Multi-minicore Disease

Heinz Jungbluth

doi:10.1186/1750-1172-2-31

Abstract

Multi-minicore Disease (MmD) is a recessively inherited neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown. Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD due to dominant RYR1 mutations, reflecting the common genetic background. Pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but likely to involve altered excitability and/or changes in calcium homeoestasis; calcium-binding motifs within the selenoprotein N protein also suggest a possible role in calcium handling. The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy; muscle MRI may aid genetic testing as patterns of selective muscle involvement are distinct depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of malignant hyperthermia susceptibility in RYR1-related forms. In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.

Highlights

Multi-minicore Disease; Minicore myopathy; Multicore myopathy; Multiminicore myopathy; Minicore myopathy with external ophthalmoplegia; Multicore myopathy with external ophthalmoplegia; Multiminicore disease with external ophthalmoplegia
Multi-minicore Disease (MmD) is an inherited neuromuscular disorder defined by a) multiple areas with reduced oxidative activity running along an only limited extent of the longitudinal axis of the muscle fibre ("minicores") and b) clinical features of a congenital myopathy
The condition was originally reported in a family with two affected siblings and suggestive histopathological findings [1]; various different designations

Summary

Diagnostic methods

Multi-minicore Disease (MmD) is a histologic diagnosis established on muscle biopsy. MmD is characterized by multifocal, well-circumscribed areas with reduction of oxidative staining and low myofibrillar ATPase [1]. Patients with MmD secondary to mutations in the RYR1 gene may be at risk of malignant hyperthermia reactions, an abnormal response to muscle relaxants such as succinylcholine and volatile anaesthetics [27,81], as has been reported in few cases [28,29]; minicores on muscle biopsy have been noticed in few patients with RYR1-related MH susceptibility but no other clinical features of a congenital myopathy [30,31]. SEPN1-related MmD and the majority of cases associated with mutations in the RYR1 gene are inherited as an autosomal recessive trait; only few families with multi-minicores on muscle biopsy and dominant inheritance have been documented. A proportion of patients with typical features of MmD do not harbour mutations in the RYR1 or SEPN1 genes and this group is still awaiting genetic resolution

Wallgren-Pettersson C

46. Meissner G

58. Sewry CA

Findings

70. Thomas C