Presenter
Benjamin Ellezam
Bio
Dr. Ellezam completed a neuroscience PhD, MD, and anatomic pathology residency at Université de Montréal, followed by a
neuropathology fellowship at MD Anderson Cancer Center/Methodist Hospital and Texas Children’s Hospital in Houston.
Since 2012, he has served as staff neuropathologist at Sainte-Justine Hospital and associate clinical professor in the
Department of Pathology and Cell Biology at Université de Montréal. His practice focuses on neuromuscular pathology, with
more than 200 adult and pediatric muscle biopsies reviewed annually, and his research centers on myositis in mixed connective
tissue disease.
He founded and directs the Sainte-Justine Biobank for Research on Diseases of the Nervous System, whose scope was
recently expanded to include neuromuscular disorders and expected to include over 1,000 muscle biopsy specimens.
Authors
Benjamin Ellezam 1, Yves Troyanov 2, Jean-Denis Brisson 3
1 Division of Pathology, CHU Sainte-Justine, 2 Division of Rheumatology, Hôpital du Sacré-Cœur, Université de Montréal, Montréal, QC.
3 Clinique des maladies neuromusculaires, Saguenay, QC, Université de Sherbrooke, Sherbrooke, QC.
Conflict of Interest
I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose.
Clinical Summary
A 65-year-old physically active male, on rosuvastatin for 12 years, developed progressive dyspnea and proximal weakness over a year, leading to admission 6 months ago.
Cardiac work-up showed a 45% ejection fraction with diffuse hypokinesia and atrial fibrillation (which according to his smartwatch may have been present for about a year).
CT and PET scans revealed rapidly enlarging thoracoabdominal lymphadenopathy that partially responded to dexamethasone but biopsy and flux cytometry were nondiagnostic. PET also showed full-length esophageal dysmotility.
Neurological exam: equivocal scapular winging, mild facial weakness with inability to whistle, recent loss in hearing and visual acuity, proximal weakness 3+/5, distal 4+/5. EMG myopathic.
Creatine kinase levels initially 1000-2000 IU/L, now ~600 for the past 2 months. Quickly rising alkaline phosphatase and gamma-glutamyl transferase, mild fluctuating bilirubin increase and mild AST/ALT elevation. Antinuclear antibodies 1:1280 (centromere AC3 and cytoplasmic reticular AC21). Anti-HMGCR negative. Scleroderma panel: CENP-A/B 3+. Myositis panel: negative.
Quadriceps muscle biopsy was requested.
Discussion points
- What is the clinical differential diagnosis?
- What is the differential diagnosis on muscle biopsy?
- What further testing is needed to resolve the differential diagnosis?
Reveal Diagnosis
Anti-mitochondrial M2 antibody (AM2A)-associated myositis
Additional investigations:
Anti-mitochondrial M2 antibody positivity (1:320)
Comment:
– Muscle biopsy revealed an immune-mediated necrotizing myopathy pattern with MHC1 positivity in excess of what is usually seen in anti-HMGCR or anti-SRP – and without the usual P62/LC3+ granular cytoplasmic staining or oil red-O+ lipid droplets in non-necrotic fibers – prompting consideration for IMNM mimickers such as scleromyositis including the recently characterized anti-Ku, or AM2A myositis, two myositis subsets that can present with a low ejection fraction (EF) cardiomyopathy. Arrythmia is a feature of AM2A myositis but is not characteristic of anti-Ku.
– Anti-Ku myositis has characteristic P62/LC3+ coarse or cap-like inclusions and often prominent capillary basement membrane reduplication. AM2A myositis doesn’t have conspicuous P62+ deposits or prominent capillary abnormalities.
– Anti-mitochondrial antibodies (usually for primary biliary cholangitis) are not part of standard myositis panels (unlike anti-Ku) and have to be requested separately.
– Here, cytoplasmic reticular (AC21) ANA strongly suggested an anti-mitochondrial antibody.
– Liver function labs are also suggestive of cholestasis without obstruction, characteristic of PBC. PBC is present in ~80% of patients with AM2A myositis.
– Anti-CENP-A/B-positive systemic sclerosis (SSc) here is an incidental finding and only very rarely (1%) present with myositis. Moreover, the typical cardiomyopathy of SSc is diastolic (normal EF) except occasionally in anti-RNP or anti-Ku in the context of a lupus overlap.
– This case highlights the importance of considering recently-recognized myositis subsets with biopsy findings similar to IMNM; and highlights the usefulness of integrating ANA in inflammatory muscle biopsy interpretation.
– This case allows discussion of cardiac involvement in myositis.
References
Nishimori Y et al. (2025) Anti-mitochondrial M2 antibody-positive myositis may be an independent subtype of autoimmune myositis. J Neurol. 272(3):206. PMID: 39954092
Hozler MT et al. (2024) Anti-Ku + myositis: an acquired inflammatory protein-aggregate myopathy. Acta Neuropathol 148(1):6.PMID: 39012547
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