Tibial muscular dystrophy (TMD) is a distal myopathy characterized by weakness of the muscles of anterior compartment of lower limbs, appearing in the fourth to seventh decade of life. TMD is caused by mutations in the titin gene. The inheritance is usually autosomal dominant but recessive forms have been identified recently.
TMD is highly prevalent in Finland (1/5000) due to a founder mutation, making it the most common muscle disease in Finland. The disease has also been rarely identified in families in several other European countries.
TMD manifests after the age of 35 to 40 (rarely after 60 years) as slowly progressive weakness and atrophy of anterior tibial muscles with decreased dorsiflexion. Muscle involvement may remain asymmetrical for many years. After about 10 to 20 years, long toe extensors become involved causing foot drop, tripping and clumsiness while walking. Proximal limb muscles, mainly hamstring muscles, may get involved after the age of 60 to 70 and may necessitate the use of a cane and reduced walking distances. Extensor digitorum brevis muscles are spared and involvement of upper limb is very rare. Neither cardiomyopathy nor respiratory failure has been encountered. TMD may present in a mild form (may remain unnoticed even in elderly individuals) or as aberrant phenotypic forms in about 9% of cases (proximal leg or posterior lower leg muscle involvement even at onset).
TMD is linked to mutations in the TTN gene (2q31) encoding the protein Titin. The Finnish founder mutation (FINmaj) is located in the last exon 363(Mex6). Atypical presentations in Finnish patients have recently been explained by modifying second mutations in TTN. Seven other mutations of the TTN gene causing TMD have been identified in non-Finnish populations of which some C-terminal titin mutations can be recessive, manifesting the disease in homozygosity or in compound heterozygosity (usually with recessive truncating titin mutations). FINmaj mutation in homozygosity or in combination with truncating recessive titin mutations causes early onset autosomal recessive limb girdle muscular dystrophy (LGMD2J, see this term).
Mode of inheritance of typical TMD is autosomal dominant with 50% risk of transmission to offspring while some forms of TMD may be autosomal recessive.
Last update: March 2014
- Dr Johanna PALMIO
- Pr Bjarne UDD