A 29‐Year‐Old Man with Difficulty Climbing the Stairs

Clinical History

A 29‐year‐old man described progressive difficulty climbing stairs over a decade. He did not report any other neurological symptoms including upper limb, bulbar, facial or respiratory muscle weakness. His perinatal history and development were unremarkable, although he had never been particularly good at sport. There was no family history of cardiac or neuromuscular disease. Neurological examination revealed an exaggerated lumbar lordosis and myopathic gait. He had moderate symmetrical, predominantly proximal, limb weakness, which was more marked in the lower than the upper limbs and normal tendon reflexes. There was no sensory loss, myotonia or muscle hypertrophy. Serum creatine kinase level was elevated at 1096 IU/L (upper limit of normal: 250 IU/L). Electromyogram was myopathic. Electrocardiogram and echocardiography were normal.

Microscopic Pathology

Muscle biopsy of the left vastus lateralis was performed. Light microscopy showed marked variation in fiber size (10–130 μm), split fibers, regenerating fibers, necrotic fibers and increased endomysial connective tissue (Figure 1A; bar represents 50 μm). Frequent fibers contained prominent rimmed vacuoles and occasionally contained hyaline eosinophilic material (Figure 1B; bar represents 25 μm). A Gomori trichrome preparation revealed a disturbance of the internal architecture of many fibers. No ragged red or cytochrome oxidase‐deficient fibers were present.

Figure 1.

 

Immunohistochemical staining showed a mild CD3 positive T‐lymphocyte infiltrate, comprising both CD4 and CD8 positive cells. Major histocompatibility complex class I expression was markedly upregulated at the sarcolemma and within the sarcoplasm of most fibers (Figure 2A; bar represents 50 μm). Protein accumulations in rimmed vacuoles were immunoreactive for p62, ubiquitin, desmin (Figure 2B; bars represent 100 μm in Figures 2B–2G) and myotilin (Figure 2C). Staining for spectrin, merosin, α‐sarcoglycan, dysferlin and β‐dystroglycan showed normal sarcolemmal labeling (not shown). N‐terminal (dys 3), C‐terminal (dys 2) (Figure 2D) and the rod (dys 1) domain dystrophin staining were reduced compared with controls (Figure 2E). Utrophin was markedly upregulated, and neuronal‐nitrous oxide synthase (nNOS) (Figure 2F) was barely detected at the muscle fiber sarcolemma compared with controls (Figure 2G). What is your diagnosis?

Figure 2.

 

Diagnosis

Becker muscular dystrophy (BMD).

Immunoblotting revealed a reduction in the intensity of the dystrophin and dystrophin‐associated glycoprotein bands, 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.

Discussion

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 recognized when originally described 8. Classically, the muscle biopsy is dystrophic, demonstrating variability in fiber size, increased endomysial tissue, split fibers, 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 3, 7. 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‐recognized 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) 2 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 characterized 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 B‐crystallin, myotilin, desmin and valosin containing protein.

Rimmed vacuoles are irregular vacuoles with a granular basophilic rim or containing granular basophilic material visualized in muscle biopsies when stained with hematoxylin and eosin (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 1 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 5, 6. The presence of rimmed vacuoles in a variety of different muscle diseases, particularly those associated with protein accumulation, indicates that they are a nonspecific consequence of several different types of pathology and may relate to failure of protein degradation within muscle fibers. 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.

Disclosures

The authors report no disclosures.