A 52-year-old woman presented with a gradual onset of proximal weakness and gait disturbance for five years along with muscle atrophy. She had no chronic disease or family history of neuromuscular disease. On examination, she showed weakness in the shoulder, thigh, and knee (Medical Research Council [MRC] grade 4+). Her elbow, wrist, and ankle were MRC grade 5-, showing weakness mainly in the proximal region. Her facial muscles were normal, and she had mild dysarthria. Her sensory modalities were intact, and she showed no upper motor neuron signs such as limb spasticity, brisk jaw jerk, or hyperreflexia. She presented fasciculations in both lower limbs, and the Gower's sign was positive. There were no skin lesions or bone/joint pain. Her serum creatine kinase (153 IU/L) and alkaline phosphatase (86 IU/L) were within the normal range. Pulmonary function tests showed that her vital capacity was reduced by 36% of predicted, and her maximal inspiratory pressure and maximal expiratory pressure were also reduced, indicating respiratory muscle weakness. Nerve conduction studies were normal. Electromyography showed widespread neurogenic changes; however, no myopathic potentials were identified. She showed memory impairment with stubbornness and poor hygiene maintenance. Her Mini-Mental State Examination score was 23, and the Frontal Assessment Battery score was 13. Brain magnetic resonance imaging showed atrophy of the frontal and temporal lobes, suggesting FTD. Muscle computed tomography showed diffuse atrophy with multifocal fatty changes, mainly in the limb-girdle muscles. Biopsy of the right vastus lateralis muscle revealed marked size variation of myofibers with rimmed vacuoles (Fig. 1A) and frequent observation of lobulated myofibers (Fig. 1B). Gomoritrichrome staining confirmed the presence of rimmed vacuoles in muscle fibers (Fig. 1C), with TDP 43 inclusions and ubiquitin-positive aggregates (Fig. 1E, 1F). Electron-microscopy showed rimmed vacuoles (Fig. 1D) along with myofilament disarray. Using a targeted Next-Generation Sequencing focused on limb-girdle muscular dystrophy in response to suspected proximal weakness, genetic testing identified heterozygote c.463C>T resulting in p. Arg155Cys substitution in the VCP gene, previously reported as a pathologic variant of MSP1. The patient showed gradual deterioration of respiratory function and limb weakness.

MSP is defined by the presence of two or more of the following conditions: inclusion body myositis, Paget's disease of bone, and amyotrophic lateral sclerosis (ALS)/FTD (ALS and FTD are regarded as a single spectrum) [3]. In a previous study, only 10% of patients satisfied the symptom triad, and the most common findings were myopathy (89%), PDB (43%), and FTD (29%) [4]. Muscle weakness mainly occurs in the limb-girdle region, but axial, distal dominant, and facial/tongue weakness may also be observed. In most cases, FTD is behavioral variant FTD with personality change and behavior problems [5]. Our patient showed impairment in word fluency and the Go-No-Go test, indicating a problem in executive function. The muscle pathology in MSP1 varies from nonspecific myopathy to rimmed vacuoles containing TDP-43 (TAR DNA binding protein 43) and p62 aggregates, with appearance of neurogenic/myopathic changes in some cases [1]. The c.464G>A (p.Arg155His) heterozygous mutation was found in one case of a Korean individual who presented with axial muscle weakness; another case series included a Korean family and had the same mutation (c.463C>T, p.Arg155Cys), as reported in the current study. Muscle biopsy results in the above cases ranged from normal to demonstrating fiber size variation, fat infiltration, and angulated atrophic fibers [6,7].

A lobulated myofiber exhibits an irregular cytoarchitectural pattern wherein normal lattice-shaped fibers form an abnormal spatial distribution of the intermyofibrillar mitochondria network [8,9]. This finding is observed in various neuromuscular diseases such as limb-girdle muscular dystrophy type 2A, facioscapulohumeral muscular dystrophy, and nemaline myopathy [8,10]. Regarding the VCP gene, Liewluck et al. first reported a patient with heterozygous c.1160G > A resulting in p. Asn387Ser substitution who presented myopathic symptom only; the biopsy showed fiber size variation, lobulated fiber without rimmed vacuole and intracellular deposit [11]. Thus, this is the first report on the possibility of lobulated myofibers in MSP1 patients with multisystem involvement.

Because of the diversity of clinical manifestations of MSP1 involving multiple systems, diagnosis can be challenging. However, acknowledging that unique muscle biopsy findings may be present when MSP1 is suspected through careful history-taking and neurological examinations, patients could benefit from timely genetic testing for early diagnosis and effective management.