소엽모양 근섬유를 보이는 VCP관련 다계통단백질병

VCP-related Multisystem Proteinopathy Presenting with Lobulated Myofibers

Article information

Korean J Neuromuscul Disord. 2024;16(1):17-19
Publication date (electronic) : 2024 June 30
doi : https://doi.org/10.46518/kjnmd.2024.16.1.17
1Department of Neurology, Jeonbuk National University College of Medicine, Jeonju, Korea
2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
3Department of Neurology, Seoul National University College of Medicine, Seoul, Korea
채주희1, 박성혜,2, 성정준,3
1전북대학교 의과대학 신경과학교실
2서울대학교 의과대학 병리학교실
3서울대학교 의과대학 신경과학교실
Address for correspondence: Jung-Joon Sung, MD, PhD Department of Neurology, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-1707, Fax: +82-2-3672-7553, E-mail: jjsaint@snu.ac.kr
Sung-Hye Park, MD, PhD Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-3090, Fax: +82-2-743-5530, E-mail: shparknp@snu.ac.kr
Received 2023 December 3; Revised 2024 June 14; Accepted 2024 June 24.

Trans Abstract

Valosin-containing protein (VCP)-related multisystem proteinopathy (MSP1) is a rare genetic disorder marked by abnormal protein accumulation. This study presents the case of a 52-year-old woman with MSP1, showing progressive weakness, gait disturbances, and respiratory muscle weakness over five years. The clinical examination revealed diverse presentations, including neurogenic changes in electrophysiologic study, multifocal fatty changes of muscle, and cognitive impairment with a confirmed VCP gene mutation through genetic testing. Notably, we identified lobulated myofibers in the muscle biopsy, an unusual finding in MSP1. This is the first report of lobulated myofibers in MSP1 with multisystem involvement. Identifying unique muscle biopsy results in suspected MSP1 patients through careful neurological examinations and timely genetic testing may help in early diagnosis and appropriate management.

Multisystem proteinopathy (MSP) is a rare genetic disorder characterized by the formation of abnormal protein aggregates and their accumulation in various tissues and organs. Valosincontaining protein (VCP) related multisystem proteinopathy, suggested as multisystem proteinopathy 1 (MSP1), is caused by mutations in the VCP gene on chromosome 9p13–p12; also known as inclusion body myopathy with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD (Inclusion Body Myopathy With Early-Onset Paget Disease) [1]. MSP1 leads to the accumulation of cytoplasmic proteins in vacuoles and inclusion bodies in muscles, bones, and the central nervous system. While the diversity of mutations and clinical phenotypes, there is a paucity of research on this disease. A recent study suggests that MSP1 may coexist with other neurological disorders [2]. Moreover, its prevalence may be higher due to misdiagnosis with diseases having similar symptoms. This study aims to report an unusual muscle biopsy finding in an MSP1 patient with VCP mutations presenting with various phenotypes in the context of multisystem involvement.

Case

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.

Fig. 1.

(A) Hematoxylin and eosin (H&E)-stained section of muscle tissue shows marked size variation of myofibers with rimmed vacuole (arrow) (bar=20 μm). (B) Lobulated myofibers (asterisk marks) are frequently noted (H&E; bar=50 μm). (C) The modified Gomori stain shows rimmed vacuoles (arrows) (bar=50 μm). (D) Ultrastructurally, several large myelin figures are seen, consistent with rimmed vacuoles (bar=2 μm). (E) Rimmed vacuoles and cytoplasmic inclusions consisting of phosphorylated TDP-43. (F) Rimmed vacuoles and cytoplasmic inclusions consisting of ubiquitin-positive aggregates. (G) Computed tomography (CT) of muscle shows atrophy of gluteus muscles (arrows). (H) Left vastus lateralis (arrow) and muscles of the posterior thigh (arrow) are also atrophied in muscle CT.

Discussion

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.

Acknowledgements

This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korean Government (Ministry of Science and ICT) (NRF-2019M3C7A1031867).

Notes

All authors have no conflicts of interest.

References

1. Evangelista T, Weihl CC, Kimonis V, Lochmüller H, ; VCP related diseases Consortium. 215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13-15 November 2015, Heemskerk, The Netherlands. Neuromuscul Disord 2016;26:535–547.
2. Chompoopong P, Oskarsson B, Madigan NN, Mirman I, Martinez-Thompson JM, Liewluck T, et al. Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathologicalmolecular spectrum. Ann Clin Transl Neurol 2023;10:632–643.
3. Taylor JP. Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration. Neurology 2015;85:658–660.
4. Al-Obeidi E, Al-Tahan S, Surampalli A, Goyal N, Wang AK, Hermann A, et al. Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet 2018;93:119–125.
5. Krause S, Göhringer T, Walter MC, Schoser BG, Reilich P, Linn J, et al. Brain imaging and neuropsychology in late-onset dementia due to a novel mutation (R93C) of valosin-containing protein. Clin Neuropathol 2007;26:232–240.
6. Kim EJ, Park YE, Kim DS, Ahn BY, Kim HS, Chang YH, et al. Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family. Arch Neurol 2011;68:787–796.
7. Park YE, Lee DY, Kim NR, Shin JH, Kim DS. VCP-related inclusion body myopathy presenting with axial muscle weakness. J Korean Neurol Assoc 2020;38:231–233.
8. Figarella-Branger D, El-Dassouki M, Saenz A, Cobo AM, Malzac P, Tong S, et al. Myopathy with lobulated muscle fibers: evidence for heterogeneous etiology and clinical presentation. Neuromuscul Disord 2002;12:4–12.
9. Weller B, Carpenter S, Lochmüller H, Karpati G. Myopathy with trabecular muscle fibers. Neuromuscul Disord 1999;9:208–214.
10. Monforte M, Primiano G, Silvestri G, Mirabella M, Luigetti M, Cuccagna C, et al. Sporadic late-onset nemaline myopathy: clinical, pathology and imaging findings in a single center cohort. J Neurol 2018;265:542–551.
11. Liewluck T, Milone M, Mauermann ML, Castro-Couch M, Cerhan JH, Murthy NS. A novel VCP mutation underlies scapuloperoneal muscular dystrophy and dropped head syndrome featuring lobulated fibers. Muscle Nerve 2014;50:295–299.

Article information Continued

Fig. 1.

(A) Hematoxylin and eosin (H&E)-stained section of muscle tissue shows marked size variation of myofibers with rimmed vacuole (arrow) (bar=20 μm). (B) Lobulated myofibers (asterisk marks) are frequently noted (H&E; bar=50 μm). (C) The modified Gomori stain shows rimmed vacuoles (arrows) (bar=50 μm). (D) Ultrastructurally, several large myelin figures are seen, consistent with rimmed vacuoles (bar=2 μm). (E) Rimmed vacuoles and cytoplasmic inclusions consisting of phosphorylated TDP-43. (F) Rimmed vacuoles and cytoplasmic inclusions consisting of ubiquitin-positive aggregates. (G) Computed tomography (CT) of muscle shows atrophy of gluteus muscles (arrows). (H) Left vastus lateralis (arrow) and muscles of the posterior thigh (arrow) are also atrophied in muscle CT.