Case report
Concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme a reductase antibody with reducing body myopathy: Possible double trouble

https://doi.org/10.1016/j.nmd.2019.05.007Get rights and content

Highlights

  • We report anti-HMGCR antibody positivity with reducing body myopathy in a 6-year-old boy.

  • Unusual clinical and pathological features could be a mixed result of two entities.

  • Comprehensive workup lead to the "possible double-trouble” diagnosis.

Abstract

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy is less common in children but has been associated with more favorable prognosis than adult patients after immunotherapies. We report anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody positivity in a 6-year-old boy with progressive muscle weakness, scoliosis, spinal rigidity, multiple joint contractures, mild left ventricular hypertrophy, and elevated serum creatine kinase. In contrast to most of previously reported pediatric anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myopathy, he showed little response to immunotherapies. Muscle biopsy contained changes suggestive of myofiber necrosis and regeneration and reducing bodies. The diagnosis of reducing body myopathy was later confirmed by reported c.368A>G (p.His123Arg) mutation in the FHL1 gene. Although the level of association between these two conditions is still inconclusive, this is the first report of concurrent positive anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibody with reducing body myopathy emphasizing the possibility of co-occurrence of immune mediated necrotizing myopathy and muscular dystrophy and importance of comprehensive diagnostic investigations in unusual cases.

Introduction

Immune mediated necrotizing myopathy (IMNM), a recently recognized but a common entity among the heterogenous group of inflammatory myopathies, has been classified by the ENMC Immune-Mediated Necrotizing Myopathies Working Group into (1) anti-signal recognition particle (anti-SRP) positive IMNM or anti-SRP myopathy, (2) anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) positive IMNM or anti-HMGCR myopathy, and (3) antibody negative IMNM using integrated clinical, serological, and pathological criteria [1]. Patients with proximal muscle weakness and elevated serum creatine kinase (CK) level can be classified into anti-SRP myopathy or anti-HMGCR myopathy if they are found to have anti-SRP or anti-HMGCR antibody, respectively [1]. Further workup such as muscle biopsy, electromyography (EMG), and muscle magnetic resonance imaging (MRI) is not required for subtyping these seropositive patients [1]. In contrast, compatible muscle pathology is essential to define antibody negative IMNM in patients with similar clinical features after excluding possibility of drug/toxin-induced myopathy [1]. Although most IMNM patients are adults, pediatric IMNM exists and is probably underrecognized. It is noteworthy that IMNM can be masquerading as muscular dystrophy and vice versa especially in pediatric individuals [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Instead of acute or subacute clinical presentation and necrotic and regenerating process on pathology, some IMNM patients show indolent clinical course and chronic or advance muscle pathology mimicking muscular dystrophy [3], [4], [6], [12]. On the other hand, certain types of muscular dystrophies including anoctaminopathy, laminopathy, dysferlinopathy, sarcoglycanopathies, FKRP-related muscular dystrophy and fascioscapulohumeral muscular dystrophy (FSHD) can be pathologically deceptive as IMNM by showing prominent necrotic and regenerating process with lymphohistiocytic inflammation [1], [3]. Interestingly, some of muscular dystrophy patients may show favorable response to immunotherapies [3]. Thorough clinical, laboratory, and genetic investigations are required to distinguish potentially treatable conditions, IMNM, from other non-treatable conditions.

Here, we report a case of a 6-year-old boy who has concurrent positive anti-HMGCR antibody and reducing body myopathy (RBM) emphasizing the possibility of co-occurrence of IMNM and muscular dystrophy and importance of comprehensive workup in cases with unusual presentations.

Section snippets

Case report

The patient was a 6-year-old Thai boy from a non-consanguineous family, who had presented with proximal muscle weakness for 18 months. His parents first noticed the symptoms after the patient recovered from chickenpox when he was 4 years and 6 months old. At 5 years of age, he had difficulties getting upstairs, rising from the floor, frequent falling, and walking tiptoe. At the age of 6, the patient could not walk up and down stairs and had difficulties raising his arms. The patient had

Discussion

Several cases of concurrent myositis specific autoantibody (MSA) positivity with different types of muscular dystrophy/myopathy have been reported in the literature including positive anti-HMGCR antibody with reported ANO5 [16] and LMNA [3] mutations, positive anti-SRP antibody with COL6A3 variant [5], positive anti-Jo-1 antibody with genetically confirmed, muscular dystrophy (LGMD) 2A [11], positive anti-Mi2 antibody with mitochondrial myopathy [17] and genetically confirmed FSHD [11] (Table 1

Acknowledgments

This study was supported partly by Intramural Research Grant (29–4) for Neurological and Psychiatric Disorders of NCNP, and AMED under Grant Numbers JP19ek0109285h0003 and JP18kk0205001s0203.

Conflict of interest

Dr. Lundberg has filed a patent for anti-FHL1 antibody test. The other authors do not have conflict of interest to declare.

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      Most descriptions of double trouble inherited myopathies or inherited myopathies co-existing with other rare neuromuscular disorders consist of case reports. For example, there are descriptions of isolated cases of facioscapulohumeral muscular dystrophy (FSHD), [4] McArdle's disease, [5] or myotonic dystrophy type 1 (DM1) [6–9] co-existing with myasthenia gravis; ANO5, [10] LMNA, [11] or FHL1 muscular dystrophy [12] co-occurring with immune-mediated necrotizing myopathy (IMNM); or TTN-muscular dystrophy, myotonia congenita, or myotonic dystrophy type 2 (DM2) co-existing with immune-checkpoint inhibitor-related neuromuscular disease. [13] “Triple trouble”, such as combined DM2, myasthenia gravis, and immune-mediated rippling muscle disease, has also been reported. [14]

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      Unlike most previously reported pediatric myopathies associated with HMGCR antibodies, this child showed little response to immunotherapies [5]. Muscle biopsy showed reducing bodies, in addition to changes suggestive of myofiber necrosis and regeneration [5]. The diagnosis of RBM was confirmed by a reported c.368A>G (p.His123Arg) mutation in the FHL1 gene, the same variant present in our patient [5].

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