Mitochondrial disorders in congenital myopathies

The literature review gives data on the role of mitochondrial disorders in the pathogenesis of congenital myopathies: congenital muscular dystrophies and congenital structural myopathies. It describes changes in congenital muscular dystrophies with type VI collagen, in myodystrophy with giant mitochondria, in congenital central core myopathies, myotubular myopathy, etc. Clinical and experimental findings are presented. Approaches to therapy for energy disorders in congenital myopathies are depicted

Adaptational role of mitochondrial changes in congenital central core myopathy: new proofs

The objective of the investigation was to study the ultrastructural morphology of muscle tissue mitochondria versus other clinical and laboratory indicators in 21 patients with congenital central core myopathy. The findings demonstrate that the sizes of mitochondria are correlated with the levels of lactate and pyruvate; however, the magnitude and direction of this correlation differ in the subsarco-lemmal and intermyofibrillar mitochondrial fractions. It is concluded that the baseline level of lactic acid in the blood of the patients depends on the number of mitochondria whereas the maturity of organelles largely provides a tissue response to elevated lactic acid levels. Our data are evidence in favor of an assumption that rounded mitochondria are less mature and effective in performing then-main functions. The increase in the number of ellipsoidal organelles in the subsarcolemmal region of muscle fibers is ascertained to be an important compensatory mechanism in nonmitochondrial muscle diseases. Thus, the investigation has established the role of changes in the number and sizes of mitochondria in tissue adaptation to the conditions of functional insufficiency. The found

Glycogen storage disease type II (Pompe disease) in children

The paper gives the data available in the literature, which reflect the manifestations, diagnosis, and current treatments of the rare (orphan) inherited disease glycogen storage disease type II or Pomp disease in children, as well as its classification. The infant form is shown to be most severe, resulting in death from cardiovascular or pulmonary failure generally within the first year of a child’s life. Emphasis is laid on major difficulties in the differential and true diagnosis of this severe disease. Much attention is given to the new pathogenetic treatment — genetically engineered enzyme replacement drug Myozyme®. The authors describe their clinical case of a child with the juvenile form of glycogen storage disease type II (late-onset Pompe disease). Particular emphasis is laid on the clinical symptoms of the disease and its diagnostic methods, among which the morphological analysis of a muscle biopsy specimen by light and electron microscopies, and enzyme and DNA diagnoses are of most importance. The proband was found to have significant lysosomal glycogen accumulation in the muscle biopsy specimen, reduced lymphocyte acid α-1,4-glucosidase activity to 4,2 nM/mg/h (normal value, 13,0—53,6 nM/mg/h), described in the HGMD missense mutation database from 1000 G>A p.Gly334er of the GAA in homozygous state, which verified the diagnosis of Pompe disease

Limb-girdle muscular dystrophy type 2A (calpainopathy)

The clinical presentation of progressive limb-girdle muscular dystrophy type 2A (LGMD2A) is due to loss of functionally active cal-pain-3, a skeletal muscle specific isoform of one of the calpain family proteins involved in the regulation of different tissue processes. The function of calpain-3 and the pathophysiological mechanism of LGMD2A are still not fully understood. The article discusses the features of the pathogenesis, clinical presentation, and diagnosis of LGMD2A and the possible administration of calpain-3 trans-genes as a specific therapy for this disease. Two clinical cases of patients with this condition are given

Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

The induction of heme oxygenase-1 (HO-1) may protect against tissue injury. The present study examines the induction of HO-1 in a murine model of venous thrombosis and explores the downstream consequences of this induction. In a model of stasis-induced thrombosis created by ligation of the inferior vena cava, HO-1 expression is markedly induced. Such expression occurs primarily in smooth muscle cells in the venous wall and in leukocytes infiltrating the venous wall and clot. To determine the significance of HO-1 induction in venous thrombosis, this model was imposed in HO-1+/+ and HO-1−/− mice. The initial clot size did not differ in either group by day 2, but was significantly larger in HO-1−/− mice by day 10, where an exaggerated inflammatory response in the venous wall was also observed. Following ligation of the inferior vena cava, HO-1−/− mice exhibited increased nuclear factor κB activation and markedly increased up-regulation of tissue factor, selectins, inflammatory cytokines, and matrix metalloproteinase-9, the latter incriminated in both clot lysis and vascular injury. We conclude that HO-1 deficiency impairs thrombus resolution and exaggerates the inflammatory response to thrombus formation. These findings offer insight into recent observations that polymorphisms in the HO-1 gene may increase the risk for recurrent venous thrombosis and dysfunction of hemodialysis arteriovenous fistulas, the latter caused, in part, by thrombosis