Multi-minicore Disease

Location: Naarden, The Netherlands

Fifteen clinicians and basic scientists convened from 8th - 9th November in Naarden, The Netherlands for the 2nd ENMC sponsored Workshop on Multi-minicore Disease (MmD). The 1st ENMC sponsored workshop on MmD in May 2000 had lead to collaborations between the participating groups, resulting over the ensuing two years in a rapid advance in the understanding of this particular, autosomal recessively-inherited congenital myopathy. The main objective of this workshop was to discuss the recent identification of two genes (RYR1 and SEPN1) involved in at least two of the 4 MmD phenotypes that had been defined during the previous MmD consortium meeting. These findings have demonstrated that genetic diversity corresponds to the observed clinical heterogeneity. In the light of these data, the clinical and morphological experience of the different groups was shared and discussed in order to further define the diagnostic criteria for MmD and its phenotypical spectrum, and to establish phenotype-genotype correlations. A further focus of the meeting was to analyse those groups of patients with untypical features and as yet unresolved genetic basis.

The skeletal muscle ryanodine receptor gene (RYR1) is a giant gene encoding a sarcoplasmic reticulum calcium channel (RyR1). Mutations of this gene had been previously implicated in two autosomal dominant disorders: the congenital myopathy central core disease (CCD), and the malignant hyperthermia susceptibility (MHS) trait. Recessively-inherited changes in the RYR1 gene have now also been implicated in two clinically distinct groups of patients with MmD, the phenotype previously defined as "moderate MmD with hand involvement" and a phenotype resembling CCD. Preliminary genetic results presented at the workshop suggest that also the group of patients with involvement of the muscles controlling eye movements may have changes in this gene.
These results indicate that the range of clinical and histopathological appearances associated with changes in the RYR1 gene is wider than initially anticipated. This may be partly explained by the fact that RYR1 changes associated with specific phenotypes of MmD affect functionally different parts of the RyR1 protein compared to those mutations associated with CCD. In addition, an evolution of the morphological lesions with age, from "minicores" to "cores", has been demonstrated in some of these cases. In contrast to histopathological variability, muscle MR imaging data in patients with confirmed RYR1 mutations presented at the workshop indicate a consistent and distinct pattern of selective muscle involvement and suggest muscle MR imaging as a useful ancillary tool. Functional data presented at the workshop suggested the study of RyR1 function in white blood cells from patients as a suitable approach to investigate the pathophysiological consequences of specific RYR1 changes.

Mutations of the selenoprotein N gene (SEPN1) have been recently shown to be responsible for approximately two thirds of the cases presenting with the "classical" MmD phenotype. This gene was previously known to be associated with another autosomal recessive myopathy, termed Rigid Spine Muscular Dystrophy (RSMD). The clinical, morphological and genetic data obtained from both groups of patients carrying SEPN1 mutations were presented and compared, and the reasoning behind the conclusion that all of them share a common disease, now termed "SEPN-related myopathy", was discussed. An overview on the structure and functions of the selenoprotein family, as well as selenoprotein N expression studies on zebra fish, were presented. We also shared novel, unpublished data on selenoprotein N subcellular localisation and structure, and preliminary data on microarray-based SEPN1 expression studies. The phenotype spectrum of SEPN-related myopathy (including its consistent, recognizable pattern on muscle CT-scan or MRI) was discussed, with a special attempt to establish differential diagnosis criteria with those cases of MmD or RSMD not linked to SEPN1 mutations.

In a concluding session, current concepts on MmD were re-evaluated and future collaborative strategies discussed.

The meeting provided an invaluable opportunity for all participants with a major interest in early-onset myopathies to come together and to share a stimulating forum for multidisciplinary discussion of this quickly evolving field.

A full report of the meeting will be submitted for publication in Neuromuscular Disorders.

Dr. A. Ferreiro (Paris, France)
Dr. H. Jungbluth (London, U.K.)