Background/Purpose: To describe a novel type of myositis, immune mediated megaconial myopathy (IMMM),  pathologically characterized by giant mitochondria (megaconia).

Methods: We reviewed the Mayo Clinic Muscle Pathology database, between 2018 and 2023, to identify patients with megaconial pathology, subacute progressive weakness and hyperCKemia, clinically resembling myositis. We recruited one patient from another institute, who had similar clinicopathological features.

Results: Five patients (3 females and 2 males) were identified. Age at onset of weakness ranged from 19 to 44.5 years (median 31.5 years). All patients had proximal weakness, elevated creatine kinase levels (1,214 to 5,920 U/L), negative myositis specific and associated antibodies, necrotizing pathology and non-necrotic myofibers harboring large fuchsinophilic granules, which were overreactive for oxidative enzymes, consistent with giant mitochondria. Ragged red fibers were not observed. Electron microscope confirmed the presence of markedly enlarged mitochondria. One patient had dyspnea on exertion without interstitial lung disease. None of the patients had cutaneous or joint involvement. Immunohistochemical studies showed sarcolemmal MHC-1 and C5b9 immunoreactivities. Megaconial pathology was considered pathognomonic of congenital muscular dystrophy (CMD) due to biallelic CHKB mutations. CHKB-congenital muscular dystrophy is a slowly progressive disease with an infantile to childhood onset. Sequencing of CHKB in our patients revealed no pathogenic variants. Immunomodulatory therapy improved weakness and hyperCKemia in 4 treated patients, which further reinforced its dysimmune pathomechanism. Interestingly, all patients had coexisting pancreatic diseases (3 cystic fibrosis related exocrine pancreatic insufficiency, 1 pancreatic cancer and 1 pancreatitis).  Although necrotizing pathology of IMMM resembled the myopathological findings of immune mediated necrotizing myopathy (IMNM), IMMM patients were younger than reported seronegative IMNM patients, had distinctive pathological evidence of giant mitochondria and were commonly associated with pancreatic diseases.

Conclusion: In addition to incurable CHKB-congenital muscular dystrophy, giant mitochondria can also occur in adult patients with this new type of treatable autoimmune myopathy, IMMM. The association between IMMM and pancreatic disorders remains to be elucidated.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/defining-a-novel-type-of-myositis-immune-mediated-megaconial-myopathy-immm/