18 research outputs found
Limb-girdle Muscular Dystrophy Type 2A with Mutation in CAPN3: The First Report in Taiwan
The autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 (CAPN3) gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. We report a 33-year-old woman with initial presentations of exercise intolerance and running difficulty at age 15 years. At presentation, waddling gait, positive Gowers' sign, and marked muscle atrophy in pelvic and leg muscles were noted. Muscle computed tomography (CT) imaging demonstrated symmetric involvement of the posterior thigh muscles with relative sparing of vastus lateralis, sartorius, and gracilis. Muscle biopsy revealed a dystrophic change and many lobulated fibers on NADH-tetrazolium reductase staining. Genetic analysis of the CAPN3 gene identified a novel homozygous mutation of c2047_2050 del4, p.Lys683fs mutation, confirming the first LGMD2A patient in Taiwan
Erratum: Corrigendum: Genetic diagnosis of Duchenne/Becker muscular dystrophy using next-generation sequencing: validation analysis of DMD mutations
Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.
Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene
Induction of Pluripotent Stem Cells from a Manifesting Carrier of Duchenne Muscular Dystrophy and Characterization of Their X-Inactivation Status
Three to eight percent of female carriers of Duchenne muscular dystrophy (DMD) develop dystrophic symptoms ranging from mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy due to skewed inactivation of X chromosomes during early development. Here, we generated human induced pluripotent stem cells (hiPSCs) from a manifesting female carrier using retroviral or Sendai viral (SeV) vectors and determined their X-inactivation status. Although manifesting carrier-derived iPS cells showed normal expression of human embryonic stem cell markers and formed well-differentiated teratomas in vivo, many hiPS clones showed bi-allelic expression of the androgen receptor (AR) gene and loss of X-inactivation-specific transcript and trimethyl-histone H3 (Lys27) signals on X chromosomes, suggesting that both X chromosomes of the hiPS cells are in an active state. Importantly, normal dystrophin was expressed in multinucleated myotubes differentiated from a manifesting carrier of DMD-hiPS cells with XaXa pattern. AR transcripts were also equally transcribed from both alleles in induced myotubes. Our results indicated that the inactivated X chromosome in the patient’s fibroblasts was activated during reprogramming, and XCI occurred randomly during differentiation
Exome sequencing as a diagnostic tool to identify a causal mutation in genetically highly heterogeneous limb-girdle muscular dystrophy
A Nationwide Survey on Danon Disease in Japan
Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf⁻Parkinson⁻White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease
Pathological Characteristics of BMD patients. A:
<p>On mGT staining, RVs are seen in the periphery of myofibers (<b>arrow</b>). <b>B:</b> On H&E staining, there is marked variation in fiber size with scattered small atrophic fibers. <b>C:</b> High acid phosphatase activity is seen in the areas of RVs. <b>D:</b> On ATPase staining pre-incubated at pH 4.6, RVs are seen in both type 1 and type 2 fibers. <b>Asterisks</b> indicate myofibers with RVs. Scale bar: 25 µm.</p
Summary of clinical and pathological findings of BMD patients with rimmed vacuoles.
<p>BB = biceps brachii; QF = quadriceps femoris; RF = rectus femoris; BF = biceps femoris; *per 1,000 fibers</p
Areas of RVs in BMD myofibers show typical electron microscopic characteristics of autophagic vacuoles. A:
<p>Accumulation of autophagic vacuoles (<b>arrowheads</b>), various cellular debris, and multilamellar bodies (<b>arrow</b>) are seen in myofibers of some BMD patients. Note the intact arrangement of myofibrils (<b>MF</b>) surrounding autophagic area. B: In areas with or without autophagy, lipofuscin deposit (<b>L</b>) is seen. Scale bars: 1 µm.</p