Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy

Abstract

Objective: To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations.

Methods: Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy.

Results: Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (∼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength.

Conclusions: Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.

Figure 1. Muscle MRI

Muscle MRI showing increased T1 hyperintensity in the hamstrings, adductors, and variably in quadriceps muscles. Gracillis muscle appears relatively preserved (panel A). Medial gastrocnemius is variably involved in the lower leg (panel B). STIR signal is increased predominantly in the hamstrings, quadriceps, and adductor muscles (C, arrowheads). After treatment, STIR signal is decreased in most patients, especially those evaluated later after initiation of treatment (D, arrows). VL = vastus lateralis; RF = rectus femoris; Sa = sartorius; Add = adductor magnus; Gr = gracilis; H = hamstrings; TA = tibialis anterior; So = soleus; mG = medial gastrocnemius; lG = lateral gastrocnemius.

Figure 2. Muscle ultrasound

Muscle ultrasound showing selective involvement and increased echogenicity in the biceps muscle (row A) when compared with the triceps muscle (row B).

Figure 3. Muscle biopsy showing myofiber atrophy and degeneration

Muscle biopsy showing profound myofiber atrophy (black arrowhead, A, F, and I), myofiber degeneration (black arrows, A, F, and I), internalized nuclei (white arrowhead, A, E, and I), and increased endomysial fibrosis. Rare foci of chronic perivascular inflammation were noted in a few patients (B and J), consisting of macrophages, and CD3-positive T cells (C). Whorled fibers, a chronic myopathic change, were noted in patient 4 (E). A single red-rimmed vacuole was noted in patient 4 (blue arrow, G). Major histocompatibility complex-1 (MHC-1) immunostain was increased in degenerating fibers and nonspecifically in limited areas of the muscle biopsy (D and H). Patient 6 muscle biopsy had several myofibers with inclusions (red arrows K, L, and M) that stained positive with desmin, myotilin, ⍺β-crystallin, and periodic acid Schiff (PAS) but not after treatment with diastase (PAS-D). The inclusions did not stain positive on NADH stain. Scale bar = 100 μm (A-I, L); Scale bar = 50 μm (J, K, M).