We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.
References
[1]
Nonaka I, Sunohara N, Ishiura S, Satoyoshi E (1981) Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 51: 141–155.
[2]
Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, et al. (2002) Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 59: 1689–1693.
[3]
Horowitz SH, Schmalbruch H (1994) Autosomal dominant distal myopathy with desmin storage: a clinicopathologic and electrophysiologic study of a large kinship. Muscle Nerve 17: 151–160.
[4]
Saavedra-Matiz CA, Chapman NH, Wijsman EM, Horowitz SH, Rosen DR (2000) Linkage of hereditary distal myopathy with desmin accumulation to 2q. Hum Hered 50: 166–170.
[5]
Goldfarb LG, Park KY, Cervenakova L, Gorokhova S, Lee HS, et al. (1998) Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet 19: 402–403.
[6]
Argov Z, Yarom R (1984) "Rimmed vacuole myopathy" sparing the quadriceps. A unique disorder in Iranian Jews. J Neurol Sci 64: 33–43.
[7]
Jay CM, Levonyak N, Nemunaitis G, Maples PB, Nemunaitis J (2009) Hereditary Inclusion Body Myopathy (HIBM2). Gene Regul Syst Bio 3: 181–190.
[8]
Eisenberg I, Hochner H, Shemesh M, Levi T, Potikha T, et al. (2001) Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13. Eur J Hum Genet 9: 501–509.
[9]
Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, et al. (2001) The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 29: 83–87.
[10]
Darin N, Kyllerman M, Wahlstrom J, Martinsson T, Oldfors A (1998) Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles. Ann Neurol 44: 242–248.
[11]
Martinsson T, Darin N, Kyllerman M, Oldfors A, Hallberg B, et al. (1999) Dominant hereditary inclusion-body myopathy gene (IBM3) maps to chromosome region 17p13.1. Am J Hum Genet 64: 1420–1426.
[12]
Martinsson T, Oldfors A, Darin N, Berg K, Tajsharghi H, et al. (2000) Autosomal dominant myopathy: missense mutation (Glu-706–> Lys) in the myosin heavy chain IIa gene. Proc Natl Acad Sci U S A 97: 14614–14619.
[13]
Weihl CC, Pestronk A, Kimonis VE (2009) Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia. Neuromuscul Disord 19: 308–315.
[14]
Kovach MJ, Waggoner B, Leal SM, Gelber D, Khardori R, et al. (2001) Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab 74: 458–475.
[15]
Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, et al. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36: 377–381.
[16]
Gilchrist JM, Pericak-Vance M, Silverman L, Roses AD (1988) Clinical and genetic investigation in autosomal dominant limb-girdle muscular dystrophy. Neurology 38: 5–9.
[17]
Starling A, Kok F, Passos-Bueno MR, Vainzof M, Zatz M (2004) A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Eur J Hum Genet 12: 1033–1040.
[18]
Sandell S, Huovinen S, Sarparanta J, Luque H, Raheem O, et al. (2010) The enigma of 7q36 linked autosomal dominant limb girdle muscular dystrophy. J Neurol Neurosurg Psychiatry 81: 834–839.
[19]
Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, et al. (1999) Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum Mol Genet 8: 1329–1336.
[20]
Hauser MA, Horrigan SK, Salmikangas P, Torian UM, Viles KD, et al. (2000) Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 9: 2141–2147.
[21]
Harms MB, Sommerville RB, Allred P, Bell S, Ma D, et al. (2012) Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy. Ann Neurol.
[22]
Jongen PJ, Ter Laak HJ, Stadhouders AM (1995) Rimmed basophilic vacuoles and filamentous inclusions in neuromuscular disorders. Neuromuscul Disord 5: 31–38.
[23]
Hackman P, Sandell S, Sarparanta J, Luque H, Huovinen S, et al. (2011) Four new Finnish families with LGMD1D; refinement of the clinical phenotype and the linked 7q36 locus. Neuromuscul Disord 21: 338–344.
[24]
Argov Z, D S (2002) Hereditary inclusion body myopathies. In: G Karpati, (Ed.), Structural and Molecular Basis of Skeletal Muscle Disease.ISN Neuropath Press, Basel, 274–276.
[25]
Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, et al. (2003) Hereditary inclusion body myopathy: the Middle Eastern genetic cluster. Neurology 60: 1519–1523.
[26]
Motozaki Y, Komai K, Hirohata M, Asaka T, Ono K, et al. (2007) Hereditary inclusion body myopathy with a novel mutation in the GNE gene associated with proximal leg weakness and necrotizing myopathy. Eur J Neurol 14: e14–15.
[27]
O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63: 259–266.
[28]
Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30: 97–101.
