Clinical and Pathological Features of Immune-Mediated Necrotising Myopathies in a Single-Centre Muscle Biopsy Cohort

Objective Immune-mediated necrotising myopathy (IMNM) is a recently entitled novel subset of idiopathic inflammatory myopathies (IIM) characterized by significant elevated creatine kinase (CK) level, muscle weakness and predominant muscle fibre necrosis in muscle biopsy. This study aimed to investigate the clinical and pathological characteristics of patients with IMNM in our single-centre muscle biopsy cohort. Methods A total of 860 patients who had muscle biopsy reports in our centre from May 2008 to December 2017 were enrolled in this study. IMNM was diagnosed in according with 2018 European Neuromuscular Centre (ENMC) clinicopathological diagnostic criteria for IMNM. Results The muscle biopsy cohort consisted of 531 patients with IIM (61.7%), 253 patients with non-IIM (29.4%), and 76 undiagnosed patients (8.8%). Among IIM patients, polymyositis (PM), dermatomyositis(DM), amyopathic dermatomyositis, juvenile DM, and inclusion body myositis were 182(21.2%), 236(27.4%), 83(9.7%), 18(2.1%) and 3(0.3%), respectively. In PM subgroup, 59 patients met serological and pathological characteristics of IMNM according to 2018 ENMC criteria including 29 anti-SRP-positive patients,10 anti-HMGCR-positive patients and 20 MSA-negative patients. Limb girdle muscular dystrophy (LGMD) 2B and lipid storage myopathy (LSM) were 29 and 16 respectively, which present similar manifestations of IMNM with elevated CK levels and muscle weakness among non-IIM group. IMNM patients had older age of onset (mean: 42.25 vs 21.66 and 24.56, p<0.0001), shorter duration of diseases (mean: 22.56 vs 66.69 and 48.94, p<0.0001) and more frequent of dysphagia (33.9% vs 3.4% and 6.3%, p<0.0001) compare to patients with LGMD 2B and LSM. Muscle biopsy from IMNM patients showed frequent muscle fibre necrosis (96.6% vs 72.4% and 56.3%, p<0.0001), overexpression of MHC-I on sarcolemma (81.4% vs 37.9% and 12.9%, p<0.0001) and CD4+ T cell endomysial infiltration (89.9% vs 53.6% and 50%, p<0.0001) compared with LGMD 2B and LSM patients. Conclusions It is easy to distinguish IMNM from other subtype of IIM according to clinical symptoms and MSAs profiles. However, distinguishing IMNM from disorders clinically similar non-IIM need to combine with clinical, serological and pathological features.

Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series

Background: Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by ETFDH mutations that result in defects in ETF-ubiquinone oxidoreductase. Almost all patients are responsive to riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients.Methods: From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data.Results: This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum creatine kinase (CK) levels were significantly elevated in all patients, and plasma acylcarnitine profiles revealed an increase in long-chain acylcarnitine species in three cases. The urinary organic acid study revealed a high level of hydroxyglutaric acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in ETFDH. Exercise intolerance and muscle weakness were dramatically improved in all patients treated with riboflavin (100 mg) daily following diagnosis.Conclusions: LO-MADD is caused by ETFDH variants and responds well to riboflavin. Three novel ETFDH pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of ETFDH mutations.

Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China

Objectives Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. Methods From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. Results Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). Conclusions These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.

Late-onset multiple acyl-CoA dehydrogenase deficiency mimicking myositis in an elderly patient: a case report

Background Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare and treatable inherited lipid storage myopathy. Here, we report an elderly patient with MADD mimicking myositis. Case presentation An 80-year-old woman had progressive weakness in her limbs, exercise intolerance, and no muscle pain for 3 months. The patient’s serum creatine kinase level was slightly elevated. The initial diagnosis was myositis. However, muscle biopsy showed many cytoplasmic vacuoles stained with oil red O, indicating the presence of lipid storage myopathy. The plasma acylcarnitine profile showed increased medium-chain and long-chain acylcarnitine species, consistent with the diagnosis of MADD. Riboflavin treatment dramatically improved muscle weakness. Conclusions MADD should be considered when evaluating elderly patients with subacute muscle weakness.

Late-Onset Lipid Storage Myopathy with Fatal Hepatosteatosis

Hepatosteatosis, a common condition, is increasing in prevalence. It is typically associated with diet, alcohol consumption and obesity. In some cases, a rare genetic disease may be the underlying defect. Lipid storage myopathy (LSM) is a genetic disease caused by lipid metabolism defects. LSM often affects the muscles, heart and liver. Coenzyme Q, riboflavin or carnitine replacement can be beneficial in some cases. We describe a patient who presented with liver failure and was unresponsive to treatment.