A Child with Refractory and Relapsing Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Myopathy: Case-Based Review

Abstract

Background/Objective: Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) myopathy is rare in children. Here, we present a boy with relapsing refractory anti-HMGCR myopathy along with a systematic literature review. Case Report: 17-year-old boy with five years of muscle weakness, rash, high creatinine kinase (CK) levels, and muscle biopsy compatible with inflammatory myopathy was diagnosed with juvenile dermatomyositis. He was treated with corticosteroids, intravenous immunoglobulin (IVIG), and methotrexate. His muscle weakness improved with this treatment although never completely resolved. CK levels decreased from ∼15000 U/L to ∼3000 U/L. At the age of 15, muscle weakness relapsed after an upper respiratory tract infection; pulse corticosteroid treatment was administered. The re-evaluated muscle biopsy showed a necrotizing pattern and the HMGCR antibody was positive confirming anti-HMGCR myopathy when he was 16. The diagnostic delay was 50 months. Disease activity was monitored by Medical Research Council score, MRI and functional tests. Despite corticosteroids, methotrexate, IVIG, cyclosporine A, and rituximab therapies, muscle weakness improved only slightly during the first three months and remained stable afterwards. Results of the Literature Search: We identified 16 articles describing 50 children (76% female) with anti-HMGCR myopathy by reviewing the English literature up to March 1st, 2022. Proximal muscle weakness was the most common clinical symptom (70.8%). Corticosteroids (84.8%), IVIG (58.7%), and methotrexate (56.5%) were preferred in most cases. Complete remission was achieved in nine patients (28.1%). Conclusion: Diagnosis and management of children with anti-HMGCR myopathy are challenging. Complete remission is achieved in only one third of these patients. Imaging biomarkers may aid treatment.

Absence of Pathogenic Mutations and Strong Association With HLA-DRB1*11:01 in Statin-Naïve Early-Onset Anti-HMGCR Necrotizing Myopathy

“…Patients tend to develop proximal muscle weakness early on in childhood or adolescence, and evolution is characteristically chronic and slowly progressive, resembling a muscular dystrophy, often resulting in a delayed diagnosis. [14][15][16][17] Therefore, a systematic suspicion of IMNM and testing for specific autoantibodies, especially in children and adolescents with suspected but not genetically confirmed LGMD, may help improve diagnostic time lines and lead to early treatment before muscle damage becomes irreversible.…”

“…A recent retrospective study in patients with IMNM showed that muscle MRI can be useful for monitoring disease activity and that the percentage of STIR+ muscles correlated with higher risk of fat replacement at follow-up, but a specific pattern of involvement was not identified either. 49 Regarding young statin-naïve patients, only few imaging data from case reports are available with similar findings, 11,17 and there are not larger series to allow a proper comparation.…”

“…15,16 In fact, a recent case-based review reported that only one-third of children achieve complete remission after a mean follow-up of 31 months. 17 A chronic progressive course, often resembling limb-girdle muscular dystrophy (LGMD), may manifest in statin-naïve patients affected by anti-HMGCR IMNM, and this may lead to misdiagnosis or a lengthy diagnostic delay, sometimes of years, until the anti-HMGCR antibodies are tested. We previously reported a series of 5 young patients with anti-HMGCR IMNM mimicking LGMD, 18 and several subsequent reports have documented similar phenotypes.…”

“…13,16,19,20 Two recent case reports have attested to muscle imaging evidence of progression from muscle edema to fatty infiltration over the years, demonstrating irreversible muscle damage. 11,17 This fact would suggest that treatment must be prompt, given that immunomodulatory therapy initiated years after onset is usually unsuccessful in controlling the disease.…”