Elsevier

Neuromuscular Disorders

Volume 12, Issue 10, December 2002, Pages 930-938
Neuromuscular Disorders

The spectrum of pathology in central core disease

https://doi.org/10.1016/S0960-8966(02)00135-9Get rights and content

Abstract

Central core disease is a congenital myopathy with muscle weakness defined pathologically by the presence of extensive areas in muscle fibres that are devoid of oxidative enzyme activity. The gene responsible has been shown to be the ryanodine receptor 1 on chromosome 19q13 and mutations have now been identified in several patients. Some cases with the morphological defect remain molecularly undefined, particularly those studied before molecular studies were available. We have studied three families with congenital onset, each with a dominantly inherited mutation in a C-terminal exon of the ryanodine receptor 1. They illustrate the spectrum of pathology that can be observed in patients with the myopathic features of central core disease. We show that extensive fibrosis and fat may be present, type 1 fibre uniformity may occur in the absence of cores; cores may be central or peripheral, single or multiple; and that an appearance of multiple focal minicores might cause a diagnostic pathological dilemma. In addition, we show the value of immunocytochemistry in identifying cores, in particular the use of antibodies to desmin and γ-filamin.

Introduction

Congenital myopathies, such as minicore disease, central core disease and nemaline myopathy are characterised by the abundance of a structural defect in muscle fibres, in association with a combination of clinical features [1], [2], [3]. In muscle biopsies from patients with minicore or central core disease areas devoid of oxidative enzyme activity are seen, resulting from an absence, or very low number, of mitochondria in these regions. The degree of myofibrillar disruption in these regions is variable [4], [5].

Central core disease was first reported by Shy and Magee [6], and since then many cases have been morphologically identified. The cores (i.e. the areas devoid of oxidative enzyme activity) have been reported to be clearly defined, some with a dark rim, and they may be peripheral, central or eccentric [4], [5]. In longitudinal section they characteristically run over an extensive length of the fibre. In contrast, minicores are multiple, focal areas devoid of mitochondria associated with focal disruption or misalignment of myofibrils. In some muscle biopsies unevenness of oxidative enzyme staining is observed, and the characteristic cores may be absent [7, see also 23].

Typical clinical features of central core disease are hypotonia, muscle weakness and skeletal abnormalities, but not cardiac defects [4]. These patients are at risk for malignant hyperthermia, as mutations in the ryanodine receptor (RYR1) on chromosome 19q13.1, or linkage to its locus, have been detected in some, but not all, cases with malignant hyperthermia [8], [9]. In cases with malignant hyperthermia skeletal muscle weakness may be minimal or absent, and muscle biopsies may, or may not, show central cores. Thus, there is a clinical distinction between cases of central core disease with congenital muscle weakness, and those that only have a susceptibility to malignant hyperthermia, with no weakness, who may or may not have the pathological feature of cores.

Mutations in the RYR1 on chromosome 19q13.1 have now been detected in many cases of central core disease. To date, only mutations in the RYR1 gene have been found in cases of clinically defined central core disease, unlike other congenital myopathies which are proving to be molecularly heterogeneous [3]. Reported cases of central core disease are sporadic or dominantly inherited; and recent data suggest that recessive inheritance may also occur [10].

Diagnosis of all congenital myopathies is based mainly on the clinical phenotype and the pathological assessment of the muscle biopsy. Linkage may be non-informative and gene analysis is laborious, especially of large genes such as RYR1, which has 106 exons. Identification of the primary gene defect may be difficult if the defining feature is absent, or in cases in which dual pathology exists. The latter is illustrated by cases in which abundant nemaline rods and cores both occur, and patients have a molecular defect in the RYR1 gene [11], [12]. Cores can also occur in skeletal muscle in patients with hypertrophic cardiomyopathy caused by defects in the gene for β-myosin [13]. Cardiomyopathy, however, is not a feature of central core disease.

We present the pathological features of muscle biopsies from three families with identified mutations in the RYR1 gene. They illustrate the spectrum of pathology in this disorder and the difficulties in diagnosis based on pathology alone. Previous pathological reports in CCD have rarely been on cases with known mutations. In addition, we show the value of immunohistochemistry in the identification of cores and myofibrillar disruption.

Section snippets

Clinical features

Detailed clinical features in these families will be reported separately (Quinlivan et al., in preparation). They are summarised here.

Materials and methods

Muscle biopsies were open biopsies. They were frozen in isopentane cooled in liquid nitrogen, and 10 μm cryostat sections stained with standard histological and histochemical techniques [14]. In addition, 6 μm sections were immunolabelled with antibodies to β-spectrin, dystrophin, sarcoglycans, fast (MHCf), slow (MHCs) and foetal (MHCn) myosin isoforms (all mouse monoclonals from Novocastra), α-actinin (rabbit polyclonal 4B2, kind gift of Dr A. Beggs), calcium activated sarcoplasmic reticulum

Molecular analysis

In family 1 a Tyr4864Cys mutation in exon 101 of RYR1 was found to segregate with the disease, i.e. clinically unaffected members did not have the mutation. Similarly, in family 2 the mutation Arg4893Trp in exon 102 segregated with the disorder. In family 3 a mutation Ala4940Thr in exon 103 was found in the child and mother.

Muscle pathology

Histology and histochemistry Biopsies from the two siblings in family 1 showed variation in fibre size, no increase in internal nuclei, no fibrosis and no distinct fibre

Discussion

These families illustrate the variable histopathology that can be observed in patients with central core disease. A RYR1 mutation in each family has been identified; thus it is possible to assign the observed features to central core disease. Although many of our observations are not novel and have been observed by others over the decades, previously published cases have not been molecularly defined, and many workers in the field are not aware of the wide spectrum of pathology in this disorder.

Acknowledgements

We are grateful for the technical assistance of Miss P. Evans, Mr N. Harness and Mr M. Richards and the financial support of the NHS R&D support budget.

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