Detection and management of cardiomyopathy in female dystrophinopathy carriers.

Regular health checkups for mothers of patients with Duchenne muscular dystrophy have been performed at National Hospital Organization Tokushima Hospital since 1994. Among 43 mothers participated in this study, 28 dystrophinopathy carriers were identified. Skeletal and cardiac muscle functions of these subjects were examined. High serum creatine kinase was found in 23 subjects (82.1%). Obvious muscle weakness was present in 5 (17.8%) and had progressed from 1994 to 2015. Cardiomyopathy was observed in 15 subjects (60.0%), including dilated cardiomyopathy-like damage that was more common in the left ventricular (LV) posterior wall. Late gadolinium enhancement on cardiac MRI was found in 5 of 6 subjects, suggesting fibrotic cardiac muscle. In speckle tracking echocardiography performed seven years later, global longitudinal strain was decreased in these subjects, indicating LV myocardial contractile abnormality. These results suggest that female dystrophinopathy carriers should receive regular checkups for detection and treatment of cardiomyopathy, even if they have no cardiac symptoms.

[A clinicopathological investigation of two autopsy cases of calpainopathy (LGMD2A)].

In this study, we compared the clinicopathological findings of two autopsy cases of patients with calpainopathy (LGMD2A) from different families. The patient in case 1 was a 72-year-old man with a history of type 2 diabetes mellitus. He exhibited recent memory impairments from the age of 70. ECG revealed an incomplete right bundle branch block. A homozygous frameshift mutation c.1796dupA was found in the CAPN3 gene. Cause of death was respiratory insufficiency and heart failure. The patient in case 2 was a 70-year-old man with a history of hypertension. ECG revealed an incomplete right bundle branch block. A homozygous missense mutation c.1080G>C (p.Trp360Cys) in CAPN3 gene was identified. Cause of death was ischemic cardiomyopathy and systemic circulatory failure. In both cases, muscle pathology revealed severe dystrophic changes. In case 2, cardiac hypertrophy and old myocardial infarcts with stenosis of coronary arteries were observed. Histological examination of the sinoatrial node showed fatty infiltration with ischemic changes in case 2. In both cases, the patients' brains showed cerebral atrophy and well preserved neurons. Calpain 3 abnormality was correlated with skeletal muscle involvement. It should be considered that LGMD2A might be complicated by dysfunction of the cardiac conduction system.

[Miyoshi distal muscular dystrophy (Miyoshi myopathy)].

We present an overview of autosomal recessive distal muscular dystrophy (ARDMD), including recent molecular genetic findings. ARDMD is often referred to as Miyoshi-type distal muscular dystrophy (MDMD) or Miyoshi myopathy (MM). The onset of MDMD occurs in early adulthood. Muscle atrophy is most dominant in distal leg muscles, especially the flexor muscles, i.e., gastrocnemius and soleus. As MDMD advances, muscle atrophy progresses to the thigh and hip muscles. Toe standing is impaired but heel standing can still be accomplished early in the disease course. This is followed by difficulty in standing and walking. The patients rarely become confined to bed. Serum creatine kinase level is markedly elevated, e.g., 100 times the upper limit of the normal range early in the disease course. Pre-symptomatic patients may also have high creatine kinase levels. Heterozygous individuals may have only slightly elevated creatine kinase levels. Recent development revealed that MDMD and LGMD2B are both caused by mutations in the dysferlin gene (DYSF). C1939G, G3370T, 3746delG, and 4870delT are reported to be common mutations among patients with MDMD. The dysferlin protein is presumably involved in the repair of muscle cell membranes. Among the patients reported originally by Miyoshi et al., 3 affected individuals from 3 different families were confirmed carriers of dysferlin mutations. Additionally, 1 heterozygous individual was identified. Although MDMD and LGMD2B are caused by the mutation of the same gene, ARDMD is characterized by initial involvement of leg flexors while LGMD2B is characterized by involvement of the proximal leg muscles. The difference in the distribution becomes obscure as the 2 diseases progress. The temporal profiles of functional impairment in the 2 diseases are reportedly very similar. When MDMD is suspected, it is important to carefully observe the relevant leg, more specially the flexor muscle group.

Proteolysis of beta-dystroglycan in muscular diseases.

Alpha-dystroglycan is a cell surface peripheral membrane protein which binds to the extracellular matrix (ECM), while beta-dystroglycan is a type I integral membrane protein which anchors alpha-dystroglycan to the cell membrane via the N-terminal extracellular domain. The complex composed of alpha-and beta-dystroglycan is called the dystroglycan complex. We reported previously a matrix metalloproteinase (MMP) activity that disrupts the dystroglycan complex by cleaving the extracellular domain of beta-dystroglycan. This MMP creates a characteristic 30 kDa fragment of beta-dystroglycan that is detected by the monoclonal antibody 43DAG/8D5 directed against the C-terminus of beta-dystroglycan. We also reported that the 30 kDa fragment of beta-dystroglycan was increased in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animals of sarcoglycanopathy, and that this resulted in the disruption of the link between the ECM and cell membrane via the dystroglycan complex. In this study, we investigated the proteolysis of beta-dystroglycan in the biopsied skeletal muscles of various human muscular diseases, including sarcoglycanopathy, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy, Miyoshi myopathy, LGMD2A, facioscapulohumeral muscular dystrophy, myotonic dystrophy and dermatomyositis/polymyositis. We show that the 30 kDa fragment of beta-dystroglycan is increased significantly in sarcoglycanopathy and DMD, but not in the other diseases. 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.

Overexpressions of myoglobin and antioxidant enzymes in ragged-red fibers of skeletal muscle from patients with mitochondrial encephalomyopathy.

To determine the relationship between myoglobin (Mb) and the defense system against reactive oxygen species in various myopathies, we performed immunohistochemical analyses of Mb and various antioxidant enzymes, including manganese superoxide dismutase (Mn-SOD), copper zinc SOD (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Biopsied muscle specimens were obtained from patients with chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), Duchenne muscular dystrophy (DMD), and polymyositis (PM). In patients with CPEO/KSS, stainings of Mb, SOD, CAT, and GSH-Px in nonatrophic ragged-red fibers (RRFs) were more intense than those in non-RRFs. These pronounced stainings corresponded to ragged-red lesions. The staining intensities of these antioxidant enzymes were significantly correlated with that of Mb (P < 0.001). Atrophic RRFs in specimens from patients with CPEO/KSS showed intense stainings of these antioxidant enzymes but not intense staining of Mb. In specimens from patients with DMD/PM, the antioxidant enzymes but not Mb were overexpressed in degenerative fibers. These results suggest that oxidative stress is associated with Mb expression specifically in mitochondrial diseases. The antioxidant enzymes seem to be upregulated to protect against muscle damage in nonatrophic RRFs. However, the Mb-mediated oxidative damage may become more extensive and result in further mitochondrial dysfunction and progressive atrophy of RRF with impaired upregulation of Mb.