Inclusion body myopathy 2

Inclusion body myopathy 2 is a condition that primarily affects skeletal muscles, which are muscles that the body uses for movement. This disorder causes muscle weakness that appears in late adolescence or early adulthood and worsens over time.

The first sign of inclusion body myopathy 2 is weakness of a muscle in the lower leg called the tibialis anterior. This muscle helps control up-and-down movement of the foot. Weakness in the tibialis anterior alters the way a person walks and makes it difficult to run and climb stairs. As the disorder progresses, weakness also develops in muscles of the upper legs, hips, shoulders, and hands. Unlike most forms of myopathy, inclusion body myopathy 2 usually does not affect the quadriceps, which are a group of large muscles at the front of the thigh. This condition also does not affect muscles of the eye or heart, and it does not cause neurological problems. Weakness in leg muscles makes walking increasingly difficult, and most people with inclusion body myopathy 2 require wheelchair assistance within 20 years after signs and symptoms appear.

People with the characteristic features of inclusion body myopathy 2 have been described in several different populations. When the condition was first reported in Japanese families, researchers called it distal myopathy with rimmed vacuoles (DMRV) or Nonaka myopathy. When a similar disorder was discovered in Iranian Jewish families, researchers called it rimmed vacuole myopathy or hereditary inclusion body myopathy (HIBM). It has since become clear that these conditions are variations of a single disorder caused by mutations in the same gene.

More than 200 people with inclusion body myopathy 2 have been reported. Most are of Iranian Jewish descent; the condition affects an estimated 1 in 1,500 people in this population. Additionally, at least 15 people in the Japanese population have been diagnosed with this disorder. Inclusion body myopathy 2 has also been found in several other ethnic groups worldwide.

Mutations in the GNE gene cause inclusion body myopathy 2. The GNE gene provides instructions for making an enzyme found in cells and tissues throughout the body. This enzyme is involved in a chemical pathway that produces sialic acid, which is a simple sugar that attaches to the ends of more complex molecules on the surface of cells. By modifying these molecules, sialic acid influences a wide variety of cellular functions including cell movement (migration), attaching cells to one another (adhesion), signaling between cells, and inflammation.

The mutations responsible for inclusion body myopathy 2 reduce the activity of the enzyme produced from the GNE gene, which decreases the production of sialic acid. As a result, less of this simple sugar is available to attach to cell surface molecules. Researchers are working to determine how a shortage of sialic acid leads to progressive muscle weakness in people with inclusion body myopathy 2. Sialic acid is important for the normal function of many different cells and tissues, so it is unclear why the signs and symptoms of this disorder appear to be limited to the skeletal muscles.

Genetic Testing Information

• Genetic Testing Registry: GNE myopathy

Genetic and Rare Diseases Information Center

• Inclusion body myopathy 2

Patient Support and Advocacy Resources

• Disease InfoSearch
• National Organization for Rare Disorders (NORD)

Research Studies from ClinicalTrials.gov

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• NONAKA MYOPATHY; NM

Scientific Articles on PubMed

• PubMed

• Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, Mitrani-Rosenbaum S. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology. 2003 May 13;60(9):1519-23. doi: 10.1212/01.wnl.0000061617.71839.42. Citation on PubMed
• Carrillo N, Malicdan MC, Huizing M. GNE Myopathy. 2004 Mar 26 [updated 2020 Apr 9]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1262/ Citation on PubMed
• Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, Barash M, Shemesh M, Sadeh M, Grabov-Nardini G, Shmilevich I, Friedmann A, Karpati G, Bradley WG, Baumbach L, Lancet D, Asher EB, Beckmann JS, Argov Z, Mitrani-Rosenbaum S. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet. 2001 Sep;29(1):83-7. doi: 10.1038/ng718. Citation on PubMed
• Kayashima T, Matsuo H, Satoh A, Ohta T, Yoshiura K, Matsumoto N, Nakane Y, Niikawa N, Kishino T. Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE). J Hum Genet. 2002;47(2):77-9. doi: 10.1007/s100380200004. Citation on PubMed
• Malicdan MC, Noguchi S, Nishino I. Perspectives on distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy: contributions from an animal model. Lack of sialic acid, a central determinant in sugar chains, causes myopathy? Acta Myol. 2007 Dec;26(3):171-5. Citation on PubMed or Free article on PubMed Central
• Malicdan MC, Noguchi S, Nishino I. Recent advances in distal myopathy with rimmed vacuoles (DMRV) or hIBM: treatment perspectives. Curr Opin Neurol. 2008 Oct;21(5):596-600. doi: 10.1097/WCO.0b013e32830dd595. Citation on PubMed
• Mastaglia FL, Lamont PJ, Laing NG. Distal myopathies. Curr Opin Neurol. 2005 Oct;18(5):504-10. doi: 10.1097/01.wco.0000175936.23945.b6. Citation on PubMed
• Nishino I, Malicdan MC, Murayama K, Nonaka I, Hayashi YK, Noguchi S. Molecular pathomechanism of distal myopathy with rimmed vacuoles. Acta Myol. 2005 Oct;24(2):80-3. Citation on PubMed
• Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, Nagata T, Chida K, Takahashi T, Takusa Y, Ohi T, Nishimiya J, Sunohara N, Ciafaloni E, Kawai M, Aoki M, Nonaka I. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology. 2002 Dec 10;59(11):1689-93. doi: 10.1212/01.wnl.0000041631.28557.c6. Citation on PubMed
• Nonaka I, Noguchi S, Nishino I. Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy. Curr Neurol Neurosci Rep. 2005 Feb;5(1):61-5. doi: 10.1007/s11910-005-0025-0. Citation on PubMed
• Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant. Neurology. 2004 May 11;62(9):1607-10. doi: 10.1212/01.wnl.0000123115.23652.6c. Citation on PubMed