Hereditary inclusion body myopathy (hIBM)
- Hereditary inclusion-body myopathies (hIBMs) are rare muscle disorders with autosomal recessive or dominant inheritance that are unified by the presence of rimmed vacuoles.
- Myopathies that come under the scope of hIBMs include GNE myopathy, hIBM with Paget’s disease of the bone and frontotemporal dementia (IBMPFD), hIBM with congenital joint contractures and external ophthalmoplegia (IBMCJCEO), proximal myopathy with ophthalmoplegia (PMO), and isolated inclusion-body myopathy (IIBM).
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Among the hIBMs, autosomal recessive GNE myopathy (Nonaka myopathy) is the most frequent. GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) protein is encoded by the GNE gene located on chromosome 9p13.3. GNE is the rate-limiting enzyme in the biosynthesis of sialic acids. Mutations in the GNE gene cause abnormality in sialylation of glycoproteins that may culminate in muscle fiber degeneration.
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The VCP (valosin-containing protein) gene located on chromosome 9p13-p12 encodes the protein VCP. Under normal circumstances, VCP sequesters ubiquitinated proteins and plays a key role in autophagy. Mutations in the VCP gene have been implicated in autosomal dominant IBMPFD, amyotrophic lateral sclerosis (ALS), and Charcot-Marie-Toot disease type 2 (CMT2).
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The MYH2 (Myosin Heavy Chain II) gene located on chromosome 17p13.1 encodes a member of the myosin class IIa heavy chains and plays a vital role in skeletal muscle contraction. Mutations in the MYH2 gene have been linked to autosomal dominant IBMCJCEO and autosomal dominant and recessive PMO.
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The HNRNPA1 (heterogeneous nuclear ribonucleoprotein A1) gene located on chromosome 12q13.13 encodes for a family of proteins hnRNPs. These proteins bind to pre-mRNAs in the nucleus and influence pre-mRNA processing, metabolism, and transport. Mutations in this gene have been associated with ALS and IIBM.
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The IIBM patients are middle aged and have an LGMD phenotype in the absence of neurogenic or inflammatory myopathy features on muscle biopsy.
References
- Gaspar BL, Vasishta RK, Radotra BD. Myopathology: A Practical Clinico-Pathological Approach to Skeletal Muscle Biopsies. Springer Nature: Singapore, 2019.
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