Workshop reportWorkshop report of the 89th ENMC International Workshop: Central Core Disease, 19th–20th January 2001, Hilversum, The Netherlands
Introduction
The first ENMC Workshop on central core disease (CCD) was held in Hilversum (The Netherlands) on 19th and 20th January 2001. Seventeen participants from Belgium, France, Germany and the UK attended this meeting. The participants covered the various specialties working on CCD: neurologists, paediatric neurologists, neuropathologists, geneticists, a physiopathologist and an anaesthesiologist.
After the welcoming address of Andoni Urtizberea, research directer of the ENMC, Harald De Cauwer (Antwerp, Belgium) gave an introductory presentation in which several questions to be discussed at this workshop were raised.
First a family referred to the Belgian MH centre in Antwerp after a fatal malignant hyperthermia accident during general anaesthesia was presented. Postmortem study of different muscles of the young male proband pointed retrospectively to the presence of CCD. The follow-up results obtained in several family members, all clinically asymptomatic but malignant hyperthermia susceptible, illustrated the variability in histogical expression. Several subjects expressed ‘classical lesions’ e.g. centrally located cores in up to 90% of type 1 fibres and fibre type 1 predominance. Other family members showed multiple core lesions in one and the same fibre and still others showed only very rare cores. In one of the latter the first routine histological and histochemical stainings did not reveal any core lesions. Because of the positive family history and a positive in vitro contracture test (IVCT), however, a second set of muscle sections were studied, finally showing some typical cores. Furthermore, in the propositus cores were found in some, but not in all muscles examined. In the family members shown not to be MH-susceptible no cores could be demonstrated whatsoever.
This family was earlier reported in Clinical Neuropathology [1].
The histology on cross sections alone could not readily differentiate between CCD and multi-minicore disease (MmD), only in the longitudinal sections (as later on presented by Martin) a ‘definite’ histological diagnosis of CCD was made.
This family therefore raises several questions to be discussed: can we diagnose CCD in this family given that no myopathic signs were found in any of the family members studied, but with a typical histological CCD pattern in these same individuals? What explains the histological differences observed within this one family? Does CCD affect selective muscle groups or is it a generalized phenomenon? Do we differentiate between CCD and MmD on histological grounds only or do we have to include clinical and/or genetic data? How to explain the complete lack of clinical symptoms even in patients with a high proportion of affected fibres? Do we need to implement IVCT in all patients with a family history of CCD?
Other, mostly sporadic cases, challenge the definite(?) association between CCD and malignant hyperthermia susceptibility (MHS), put forward as an additional feature in the 1995 criteria.
Islander's, Romero's, Manzur's cases as well as two sporadic cases evaluated in Antwerp were briefly discussed [2], [3], [4].
Section snippets
Clinical phenotypes
Heinz Jungbluth (London, UK) opened this session with a review of ten cases evaluated at the Hammersmith Hospital. Hypotonia at birth (n=7) and signs of proximal weakness (n=3) were the major presenting features. Disease course was static in the majority. Some patients showed considerable functional improvement during infancy and childhood.
Typical clinical features included mild facial weakness with inability to completely bury the eyelashes. Eye movements were normal. Some patients had
Histology
The 1995 diagnostic criteria state that histological diagnosis can be made on the following grounds:
- (a)
Central, well demarcated cores visible with oxidative enzyme reactions and confined to type 1 fibres. The cores are long and may be eccentric or multiple.
- (b)
Distinctive electronmicroscopy.
- (c)
Type 1 fibre predominance.
- (d)
Minor myopathic features may occur but necrosis or regeneration is rare.
Jean-Jacques Martin (Antwerp, Belgium) reviewed the light microscopic findings in CCD and the differential diagnosis
Inheritance pattern and genetics
Joel Lunardi (Grenoble, France) reviewed current knowledge on the inheritance pattern of CCD. CCD is generally considered as inherited as an autosomal dominant trait. Based on linkage analysis, the CCD locus was mapped on chromosome 19q12-q13.1 [9]. CCD is usually closely associated with malignant hyperthermia susceptibility. Moreover, several mutations in the RYR1-gene were identified in CCD patients [10]. Therefore, CCD and MHS were considered to be allelic diseases. Recently, a mutation in
Other topics
Heinz Jungbluth (London, UK) presented his data on a cohort of 11 patients with CCD studied as part of a larger muscle MRI study of 34 patients with various structural congenital myopathies.
Patients with CCD had a distinct and consistent pattern of selective muscle involvement in the thighs and in the legs. In the thighs, there was marked involvement of the vasti, sartorius and adductor magnus muscles, but rectus femoris, adductor longus, gracilis and hamstring muscles were relatively spared.
The revised diagnostic criteria
The most important task of this workshop was to revise the 1995 diagnostic criteria, based on current knowledge on CCD and based on the different cases known from literature and presented at this workshop by the different centres.
The different topics were discussed extensively and changes were to be approved by all participants. This resulted in new revised diagnostic criteria (see Appendix A) that can serve as a tool for multi-centre studies.
A brief discussion on the adjustments is provided in
Future research
A European Consortium on Central Core Disease was constituted. The various reference centres will take joint action for future projects. Some of them were already discussed in the workshop.
The need for the installation of a database on CCD serving as a tool for collaborative research is recognized. The ENMC-homepage is one of the possible hosts for such a European on-line registry.
The three available databases were already mentioned above. They will be modulated (e.g. translated into English)
Acknowledgements
This workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Group of Great Britain and Northern Ireland (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Verein zur
References (13)
- et al.
Malignant hyperthermia susceptibility without central core disease (CCD) in a family where CCD is diagnosed
Neuromuscul Disord
(1995) - et al.
Malignant hyperthermia and central core disease: analysis of two families with heterogeneous clinical expression
Neuromuscul Disord
(1993) - et al.
A severe clinical and pathological variant of central core disease with possible autosomal recessive inheritance
Neuromuscul Disord
(1998) - et al.
Segregation of malignant hyperthermia, central core disease and chromosome 19 markers
Br J Anaesth
(1999) - et al.
Gly341Arg mutation indicating malignant hyperthermia susceptibility: specific cause of chronically elevated serum creatine kinase activity
J Neurol Sci
(1998) - et al.
Discordant light microscopic, electron microscopic, and in vitro contracture test study findings in a family with central core disease
Clin Neuropathol
(1997)
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