Multi-minicore Disease

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.

Figure 1

Selective muscle involvement in RYR1-related central core disease (CCD) and multi-minicore disease (MmD). Muscle MRI of the thigh, T1-weighted images. A) A transverse section from the proximal thigh in a 12-year-old patient with central core disease (CCD) due to a dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. There is a distinct pattern of selective involvement characterized by marked increase in signal within the vasti, sartorius (S), and adductor magnus (AM), and relative sparing of the rectus femoris (RF), adductor longus (AL), gracilis (G), and hamstring muscles. B) A transverse section from the proximal thigh in a 17-year-old girl with Multi-minicore disease due to a homozygous recessive RYR1 mutation demonstrating a comparable pattern of selective involvement. * Reprinted from [24] Neurology 2002 Jul 23;59(2):284–7. Jungbluth et al.: Autosomal-recessive inheritance of RYR1 mutations in a congenital myopathy with cores.With permission from Lippincott Williams & Wilkins (LWW).

Figure 2

Schematic representation of the skeletal muscle ryanodine receptor (RYR1) gene and distribution of dominant and recessive (*) mutations associated with central core disease (CCD, in black) and Multi-minicore Disease (MmD, in red). Dominant mutations associated with a CCD phenotype predominantly affect the RYR1 C-terminal domain encoding the calcium release channel pore of the ryanodine receptor protein, whereas recessive mutations predominantly associated with a MmD phenotype are distributed evenly throughout the gene. N-terminal, central and C-terminal mutational hotspots within the RYR1 gene are highlighted in grey. (Figure courtesy of Dr Haiyan Zhou)

Figure 3

Histopathological features of Multi-minicore disease. NADH-TR (a–c) and cytochrome oxidase (COX) (d) stains, horizontal (a,c) and transverse (b,d) sections from a 3-year-old (a–b) and a 9-year-old girl (c–d) from different families. Predominance of darker staining type 1 fibres is prominent in both patients, whilst appearance of core lesions is widely variable, ranging from numerous small lesions of limited extent ("minicores") (a-b) to few multiple large lesions often extending throughout the entire fibre diameter ("multicores") (c, →) and occasionally affecting the same area in adjacent fibres (d, →). Whilst "minicores" are more frequently found in SEPN1-related MmD, the latter appearance is more typical of the RYR1-related form and indicates a possible histopathologic continuum with central core disease (CCD) due to mutations in the same gene.