DIAGNOSIS Becker muscular dystrophy (BMD).
Immunoblotting revealed a reduction in the intensity of the dystrophin and dystrophin associated glycoprotein bands (Figure 10) and genetic analysis of the dystrophin gene demonstrated a deletion of exons 45-47 confirming the diagnosis. The same deletion was present in the patient's asymptomatic mother.
Becker muscular dystrophy (BMD) is an X-linked recessive disorder caused by a mutation in the dystrophin gene. The clinical spectrum of BMD has broadened over recent years and is now much more heterogeneous than recognised when originally described (8). Classically the muscle biopsy is dystrophic, demonstrating variability in fibre size, increased endomysial tissue, split fibres and evidence of regeneration and necrosis. Rimmed vacuoles are not typically associated with BMD and there have been few reports of rimmed vacuoles in BMD (1,5). However, a recent case series found rimmed vacuoles to be present in 12 (18.5%) cases of BMD studied and therefore rimmed vacuoles may previously have been under recognised in BMD (4). In this study lysosomal and autophagic markers were found to be associated with rimmed vacuoles, together with ubiquitin, amyloid precursor protein and β amyloid 1-42.
Previously, rimmed vacuoles were thought to be specific for a diagnosis of inclusion body myositis (IBM) (3) but subsequently have been reported in a number of other inflammatory and dystrophic myopathies. The differential diagnosis when rimmed vacuoles and myofibrillar protein aggregates are observed includes myofibrillar myopathy (MFM), IBM and hereditary inclusion body myopathy with Paget's disease and frontotemporal dementia (IBMPFD). In a patient of this age and clinical presentation the most likely is MFM, a genetically heterogeneous group of disorders characterised by a common histopathological phenotype. However, the clinical phenotype is more variable with progressive limb-girdle, scapuloperoneal or distal weakness commencing in childhood, adolescence and adulthood. Cardiomyopathy and peripheral neuropathy may accompany the weakness. We found no mutations in genes associated with MFM and IBMPFD, namely four and half LIM protein 1, α β-crystallin, myotilin, desmin and valosin containing protein.
Rimmed vacuoles are irregular vacuoles with a granular basophilic rim or containing granular basophilic material visualised in muscle biopsies when stained with H&E or stained red in the Gomori trichrome preparation. The exact nature and cause of rimmed vacuoles is unknown. Immunohistochemical staining has demonstrated both myonuclear (2) and lysosomal (6) markers present in and around rimmed vacuoles in other muscle diseases. This has led to suggestions that they are derived from either degenerating muscle nuclei, lysosomes or both. However, these findings have not been consistently replicated (6,7). The presence of rimmed vacuoles in a variety of different muscle diseases, particularly those associated with protein accumulation, indicates that they are a non-specific consequence of several different types of pathology and may relate to failure of protein degradation within muscle fibres. Disease duration may also play a role. It was recently observed that BMD patients with rimmed vacuoles were older at the time of muscle biopsy than those without (4), suggesting that longer disease duration may contribute to their formation.
Our case is the first description of rimmed vacuoles and protein deposits immunoreactive for myofibrillar proteins in a dystrophinopathy. Negative genetic tests for MFM and previous reports of rimmed vacuoles in BMD make it unlikely to be a case of 'double-trouble'. This adds further weight to the evidence that rimmed vacuoles lack specificity even in the presence of myofibrillar protein deposits and urges caution in attributing these histopathological features to a specific diagnosis. As the clinical spectrum of BMD increases with better recognition of the condition we suggest that the diagnosis should be considered despite the presence of 'atypical' findings on muscle biopsy.
This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. JLH is supported by the Myositis Support Group and the Reta Lila Weston Institute for Neurological Studies. SB is supported by the Myositis Support Group.
The authors report no disclosures
Contributed by Stefen Brady, MRCP, Rita Barresi, PhD, Richard Charlton, PhD, Christopher Turner, PhD MRCP, Janice L. Holton, PhD FRCPath