Abstract
Tibial muscular dystrophy (TMD) or Udd myopathy is an autosomal dominant distal myopathy with late onset, at first described in the Finnish population. We report here the first Italian cases of TTN mutated titinopathy. The proband, a 60 year-old female, had the first muscular signs at the age of 59 years, with difficulty in walking and right foot drop. Muscle imaging showed selective fatty degenerative change in the anterior compartment of leg muscles. Her 67 year-old brother, started to show muscle weakness, pain at lower limbs and hypertrophy of calf muscles at the age of 66 years. Their mother began to show foot drop and impaired walking from the age of 60 years. Other relatives are reported to be affected in a similar way. Because the phenotype appeared compatible with TMD, we analyzed the TTN gene in the DNA of the proband and we identified a heterozygous mutation 293326A>C. This mutation is also present in the brother and in the other affected individuals of the same family. The mutation predicts a His33378Pro change located next to the previously known Belgian TMD mutation. The mutation was not found in 100 Italian control DNA samples. Then, since the introduction of a proline in the last domain of titin was previously known to cause TMD in French families, we can conclude that this missense mutation is the obvious pathogenetic mutation in the affected patients. No other disease causing mutations in the TTN gene have so far been reported in the Italian population.
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References
Udd B, Kaarianen H, Somer H (1991) Muscular dystrophy with separate clinical phenotypes in a large family. Muscle Nerve 14(11):1050–1058
Udd B, Partanen J, Halonen P, Falck B, Hakamies L, Heikkila H, Ingo S, Kalimo H, Kaariainen H, Laulumaa V et al (1993) Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients. Arch Neurol 50(6):604–608
de Seze J, Udd B, Haravuori H, Sablonniere B, Maurage CA, Hurtevent JF, Boutry N, Stojkovic T, Schraen S, Petit H, Vermersch P (1998) The first European family with tibial muscular dystrophy outside the Finnish population. Neurology 51(6):1746–1748
Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B (2003) Tibial muscular dystrophy in a Belgian family. Ann Neurol 54(2):248–251
Hackman P, Marchand S, Sarparanta J, Vihola A, Penisson-Besnier I, Eymard B, Pardal-Fernandez JM, el Hammouda H, Richard I, Illa I, Udd B (2008) Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Neuromuscul Disord 18(12):922–928
Haravuori H, Vihola A, Straub V, Auranen M, Richard I, Marchand S, Voit T, Labeit S, Somer H, Peltonen L, Beckmann JS, Udd B (2001) Secondary calpain3 deficiency in 2q-linked muscular dystrophy: titin is the candidate gene. Neurology 56(7):869–877
Udd B, Vihola A, Sarparanta J, Richard I, Hackman P (2005) Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J. Neurology 64(4):636–642
Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A (2007) C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol 61(4):340–351
Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A (1999) Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun 262(2):411–417
Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet 30(2):201–204
Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M (2005) The kinase domain of titin controls muscle gene expression and protein turnover. Science 308(5728):1599–1603
Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71(3):492–500
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An erratum to this article is available at http://dx.doi.org/10.1007/s00415-009-5422-x.
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Pollazzon, M., Suominen, T., Penttilä, S. et al. The first Italian family with tibial muscular dystrophy caused by a novel titin mutation. J Neurol 257, 575–579 (2010). https://doi.org/10.1007/s00415-009-5372-3
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DOI: https://doi.org/10.1007/s00415-009-5372-3