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Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR
Laura Llansó1, Alba Segarra-Casas1, Cristina Domínguez-González1
1From the Department of Neurology (L.L., C.L., M.C.-Á., Á.C., A.V., L.Q., E.G., M.O.), Neuromuscular Diseases Unit; Department of Genetics (A.S.-C., B.R.-S.), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Department of Neurology (C.D.-G.), Neuromuscular Diseases Unit, Hospital Universitario 12 de Octubre. Research Institute imas12, Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Université Paris-Est Créteil (E.M.), INSERM, U955 IMRB; AP-HP, Hôpital Mondor, FHU SENEC, Service d'Histologie, Créteil, France; Department of Neurology (S.K.), Neuromuscular Diseases Unit, Osakidetza Basque Health Service, Basurto University Hospital, Universidad del País Vasco, Bilbao; Institut de Recerca Sant Pau (IR Sant Pau) (B.R.-S., R.B., C.L., L.Q., E.G., M.O.), Barcelona; Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid; Genomic Instability Syndromes and DNA Repair Group and Join Research Unit on Genomic Medicine UAB (B.R.-S.), Institut de Recerca Sant Pau (IR Sant Pau), Hospital de la Santa Creu i Sant Pau; Immunology Department (O.C., A.M.), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Institut de Recerca Sant Pau (IR Sant Pau), Barcelona, Spain; Department of Genetics (A.D.), Craiova University Hospital, Romania; Neuropaediatrics Department (A.N.O.), Neuromuscular Diseases Unit, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, CIBERER - ISC III; Neurology Department (A.P., L.G.-M.), Neuromuscular Unit, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona; Pathology Department (A.H.-L.), Neuropathology Unit, Hospital Universitario 12 de Octubre, Madrid; Pathology Department (C.J.), Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, and MetabERN, Barcelona; Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid; Department of Neurology (L.G.-M.), Hospital de Viladecans, Barcelona; and Department of Genetics (A.A.), Hospital Universitario 12 de Octubre, Research Institute imas12, Madrid, Spain.
Background And Objectives:
Immune-mediated necrotizing myopathy (IMNM) caused by antibodies against 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an inflammatory myopathy that has been epidemiologically correlated with previous statin exposure. We characterized in detail a series of 11 young statin-naïve patients experiencing a chronic disease course mimicking a limb-girdle muscular dystrophy. With the hypothesis that HMGCR upregulation may increase immunogenicity and trigger the production of autoantibodies, our aim was to expand pathophysiologic knowledge of this distinct phenotype.
Methods:
Clinical and epidemiologic data, autoantibody titers, creatine kinase (CK) levels, response to treatment, muscle imaging, and muscle biopsies were assessed. HMGCR expression in patients' muscle was assessed by incubating sections of affected patients with purified anti-HMGCR+ serum. Whole-exome sequencing (WES) with a special focus on cholesterol biosynthesis-related genes and high-resolution human leukocyte antigen (HLA) typing were performed.
Results:
Patients, aged 3-25 years and mostly female (90.9%), presented with subacute proximal weakness progressing over many years and high CK levels (>1,000 U/L). Diagnostic delay ranged from 3 to 27 years. WES did not reveal any pathogenic variants. HLA-DRB1*11:01 carrier frequency was 60%, a significantly higher proportion than in the control population. No upregulation or mislocalization of the enzyme in statin-exposed or statin-naïve anti-HMGCR+ patients was observed, compared with controls.
Discussion:
WES of a cohort of patients with dystrophy-like anti-HMGCR IMNM did not reveal any common rare variants of any gene, including cholesterol biosynthesis-related genes. HLA analysis showed a strong association with HLA-DRB1*11:01, previously mostly described in statin-exposed adult patients; consequently, a common immunogenic predisposition should be suspected, irrespective of statin exposure. Moreover, we were unable to conclusively demonstrate muscle upregulation/mislocalization of HMGCR in IMNM, whether or not driven by statins.
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