Anti-HMGCR myopathy may resemble limb-girdle muscular dystrophy

Identification and characterization of patients

Eleven patients met the clinico-pathologic entry criteria as described in the Methods section, 6 of whom (1 previously reported⁶) had positive anti-HMGCR autoantibodies, with titers 2–10 times the upper limit of normal. None of the 6 patients with anti-HMGCR myopathy tested positive for anti-SRP autoantibodies or other myositis-specific autoantibodies when tested. The summary of relevant clinical findings in the patients with anti-HMGCR autoantibodies is provided in table 1. In contrast to classic cases of anti-HMGCR myopathy, the disease course was indolent in these patients. Elevated CK, aspartate transaminase, or alanine transaminase (presumably originating from muscle), often preceded the onset of overt muscle weakness, in some cases by more than 10 years. None of the patients took statin drugs, but 1 patient (P6) took mushroom supplements (a natural source of statins) before developing muscle weakness.

A predominantly proximal pattern of muscle weakness was notable in all patients with near-complete sparing of distal muscles (e.g., anterior tibial group). Lower extremity weakness preceded upper extremity weakness and was more severe. Moderate to severe scapular winging was noted in 5 of the 6 patients, without selective involvement of scapular fixators. At the time of presentation, P1-P4 remained independently ambulatory. P5 relied on the assistance of a cane for outdoor ambulation, whereas P6 relied on a motorized wheelchair. Neck flexion, arm abduction (deltoid), elbow flexion, and to a lesser degree elbow extension were affected in the upper extremities. In the lower extremities, hip flexion, hip adduction, hip extension, hip abduction, knee flexion, and to a lesser degree knee extension were most commonly affected. Extraocular and facial muscles were spared.

Muscle imaging

Muscle MRI of the lower extremities showed a common pattern of involvement. Patients with shorter duration of disease showed minimal changes in T1 signal in the thighs or lower legs, whereas those with longer duration of disease showed T1 hyperintensity in paraspinal muscles, glutei, hamstrings, and adductors with variable involvement and atrophy of the quadriceps muscles. The gracilis muscle was relatively preserved (figure 1, A). In the lower leg, the pattern was more variable, with the medial gastrocnemius showing increased T1 signal in a heterogeneous and patchy distribution (3 of 6 patients). The tibialis anterior was relatively preserved (figure 1, B). In addition, thigh and lower leg muscles had hyperintense STIR signal with a heterogeneous and patchy distribution (figure 1, C). STIR signal hyperintensity was not limited to areas of T1 hyperintensity, suggestive of ongoing disease activity.

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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.

Muscle ultrasound showed an overall patchy and granular pattern of increased echogenicity in the patients with a shorter disease duration and more diffusely echodense muscles in those with longer disease duration. In the upper extremities, ultrasound highlighted selective involvement of certain muscle groups (e.g., biceps more than triceps) (figure 2).

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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).

Muscle histology

Severe myofiber atrophy, fiber size variability, and increased internalized nuclei were nearly universal findings (figure 3). Most biopsies included other chronic myopathic features such as splitting myofibers and increased endomysial fibrosis. Myofiber degeneration/necrosis and regeneration was a variable feature. Some biopsies showed many degenerating/necrotic myofibers, some actively undergoing myophagocytosis (P2), whereas others had only a single degenerating fiber (P4). A few biopsies showed a single or 2 small foci of chronic perivascular inflammation composed of macrophages and CD3-positive T cells. None of the biopsies showed prominent primary inflammation—nonnecrotic myofibers surrounded and/or invaded by chronic inflammatory cells. MHC-1 was increased in degenerating fibers and rare nonnecrotic fibers, but it appeared normal or only minimally increased in other areas. None of the patients had diagnostic changes in known LGMD proteins based on immunostaining.

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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).

A few additional nonspecific histologic findings were noted: muscle biopsy of P6 had inclusions in some muscle fibers that stained positive with periodic acid Schiff (PAS) stain, as well as with desmin, myotilin, and ⍺β-crystalllin immunostains. These PAS-positive inclusions were ⍺-amylase sensitive and did not stain with adenosine triphosphatase or oxidative stains, suggesting that they do not contain polyglucosan bodies, myosin, or intermyofibrillar material. A single subsarcolemmal red-rimmed vacuole was noted in the muscle biopsy of P4.

Genetic testing

All anti-HMGCR–positive patients (n = 6) had undergone commercial genetic testing for common LGMDs using next-generation sequencing (NGS) panels before referral to the NIH (table 1). Because of the presence of asymmetric findings and scapular winging, 2 patients were tested for facioscapulohumeral dystrophy (FSHD). Other patients lacked typical features of FSHD and were not directly tested. Because of the preponderance of internalized nuclei in P4, myotonic dystrophy type 2 was also considered and ruled out by direct testing. Four patients also underwent WES, 3 at the NIH (P2, P4, and P5) and one through a commercial laboratory (P6). Because of the presence of myofibrillar inclusions in P6's muscle biopsy and a suspicion for an underlying myofibrillar myopathy, she also underwent WGS. None of the patients had pathogenically relevant variants (excluding benign variants) that matched familial segregation studies or mode of inheritance of the disease associated with the gene in question.

Most (∼70%) adult patients with anti-HMGCR myopathy possess the HLA-DRB1*11:01 allele,^16,17 whereas HLA DRB1*07:01 is recently reported in several pediatric patients with anti-HMGCR myopathy.⁷ We tested these 6 patients for the presence of either allele. All but 1 patient had the HLA-DRB1*07:01 or 11:01 allele (table 1).

Follow-up after treatment

After confirmation of anti-HMGCR myopathy, all patients (n = 6) were treated with IV immunoglobulins (IVIg) and seen in follow-up at the NIH. Steroids (methylprednisolone, 750 mg every 3 weeks) were added to P6's regimen after 4 months of IVIg therapy. The patients were re-examined, CK was remeasured, and a muscle MRI was repeated. Most patients reported improved function and improved muscle strength. Manual muscle testing using MRC grading or handheld dynamometry showed improvement in muscle strength, at least in select muscle groups (table 2). P2 also showed significant improvement in timed rise from the floor, a commonly used outcome measure in pediatric muscular dystrophy.¹⁸ All patients showed a marked reduction in CK levels. Most patients also had a marked reduction in muscle MRI STIR signal intensity (figure 1, D). The pediatric patients (n = 2; mean age 12 years), who had a shorter duration of symptoms before initiation of therapy, demonstrated the most dramatic improvements in strength and function to normal or near-normal levels (table 2).

After 1 year of follow-up, all patients remain on immunosuppression, and most continue to report improvement or stabilization of weakness; none report worsening weakness. P6 is able to ambulate with a walker for the first time in 2 years. P2 reports regaining the ability to run. P1 attempted to lengthen the treatment interval of IVIg to every 5 weeks and developed elevated CK levels (∼1,100 U/L). A few months later, he noted a decline in athletic performance. Two months after returning to his previous IVIg schedule (every 4 weeks), his CK has decreased (∼800 U/L), and his athletic performance has improved.

Validation cohort

We subsequently investigated another patient cohort in a large neuromuscular referral center in France. We asked the reverse question: how prevalent is a chronic, LGMD-like presentation among patients with already-established anti-HMGCR myopathy? Among 51 anti-HMGCR myopathy cases examined, 17 patients (∼33%) were initially suspected to have LGMD based on clinical findings and muscle biopsy criteria, all without genetic diagnostic confirmation. All 17 patients underwent specific molecular or genetic testing for LGMD (including dystrophin [DMD], dysferlin [DYSF], sarcoglycans [SGCA, SGCB, SGCG, and SGCD], calpain-3 [CAPN3], caveolin-3 [CAV3], anoctamin 5 [ANO5], fukutin-related protein [FKRP]), or other hereditary myopathies such as acid maltase deficiency or type 2 myotonic dystrophy. These 17 patients had a clinical presentation and course of disease evolution similar to the initial cohort (table 3). Most patients had a prolonged disease course that initially presented with asymptomatic or oligosymptomatic hyperCKemia, exercise intolerance, or myalgia (table e-1, links.lww.com/NXI/A90). A third of the patients had scapular winging. In those who had individual muscle group strength data available, the majority (∼62%) had weakness of knee flexion greater than extension; however, 3 (23%) had knee extension greater then flexion weakness, whereas there was no difference in 2 (15%) patients. All patients displayed markedly elevated CK levels (mean: 6,580 U/L). Muscle histologic findings included myofiber degeneration and regeneration in all patients and chronic myopathic changes in most patients. Most patients were treated with various regimens and immunosuppressive agents, although a few patients declined treatment, typically those with only mild weakness or asymptomatic hyperCKemia. Only a minority of these patients had exposure to statins (∼24%). Overall, most patients treated with immunosuppressant therapies demonstrated improved muscle strength and functional capacity, especially those with relatively shorter disease duration (table e-2, links.lww.com/NXI/A91). Some patients with prolonged disease duration and evidence of severe muscle damage documented on muscle MRI did not show clear improvements in muscle strength testing. However, a decline in CK levels was seen in all treated patients. At the last follow-up, most of these patients (10 of 13; 77%) were still receiving IVIg either as monotherapy or in combination with another immunosuppressant.