Contributed by Stefen Brady, MRCP1, Rita Barresi, PhD2, Richard Charlton, PhD2, Christopher Turner, PhD MRCP3, Janice L. Holton, PhD FRCPath4
1Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
2NSCT Diagnostic & Advisory Service for Rare Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital, Richardson Road, Newcastle upon Tyne, UK.
3MRC Centre for Neuromuscular Disease, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
4MRC Centre for Neuromuscular Diseases and Division of Neuropathology, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
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.
Muscle biopsy of the left vastus lateralis was performed. Light microscopy showed marked variation in fibre size (10-130 Ám), split fibres, regenerating fibres, necrotic fibres and increased endomysial connective tissue (Figure 1; bar represents 50 Ám). Frequent fibres contained prominent rimmed vacuoles and occasionally contained hyaline eosinophilic material (Figure 2; bar represents 25 Ám). A Gomori trichrome preparation revealed a disturbance of the internal architecture of many fibres. No ragged red or cytochrome oxidase deficient fibres were present.
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 up-regulated at the sarcolemma and within the sarcoplasm of most fibres (Figure 3; bar represents 50 Ám). Protein accumulations in rimmed vacuoles were immunoreactive for p62, ubiquitin, desmin (Figure 4; bars represent 100Ám in Figures 4-9) and myotilin (Figure 5). Staining for spectrin, merosin, α-sarcoglycan, dysferlin and β-dystroglycan showed normal sarcolemmal labelling (not shown). N-terminal (dys 3), C-terminal (dys 2) (Figure 6) and the rod (dys 1) domain dystrophin staining were reduced compared to controls (Figure 7). Utrophin was markedly up-regulated and neuronal-nitrous oxide synthase (nNOS) (Figure 8) was barely detected at the muscle fibre sarcolemma compared to controls (Figure 9). What is your diagnosis?