Brain, Vol. 126, No. 11, 2339-2340,
November 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg288
Editorial |
Central core disease: new findings in an old disease
Dubowitz Neuromuscular Centre, Imperial College, London and 1 Department of Histopathology, Robert Jones and Agnes Hunt Orthopaedic and District Hospital, Oswestry, UK
Central core disease (CCD) is a clearly defined clinical condition with striking pathological changes that facilitate the diagnosis. The condition was first reported in 1956 by Shy and Magee (1956
) who described a dominant family in which muscle fibres had a central area devoid of oxidative enzyme activity. They named the disorder central core disease, after this histopathological feature. Since then many similar cases have been identified, confirming that this is a distinct disorder.
Relatively little happened between 1956 and 1990, when linkage to chromosome 19q.13 was established, followed in 1993 by the identification of mutations in the ryanodine receptor gene (RYR1). Mutations in the same gene also occur in patients with malignant hyperthermia susceptibility (MHS) (McCarthy et al., 2000), some of whom show core lesions, although they may have no muscle weakness.
The large size of the RYR1 gene (106 exons) has made it difficult to study large populations of patients and establish a genotype–phenotype correlation. However, significant pathological and molecular advances have recently been made. We now know that cases with eccentric or peripheral cores, and/or multiple minicores, or cases showing only uniformity of type 1 fibres with an absence of cores, or cases with only mild unevenness of oxidative enzyme staining, or cases with marked muscle replacement by fatty tissue in association with cores, are within the spectrum of changes caused by mutations in the RYR1 gene (Fig. 1) (Sewry et al., 2003). An increase in internal nuclei, which are often central, is another pathological clue. Immunohistochemistry can be helpful in reflecting myofibrillar disruption but no changes specific for RYR1 mutations have yet been found. So, as with the clinical features, the spectrum of pathological changes is wide. The presence of excessive fatty tissue or absence of classical cores does not exclude a mutation in RYR1.
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The increasing application of genetic tools has helped to expand the spectrum of RYR1-related myopathies. CCD has been considered as a dominant disorder for many years but our group, and Romero et al. (2003
) in this issue of Brain, have described cases with recessive inheritance. Our cases had a typical clinical phenotype but mixed pathological features with large cores and multiple-minicores (Jungbluth et al., 2002). Recessive mutations in the RYR1 gene have also been identified in patients who showed minicores in early muscle biopsies but centrally located cores later in life (Ferreiro et al., 2002), and in patients with multiminicore disease and ophthalmoplegia (Monnier et al., 2003). This expansion of the clinical and pathological spectrum, however, was only the tip of the iceberg: the manuscript in the current issue takes a dive under the surface of the water to explore how deep the ice is. Romero et al. have not only identified novel severe dominant and recessive RYR1 mutations, but also defined the severe end of the clinical spectrum of the RYR1-related myopathies by including foetal akinesia, severe facial weakness and ptosis, features that have not been associated with classical cases. All these observations suggest that the incidence of this condition is probably considerably higher than currently recognised. This has implications for genetic counselling, and raises specific and difficult issues in relation to the clinical management of patients at the severe end of the clinical spectrum. The patients described by Romero et al. range from foetal death following termination of pregnancy because of severe arthrogryposis, to infants who presented at birth with weakness, contractures and respiratory failure and either died in infancy or are alive at 5 and 9 years of age. Despite their severe problems, the outcome of the two patients who survived was better than predicted. In particular, one child required tracheotomy-assisted ventilation at birth but acquired diurnal respiratory autonomy from the age of 2 years. His motor abilities also improved and by the age of 6 years he had achieved unassisted ambulation. While we are aware that functional improvement is common in CCD, the degree of improvement experienced by this severely affected child is unusual and raises issues related to the level of support and intervention for children presenting with similar clinicopathological features.
Molecular advances have helped identify the C-terminal exons of RYR1 as a ‘hot spot’ for CCD mutations (Davis et al., 2003) and this greatly assists the identification of affected individuals. A number of de novo dominant cases have now been characterised, and probably account for the majority of sporadic cases. However, recessive mutations clearly exist and this needs to be considered when providing genetic counselling. As all cases of CCD do not have a mutation in the C-terminal hot spot there is a continuing problem in mutation detection, unless the whole gene is screened.
So, clinicians and pathologists alike have to be aware of the broad spectrum and high prevalence of disorders related to defects in RYR1. The large size of the gene and the fact that only a few laboratories around the world offer diagnostic mutational screening makes genetic analysis tedious, especially for cases with no mutation in the hot spot region. In addition, pathology may not always show classical features. The association of CCD and MHS is strong, but not invariable, so all cases of CCD should be considered at risk for MHS. There is a clear need for a simple test for MHS as current procedures are invasive, tedious and not standardised in children. Perhaps the recently published studies on the release of stored calcium in lymphoblastoid cells (Zorzato et al., 2003) may lead to the development of a simple assay for MHS, at least in some cases, and may help to correlate individual mutations with phenotype. So, there is much still to learn and we do not yet know how big the iceberg is that the titanic RYR1 has hit.
References
Davis MR, Haan E, Jungbluth H, Sewry C, North K, Muntoni F et al. Prinicipal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene. Neuromuscul Disord 2003; 13: 151–7.[CrossRef][Web of Science][Medline]
Ferreiro A, Monnier N, Romero NB, Leroy JP, Bonnemann C, Haenggeli CA, et al. A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene. Ann Neurol 2002; 51: 750–9.
Jungbluth H, Müller CR, Halliger-Keller B, Brockington M, Brown SC, Feng L, et al. Autosomal recessive inheritance of RYR1 muta tions in a congenital myopathy with cores. Neurology 2002; 59: 284–7.
McCarthy TV, Quane KA, Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease. Hum Mut 2000; 15: 410–7.[CrossRef][Web of Science][Medline]
Monnier N, Ferreiro A, Marty I, Labarre-Vila A, Mezin P, Lunardi J. A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with opthalmoplegia. Hum Mol Genet 2003; 12: 1171–8.
Romero NB, Monnier N, Viollet, L, Cortey A, Chevallay M, Leroy JP et al. Dominant and recessive central core disease associated with RYR1 mutations and foetal akinesia. Brain 2003; 126: 2341–49.
Sewry CA, Müller C, Davis M, Dwyer JSM, Dove J, Evans G et al.The spectrum of pathology in central core disease. Neuromuscul Disord 2003; 12: 930–8.
Shy GM and Magee KR. A new congenital non-progressive myopathy. Brain 1956; 79: 610–21.
Zorzato F, Yamaguchi N, Le X, Meissner G, Müller C, Pouliquin P et al. Clinical and functional effects of a deletion in a COOH-terminal lumenal loop of the skeletal muscle rynaodine receptor. Hum Mol Genet 2003; 12: 379–88.
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