Central core disease. A correlated genetic, histochemical, ultramicroscopic, and biochemical study.

Abstract

SYNOPSIS Two patients suffering from central core disease are presented. The condition is associated with musculoskeletal abnormalities which have been traced back over five generations. In addition to the typical histochemical findings, electronmicroscopic study has revealed the presence of both structured and non-structured cores in adjacent areas. The calcium uptake by the sarcoplasmic reticulum was reduced to one-third of normal. Phosphorylase activity was normal in the one case and reduced to 63% in the other. Actomyosin Mg2 +-activated ATPase activity was decreased, as was the Ca2+-dependent ATPase of the sarcoplasmic reticulum.

Characterization and temporal development of cores in a mouse model of malignant hyperthermia

“…Reports of cores in human CCD muscle include many characteristics of the contracture and unstructured cores described here in skeletal muscle from RyR1 Y522S/WT mice. Specifically, contracture cores that lack mitochondria; exhibit disintegration of the contractile machinery; and exhibit altered structure and content of SR, T-tubules, and mitochondria have previously been documented in EM analyses of muscle biopsies from human CCD patients (8,10,28). Importantly, lack of histological staining of oxidative enzymes in human CCD muscle may well correspond to the mitochondrial-free contracture and unstructured cores observed in muscle from RyR1 Y522S/WT mice (Fig.…”

“…EM of cores in biopsies from CCD patients reveals a wide variety of structural alterations affecting the contractile elements, SR, and transverse tubules (T-tubules) (7)(8)(9)(10)(11). Cores vary in the degree of damage/disruption to the myofibrils, including heavily contracted regions (contracture cores), disorganized and damaged regions (structured cores), and regions lacking contractile filaments (unstructured cores) (11,12).…”

Effect of Ryanodine Receptor Mutations on Interleukin-6 Release and Intracellular Calcium Homeostasis in Human Myotubes from Malignant Hyperthermia-susceptible Individuals and Patients Affected by Central Core Disease

“…Later in life, the predominant symptom is a generalized muscle weakness affecting the proximal muscle groups more than the distal ones. The clinical severity is highly variable, but disease course is usually slow or nonprogressive (1)(2)(3)(4). On the basis of clinical findings alone the diagnosis is difficult, and a histological examination of muscle tissue is essential.…”

Ca2+ signalling and muscle disease

“…In this case, crises are brought on by physical and emotional stresses, including overheating, exercise, mating, transportation to market and fear [24]. CCD is a rare, congenital myopathy, inherited as an autosomal dominant trait [25,26] and characterized by hypotonia and proximal muscle weakness, which presents in infancy and leads to the delay of motor milestones [27,28]. Both clinical and histological variability is observed, but the clinical course is usually slow or nonprogressive in adults.…”

“…Diagnosis is made on the basis of histological examination, which reveals the lack of oxidative or phosphorylase activity in central regions (cores) of both type I and type II skeletal muscle fibers [29]. Electron microscopic analysis shows disintegration of the contractile apparatus, ranging from blurring and streaming of the Z lines to total loss of myofibrillar structure [25,26,30]. The sarcoplasmic reticulum and transverse tubular systems are greatly increased in content and are, in general, less well structured.…”