Tibial muscular dystrophy
| Tibial muscular dystrophy | |
|---|---|
| Other names | Udd (Distal) Myopathy, Tardive tibial muscular dystrophy, Udd-Markesbery muscular dystrophy[1] |
| Selected MR images from different patients with TMD. Tibialis anterior (TA) is early involved, even in patients with minimal fat replacement (A). Generally tibialis anterior is severely involved (B–D). Extensor digitorum longus (EDL) is assymetrically involved. Some patients have assymetric and non-homogeneous involvement of soleus (SOL) and gastrocnemius (GM). Axial images from pelvis and thigh of four different patients. Notice the asymmetry and very selective involvement of some muscles. The involvement of gluteus minimus (Gmin) that could be mild (G) / severe (E). Gluteus medium (GMed) could also be involved (E). Semimembranosus (SM), semitendinosus (ST) and biceps femoris (BFSH-short head and BFLH—long head) are the other most commonly involved muscle outside the leg. Some patients may have severe atrophy of rectus femoris (RF). | |
| Specialty | Neurology |
| Symptoms | Weakness and atrophy of tibialis anterior, extensor digitorum longus, extensor hallucis longus |
| Usual onset | 35-55 years |
| Prognosis | Patients usually remain ambulant, although some of them need mobility aids |
Tibial muscular dystrophy (TMD) (also known as Udd myopathy) is a rare hereditary disorder, which is caused by a mutation in a gene TTN.[2] TMD usually begins at the age of 35-55 years and the disease progresses slowly.[3] The disorder causes weakness and atrophy of tibialis anterior, extensor digitorum longus, extensor hallucis longus.[3] TMD is an autosomal dominant condition.[4]
TMD is most common in Finland, which is estimated to be 15:100,000 individuals due to founder effect.[4]
Symptoms
Usually patients first experience weakness of dorsiflexion of feet and incapability to walk on the heels, because of atrophy of anterior compartment of leg . Later (usually after 10 to 20 years), patients experience weakness in long toe extensors, which causes foot drop.[4]
In atypical cases, there's proximal lower limb weakness with/without posterior calf muscle weakness.[5]
Diagnosis
The diagnosis of TMD is suspected by its typical findings, and confirmed by finding monoallelic mutations in the last exon of TTN gene by genetic testing.[4] Serum creatine kinase values are usually normal or slightly raised, also in MRI/CT of the leg, shows fatty degeneration of tibialis anterior.[6]
Cause
TMD is caused by a specific mutations in a gene TTN, which encodes protein titin.[10] TMD associated mutations are located on the last exon Mex6.[10] Finnish patients usually have a unique 11-bp indel mutation, which changes 4 amino acid residues.[11][4]
TMD cases have been documented in other countries, including France, Italy, and Belgium, with their own unique mutations.[7][8][9]
Pathophysiology
In the Finnish variant of TMD mutations, there is an abnormal cleavage of C-terminal part of titin by proteases, which causes disruption of another protease calpain-3.[12]
Also, there is an activation of ER stress, and its activation is insufficient to correct abnormalities of protein, which cause degenerative processes in TMD muscle fibres, in addition there are rimmed vacuoles with accumulation of VCP inside.[13] This causes distortion of pathways, that are related to controlling turnover and degradation (which includes autophagy), leading to muscle fibre loss.[13]
Treatment
TMD doesn't have a cure, but managing of symptoms is possible.[4] Management includes use of orthotic device, and in severe cases, tibial posterior tendon transposition, in addition, some of the patients need mobility aid.[4]
History
This disorder was first described by Bjarne Udd (and consequently named after him) and by his colleagues in 1991.[14]
References
- ^ "Tibial muscular dystrophy: MedlinePlus Genetics". medlineplus.gov. Retrieved 2026-01-04.
- ^ "Entry - #600334 - TIBIAL MUSCULAR DYSTROPHY, TARDIVE; TMD-OMIM-(OMIM.ORG)". omim.org. Retrieved 2026-02-15.
- ^ a b Evilä, Anni; Vihola, Anna; Sarparanta, Jaakko; Raheem, Olayinka; Palmio, Johanna; Sandell, Satu; Eymard, Bruno; Illa, Isabel; Rojas-Garcia, Ricard; Hankiewicz, Karolina; Negrão, Luis; Löppönen, Tuija; Nokelainen, Pekka; Kärppä, Mikko; Penttilä, Sini (2014). "Atypical phenotypes in titinopathies explained by second titin mutations". Annals of Neurology. 75 (2): 230–240. doi:10.1002/ana.24102. ISSN 1531-8249. PMID 24395473.
- ^ a b c d e f g Udd, Bjarne; Hackman, Peter (1993), Adam, Margaret P.; Bick, Sarah; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Udd Distal Myopathy – Tibial Muscular Dystrophy", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 20301498, retrieved 2026-01-04
- ^ Udd, B.; Vihola, A.; Sarparanta, J.; Richard, I.; Hackman, P. (2005-02-22). "Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J". Neurology. 64 (4): 636–642. doi:10.1212/01.WNL.0000151853.50144.82. PMID 15728284.
- ^ Norio, Reijo (2003-05-01). "The Finnish disease heritage III: the individual diseases". Human Genetics. 112 (5): 470–526. doi:10.1007/s00439-002-0877-1. ISSN 1432-1203. PMID 12627297.
- ^ a b Hackman, Peter; Vihola, Anna; Haravuori, Henna; Marchand, Sylvie; Sarparanta, Jaakko; De Seze, Jerome; Labeit, Siegfried; Witt, Christian; Peltonen, Leena; Richard, Isabelle; Udd, Bjarne (2002-07-26). "Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin". American Journal of Human Genetics. 71 (3): 492–500. doi:10.1086/342380. ISSN 0002-9297. PMC 379188. PMID 12145747.
- ^ a b Pollazzon, Marzia; Suominen, Tiina; Penttilä, Sini; Malandrini, Alessandro; Carluccio, Maria Alessandra; Mondelli, Mauro; Marozza, Annabella; Federico, Antonio; Renieri, Alessandra; Hackman, Peter; Dotti, Maria Teresa; Udd, Bjarne (2009-11-13). "The first Italian family with tibial muscular dystrophy caused by a novel titin mutation". Journal of Neurology. 257 (4): 575–579. doi:10.1007/s00415-009-5372-3. ISSN 1432-1459. PMID 19911250.
- ^ a b Van den Bergh, Peter Y. K.; Bouquiaux, Olivier; Verellen, Christine; Marchand, Sylvie; Richard, Isabelle; Hackman, P.; Udd, Bjarne (2003-07-25). "Tibial muscular dystrophy in a Belgian family". Annals of Neurology. 54 (2): 248–251. doi:10.1002/ana.10647. ISSN 0364-5134. PMID 12891679.
- ^ a b Hackman, Peter; Udd, Bjarne (2009), "Muscular Dystrophy, Tibial, Udd Myopathy", Encyclopedia of Molecular Mechanisms of Disease, Springer, Berlin, Heidelberg, pp. 1388–1390, doi:10.1007/978-3-540-29676-8_1748, ISBN 978-3-540-29676-8, retrieved 2026-01-04
- ^ Hackman, Peter; Vihola, Anna; Haravuori, Henna; Marchand, Sylvie; Sarparanta, Jaakko; de Seze, Jerome; Labeit, Siegfried; Witt, Christian; Peltonen, Leena; Richard, Isabelle; Udd, Bjarne (2002-09-01). "Tibial Muscular Dystrophy Is a Titinopathy Caused by Mutations in TTN, the Gene Encoding the Giant Skeletal-Muscle Protein Titin". The American Journal of Human Genetics. 71 (3): 492–500. doi:10.1086/342380. ISSN 0002-9297. PMC 379188. PMID 12145747.
- ^ Charton, Karine; Sarparanta, Jaakko; Vihola, Anna; Milic, Astrid; Jonson, Per Harald; Suel, Laurence; Luque, Helena; Boumela, Imène; Richard, Isabelle; Udd, Bjarne (2015-07-01). "CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy". Human Molecular Genetics. 24 (13): 3718–3731. doi:10.1093/hmg/ddv116. ISSN 1460-2083. PMID 25877298.
- ^ a b Screen, Mark; Raheem, Olayinka; Holmlund-Hampf, Jeanette; Jonson, Per Harald; Huovinen, Sanna; Hackman, Peter; Udd, Bjarne (2014-03-11). "Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy". PLOS ONE. 9 (3) e90819. Bibcode:2014PLoSO...990819S. doi:10.1371/journal.pone.0090819. ISSN 1932-6203. PMC 3949689. PMID 24618559.
- ^ Udd, Bjarne; Kääriänen, Helena; Somer, Hannu (1991). "Muscular dystrophy with separate clinical phenotypes in a large family". Muscle & Nerve. 14 (11): 1050–1058. doi:10.1002/mus.880141103. ISSN 1097-4598. PMID 1745277.