Preliminary Communication

OXIDATIVE ENZYMES AND PHOSPHORYLASE IN CENTRAL-CORE DISEASE OF MUSCLE

Congenital myopathies are defined by early clinical onset, slow progression, hereditary nature and disease-specific myopathological lesions – however, with exceptions - demanding special techniques in regard to morphological diagnostic and research work-up. To identify an index disease in a family requires a muscle biopsy – and no congenital myopathy has ever been first described at autopsy. The nosographic history commenced when – in addition to special histopathological techniques in the earliest classical triad of central core disease, 1956, nemaline myopathy, 1963, and centronuclear myopathy, 1966/67, within a decade - electron microscopy and enzyme histochemistry were applied to unfixed frozen muscle tissue and, thus, revolutionized diagnostic and research myopathology. During the following years, the list of structure-defined congenital myopathies grew to some 40 conditions. Then, the introduction of immunohistochemistry allowed myopathological documentation of proteins and their abnormalities in individual congenital myopathies. Together with the diagnostic evolution of molecular genetics, many more congenital myopathies were described, without new disease-specific lesions or only already known ones. These were nosographically defined by individual mutations in hitherto congenital myopathies-unrelated genes. This latter development may also affect the nomenclature of congenital myopathies in that the mutant gene needs to be attached to the individually identified congenital myopathies with or without the disease-specific lesion, such as CCD-RYR1 or CM-RYR1. This principle is similar to that of the nomenclature of Congenital Disorders of Glycosylation. Retroactive molecular characterization of originally and first described congenital myopathies has only rarely been achieved.

Core myopathies are clinically, pathologically, and genetically heterogeneous muscle diseases. Their onset and clinical severity are variable. Core myopathies are diagnosed by muscle biopsy showing focally reduced oxidative enzyme activity and can be pathologically divided into central core disease, multiminicore disease, dusty core disease, and core-rod myopathy. Although RYR1-related myopathy is the most common core myopathy, an increasing number of other causative genes have been reported, including SELENON, MYH2, MYH7, TTN, CCDC78, UNC45B, ACTN2, MEGF10, CFL2, KBTBD13, and TRIP4. Furthermore, the genes originally reported to cause nemaline myopathy, namely ACTA1, NEB, and TNNT1, have been recently associated with core-rod myopathy. Genetic analysis allows us to diagnose each core myopathy more accurately. In this review, we aim to provide up-to-date information about core myopathies.

Calcium (Ca²⁺) is one of the most diverse intracellular messengers and essential for various cellular physiological functions, including memory formation and muscle contractions. Ca²⁺ channels allow passage of Ca²⁺ ions and thus essential cellular components in enabling the strictly regulated intracellular Ca²⁺ signaling that are present in our cells. Altered Ca²⁺ channel activity is contributing to many human diseases, for example, myopathies, malignant hyperthermia, and neurological disorders such as Alzheimer’s disease, as well as different types of cancer. Here, we review established and recent studies addressing Ca²⁺ channels and their implication in human disease. We primarily focus on intracellular Ca²⁺ channels (including Ryanodine receptors, inositol trisphosphate receptors and STIM and ORAI) and diseases that affects our cognitive function and/or ability to move.