MmD - the most common synonym introduced following the European Neuromuscular Centre dedicated workshops (1,2) - will be used throughout this paper.
The number of synonyms cited above reflect the wide variability in histological findings, clinical penetrance, as well as the genetic heterogeneity of this disorder. MmD is one of the congenital myopathies (overall group prevalence of 3.5 – 5.0/100,000 in the paediatric population), recessively inherited, and morphologically defined by the presence of multiple small well-circumscribed areas devoid of oxidative activity and oxidative staining on muscle biopsy. In contrast to central cores in ‘Central Core Disease’ (CCD), minicores are multiple, excentric and only extend for a short distance along the long axis of the muscle fibre.
Several clinical forms have been identified: The “classic form”, “minicore myopathy with external opthalmoplegia”, “minicore myopathy with moderate hand involvement” and “minicore myopathy antenatal onset with arthrogryposis” . The “classic form of MmD” – formerly also called “rigid spine syndrome” or “rigid spine muscular dystrophy” - presents in infancy with hypotonia, delay in achieving motor milestones (though most children are able to walk independently by 2.5 years), feeding difficulties, and a myopathic facies. Ophtalmoparesis in this group is rare. The muscle weakness, which mainly affects trunk and neck flexors, is associated with spinal rigidity, and secondarily results in progressive scoliosis, lateral trunk deviation and severe restrictive respiratory impairment by the second decade. This may require non-invasive ventilation, even in still ambulant patients. Secondary right ventricular function impairment often evolves. In quite a number of these severe cases, the course becomes stable in late childhood and many continue to walk into adulthood despite the above-mentioned problems and the requirement for assisted ventilation.
Muscle MR imaging shows a selective involvement of thigh muscles, with adductors, sartorius and biceps femoris more markedly involved and rectus femoris and gracilis relatively spared . This phenotype is related to several mutations in the selenoprotein-N1 gene (SEPN1-gene, chrom 1p36.13), a protein involved in protecting cells from damage caused by oxidative free radicals and probably crucial in myogenesis before birth.
Other, less severe, clinical forms result from recessive mutations in the RYR1 gene (chrom 19q13.1) encoding for the calcium-release channel of the sarcoplasmic reticulum (5.038 amino-acids - 106 exons) and implicated in malignant hyperthermia susceptibility. These appear to be part of a clinical spectrum rather than true distinct entities. The clinical features comprise external ophtalmoparesis, associated or not with proximal and axial weakness, and mild-to-moderate respiratory and bulbar involvement; some present with hip girdle weakness as predominant and more or less isolated feature. Respiratory involvement is mild or absent, and impairment of cardiac function does only rarely occur in RYR1-related MmD. Primary cardiomyopathies are not a recognized feature of either SEPN1- or RYR1-associated MmD but have been reported with other genetic backgrounds .
The pattern of selective involvement of muscles on MRI is distinct from MmD due to SEPN1- mutations and comparable to the selective pattern of involvement found in CCD . It is now clear that muscle MRI is a powerful predictor of RYR1 involvement.
The variable clinical spectrum is reflected in the number of recessive homozygous and compound heterozygous mutations in the RYR1 gene. In MmD the mutations (missense, nonsense and splice mutations as well as deletions and duplications) appear to be distributed throughout the huge RYR1 gene, whereas in CCD and MH the dominantly inherited mutations – most often mis-sense - have been found to cluster in 3 “hot spots” (MHS/CCD region 1, 2 and 3).
Some MmD patients are, clinically as well as histologically, difficult to distinguish from dominantly inherited CCD. They present with moderate, non- or slowly progressive weakness in the hip girdle and axial musculature, and multiple larger lesions or ‘multicores’ on histology as a sort of continuum with the histopathologic findings of CCD. Therefore distinction between MmD and CCD can only be made based on a comprehensive clinical, radiological (MRI), histopathological and genetic assessment.