Abstract
Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.
Highlights
Central core disease (CCD) (MIM * 117000) [1] is an inherited neuromuscular disorder defined by a) areas with reduced oxidative activity running along the longitudinal axis of the muscle fibre ("central cores") and b) clinical features of a congenital myopathy
CCD was originally reported in a family with congenital hypotonia, non-progressive weakness and central areas of amorphous appearance within muscle fibres stained with the modified Gomori trichrome technique [2]
CCD is probably the most common congenital myopathy; the condition is likely to be under recognised considering that some individuals with suggestive clinical features and an identical genetic background do not necessarily exhibit the characteristic histopathological features, when biopsied at an early age
Summary
The diagnosis of CCD depends on the presence of typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle MR imaging may complement clinical assessment. The diagnosis of CCD is usually straightforward in cases where clinical features are suggestive and typical central cores are present on muscle biopsy; the typical histopathological picture may only evolve over time and may not always be present when muscle biopsy has been performed at an early age. In addition to supportive management and prevention of malignant hyperthermia reactions during general anaesthesia, the β-agonist salbutamol has been recently investigated as a pharmacological agent in the treatment of CCD with encouraging results [107] Results of this pilot study will have to be validated in a larger randomized controlled trial as a basis for future recommendation. Unresolved questions concern the pathogenesis of central cores, the impact of specific mutations on RyR1 assembly, the precise role of RyR1 in non-muscle cells such as B-lymphocytes and the effect of mutations on those tissues, and other calcium dependent signalling pathways other than E-C coupling
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