Inclusion-Body Myopathy with Paget Disease of the Bone and Frontotemporal Dementia (IBMPFD) with SCN4A Mutation: Modifying Factor or Not?

Abstract

A 56-year-old man with a family history of myopathy developed generalized muscle weakness at age 45. At age 52, he was diagnosed with inclusion-body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD), confirmed by muscle pathology and a pathogenic VCP mutation (c.464G>A, p.R155H). Concurrent testing identified a heterozygous SCN4A variant (c.215C>T, p.P72L), a known modifier in myotonic dystrophy type 2 (DM2). At age 56, neurological examination showed proximal muscle weakness (MMT grade 3), distal lower extremity weakness (grade 4–5), and areflexia. He ambulated independently with knee locking, though squatting was impossible. No myotonia or periodic paralysis was observed. Multimodal imaging captured classic IBMPFD hallmarks: skeletal muscle computed tomography (CT) showed advanced fatty degeneration of paraspinal and limb muscles; brain magnetic resonance imaging (MRI) revealed mild frontal lobe atrophy; and bone scintigraphy showed increased uptake in the lumbar spine and iliums. Although the SCN4A p.P72L variant exacerbates DM2, the patient’s three-year progression from independent walking to cane use remained consistent with the natural history of IBMPFD. This case suggests that in the presence of a robustly penetrant VCP phenotype, the SCN4A variant does not necessarily exert a clinical modifying effect.

Figure 1. Muscle computed tomography (CT) findings. The CT scan showing muscle atrophy predominantly in the proximal muscles, including the upper arms (A), paraspinal muscles (B), and thighs (C) (green arrows).

Figure 1. Muscle computed tomography (CT) findings. The CT scan showing muscle atrophy predominantly in the proximal muscles, including the upper arms (A), paraspinal muscles (B), and thighs (C) (green arrows).

Figure 2. Brain magnetic resonance imaging (MRI). T2-weighted fluid-attenuated inversion recovery (FLAIR) images showing mild atrophy in the bilateral frontal lobes (yellow arrows).

Figure 2. Brain magnetic resonance imaging (MRI). T2-weighted fluid-attenuated inversion recovery (FLAIR) images showing mild atrophy in the bilateral frontal lobes (yellow arrows).

Figure 3. ^99mTc-HMDP bone scintigraphy. Increased uptake suggestive of Paget disease of bone is observed in the pelvis and vertebral bodies (red arrows).

Figure 3. ^99mTc-HMDP bone scintigraphy. Increased uptake suggestive of Paget disease of bone is observed in the pelvis and vertebral bodies (red arrows).

Figure 4. Muscle biopsy findings. (A) On hematoxylin and eosin (H&E) staining, mild variation in muscle fiber size is observed, together with endomysial fibrosis (black arrows), fibers with centrally located nuclei (white arrows), and fibers containing vacuoles (red arrows). (B) On modified Gomori trichrome staining, fibers with rimmed vacuoles are noted (red arrows). The histopathological findings in Figure 4, including variation in muscle fiber size and internalized nuclei, reflect a chronic myopathic process [1,2]. The hallmark feature is the presence of rimmed vacuoles (RVs), which represent a fundamental failure in autophagosome maturation [3,4]. Unlike sporadic inclusion-body myositis (sIBM), this case lacks significant inflammatory infiltration, a key diagnostic separator for VCP-associated disease [1,2].

Figure 4. Muscle biopsy findings. (A) On hematoxylin and eosin (H&E) staining, mild variation in muscle fiber size is observed, together with endomysial fibrosis (black arrows), fibers with centrally located nuclei (white arrows), and fibers containing vacuoles (red arrows). (B) On modified Gomori trichrome staining, fibers with rimmed vacuoles are noted (red arrows). The histopathological findings in Figure 4, including variation in muscle fiber size and internalized nuclei, reflect a chronic myopathic process [1,2]. The hallmark feature is the presence of rimmed vacuoles (RVs), which represent a fundamental failure in autophagosome maturation [3,4]. Unlike sporadic inclusion-body myositis (sIBM), this case lacks significant inflammatory infiltration, a key diagnostic separator for VCP-associated disease [1,2].

Figure 5. Results of Sanger sequencing. (A) Analysis of the VCP gene revealed a heterozygous c.464G>A variant in exon 5 (NM_007126.5), which results in a p.R155H amino acid substitution. This p.R155H variant is a well-established pathogenic variant strongly associated with VCP-associated multisystem proteinopathy, including inclusion-body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) or the scapuloperoneal syndrome [1,4,5,6,7,8,9,10,11,12,13]. (B) Analysis of the SCN4A gene identified a heterozygous c.215C>T (p.P72L) variant in exon 1 (NM_000334.4). According to gnomAD [14], this variant is extremely rare (allele frequency: 0.006%) and is currently classified as a variant of uncertain significance (VUS) based on the American College of Medical Genetics and Genomics (ACMG) criteria [15]. Although the amino acid substitution preserves the nonpolar property (proline to leucine), it eliminates the structural constraint unique to proline residues, potentially affecting local protein folding. Functional studies of the SCN4A p.P72L variant demonstrated a hyperpolarizing shift in the voltage dependence of channel activation, suggesting increased membrane excitability [16]. Although the role of SCN4A variants as clinical modifiers has been established in myotonic dystrophy type 2 (DM2) by enhancing membrane hyperexcitability, their impact on other neuromuscular disorders remains to be elucidated [16,17]. Crucially, the modifier effect of SCN4A in DM2 relies on an additive interaction with an underlying channelopathy background (i.e., CLC-1 dysfunction) [17]. In contrast, IBMPFD is fundamentally a degenerative proteinopathy driven by impaired protein homeostasis and autophagy, lacking a primary ion channel defect [1,2,3,5,7,11,18,19]. Therefore, the increased electrical excitability conferred by the SCN4A variant is unlikely to interact with or accelerate the proteotoxic and vacuolar degenerative pathways characteristic of VCP disease. In our patient, despite the presence of the SCN4A p.P72L variant, the clinical phenotype was entirely representative of classic IBMPFD, with no additional myotonic or atypical features. This suggests that in the context of VCP-associated disease, this SCN4A variant represents an incidental co-occurrence rather than a substantial clinical modifier. Ultimately, this case underscores the indispensable role of comprehensive clinical and radiological phenotyping in interpreting complex genetic findings in the genomic era. Further studies are warranted to accumulate and evaluate the potential modifying effects of SCN4A variants across a broader range of non-myotonic muscle diseases.

Figure 5. Results of Sanger sequencing. (A) Analysis of the VCP gene revealed a heterozygous c.464G>A variant in exon 5 (NM_007126.5), which results in a p.R155H amino acid substitution. This p.R155H variant is a well-established pathogenic variant strongly associated with VCP-associated multisystem proteinopathy, including inclusion-body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) or the scapuloperoneal syndrome [1,4,5,6,7,8,9,10,11,12,13]. (B) Analysis of the SCN4A gene identified a heterozygous c.215C>T (p.P72L) variant in exon 1 (NM_000334.4). According to gnomAD [14], this variant is extremely rare (allele frequency: 0.006%) and is currently classified as a variant of uncertain significance (VUS) based on the American College of Medical Genetics and Genomics (ACMG) criteria [15]. Although the amino acid substitution preserves the nonpolar property (proline to leucine), it eliminates the structural constraint unique to proline residues, potentially affecting local protein folding. Functional studies of the SCN4A p.P72L variant demonstrated a hyperpolarizing shift in the voltage dependence of channel activation, suggesting increased membrane excitability [16]. Although the role of SCN4A variants as clinical modifiers has been established in myotonic dystrophy type 2 (DM2) by enhancing membrane hyperexcitability, their impact on other neuromuscular disorders remains to be elucidated [16,17]. Crucially, the modifier effect of SCN4A in DM2 relies on an additive interaction with an underlying channelopathy background (i.e., CLC-1 dysfunction) [17]. In contrast, IBMPFD is fundamentally a degenerative proteinopathy driven by impaired protein homeostasis and autophagy, lacking a primary ion channel defect [1,2,3,5,7,11,18,19]. Therefore, the increased electrical excitability conferred by the SCN4A variant is unlikely to interact with or accelerate the proteotoxic and vacuolar degenerative pathways characteristic of VCP disease. In our patient, despite the presence of the SCN4A p.P72L variant, the clinical phenotype was entirely representative of classic IBMPFD, with no additional myotonic or atypical features. This suggests that in the context of VCP-associated disease, this SCN4A variant represents an incidental co-occurrence rather than a substantial clinical modifier. Ultimately, this case underscores the indispensable role of comprehensive clinical and radiological phenotyping in interpreting complex genetic findings in the genomic era. Further studies are warranted to accumulate and evaluate the potential modifying effects of SCN4A variants across a broader range of non-myotonic muscle diseases.