the binding between myotilin and alpha-actinin, which is known to be important for actin bundling...

..The current study was designed to further explore the association of FKTN mutations with DCM or hypertrophic cardiomyopathy (HCM)...

..Presence of small amounts of partly glycosylated alpha-DG may have a role in reducing the clinical symptoms of alpha-dystroglycanopathy...

..This result suggests that other factors can modify clinical features of the patients with glycosylation defects of alpha-DG...

..The addition of ManNAc and NeuAc to primary cultured cells normalized sialylation levels, thus demonstrating the therapeutic potential of these compounds for this disease...

..Our findings underscore the notion that hyposialylation plays an important role in the pathomechanism of DMRV/h-IBM...

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..These results suggest that the unfolded protein response caused by the accumulation of misfolded proteins in the endoplasmic reticulum plays an important role in the formation of RBs...

..Two patients (one male and one female), who had similar clinicopathologic features, did not have any mutation in the MTM1 gene open reading frame, suggesting that they may have had an autosomal recessive disease...

..Fukuyama-type congenital muscular dystrophy is one of the disorders associated with glycosylation defects of alpha-dystroglycan, an indispensable molecule for intra-extra cell membrane linkage...

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..In this review, these disorders are briefly characterized, and the role of autophagy in the context of the pathomechanism of these disorders is highlighted...

..A chimeric fusion transcript was detected in patient's muscle by RT-PCR, suggesting this fusion gene product avoids the phenotype. This deletion led us to refine the critical region of CXorf6 for the development of male genitalia...

..This indicates the possibility of developing a therapy for DMRV/HIBM by giving these metabolites to patients although we have to await the model mice that are currently being produced at several laboratories...

..Our data suggest that fukutin and FKRP may be involved at different steps in O-mannosylglycan synthesis of alpha-dystroglycan, and FKRP is most likely involved in the initial step in this synthesis...

..The 2 patients with PNPLA2 mutations had progressive, non-episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs...

..Thus our results show that the oral therapy with NeuAc and ManNAc or their derivatives is safe and effective in preventing myopathic symptoms in Gne(-/-)hGNED176VTg mice, and could be considered as a guide for further therapeutic trials...

..The disorder may be familial with apparent autosomal dominant inheritance. We report a large kindred with essential familial myoclonus-dystonia and map a locus for the disorder to a 28-cM region of chromosome 7q21-q31...

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..In contrast, rimmed vacuoles are secondarily caused by extra-lysosomal defects, such as hyposialylation in DMRV/HIBM, and are formed at later stages of the disease...

..This is probably a unique form of distal myopathy characterized by the presence of multi-minicores with preferential involvement of type 1 fibers...

..Our results suggest that the expression and stability of the mRNA for these RNA-binding proteins are unaffected in DM1...

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..In older age, and particularly in gastrocnemius muscles, RVs and intracellular inclusions were seen in type IIA fibers, further aggravating reduction of force and specific increase in twitch-tetanus ratio...

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..The expression patterns of these genes correlated with the severity of dystrophic changes on histological examination. Our cDNA microarray provides a new tool to investigate molecular muscle pathology...

..These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future...

..This indicates that heterozygous mutations in COL6 genes diminish the anchorage of collagen VI microfibrils to the extracellular matrix surrounding myocytes. This is the cause for sarcolemma-specific collagen VI deficiency...

..This review aims to update our knowledge of this myopathy and to review studies about pathomechanism and therapeutic strategies...

..Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD...

..Reducing bodies were observed in few fibers of the patient's muscle sample. Amount of FHL1 protein was decreased on immunoblotting. In conclusion, FHL1 can be one of the causative genes for RSS...

..Thus, the compensatory overexpression of myoferlin was not detected in muscles with dysferlinopathy...

..However, no mutation was found, suggesting that these genes may not, or only rarely, be responsible for CCD. Our results indicate that CCD may be caused by RYR1 mutations in the majority of patients...

..This study might propose some clues to resolve the combination of musular dystrophies and rigid spine syndrome...

..Our results suggest that emerin deficiency causes minimal motor and cardiac dysfunctions in mice with a structural fragility of myonuclei...

..Electron microscopy demonstrated autophagic vacuoles and tubulofilamentous inclusions. This myopathy can cause dropped head syndrome in a subgroup of patients...

..Thus, in this chapter, methods applicable to both human and murine skeletal muscle preparation for the analysis and monitoring of autophagy are presented...

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..Co-expression of SHPS-1 and CHK enhanced neurite outgrowth in PC12 cells. Thus, CHK phosphorylates and associates with SHPS-1 and is involved in neural differentiation via SHP-2 activation...

..The patient had a homozygous four-base duplication (c.475_478dupCTCC) in exon 4 of PNPLA2...

..Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD...

..Besides the severe muscle involvement, these clinical findings further broaden the clinical spectrum of actinopathy phenotypes...

..These mouse models should be of use in further studies of Sco2 function, as well as in testing therapeutic approaches to treat the human disorder...

..FSHD is clinically, and most likely genetically, as well, variable. Other forms of muscular dystrophy can also mimic FSHD...

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..Although defective glycosylation to a muscle fiber has been suggested, the mechanism by which myofibrillar degeneration is followed by rimmed vacuole formation remains to be clarified...

..In contrast, in the muscle biopsy from the mother there were no vacuoles even though she had decreased LAMP-2...

..Collectively, our findings suggest that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities...

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..This finding suggests that alpha-dystroglycan is a potential target of POMGnT1 and that altered glycosylation of alpha-dystroglycan may play a critical role in the pathomechanism of MEB and some forms of muscular dystrophy...

..We also found N-terminal calponin homology domain of affixin as a binding site for dysferlin. Our results suggest that affixin may participate in membrane repair with dysferlin...

..Our findings indicate that modulation of LARGE expression or activity is a viable therapeutic strategy for glycosyltransferase-deficient congenital muscular dystrophies...

..This is the first missense mutation so far described. LAMP-2 deficiency should be considered as a cause of recurrent hyperCKemia and hypertrophic cardiomyopathy...

..We propose that the proteolysis of beta-dystroglycan may contribute to skeletal muscle degeneration by disrupting the link between the ECM and cell membrane in sarcoglycanopathy and DMD...