Tibial muscular dystrophy
Tibial muscular dystrophy '' is a rare hereditary disorder, which is caused by a mutation in a gene TTN. TMD usually begins at the age of 35-55 years and the disease progresses slowly. The disorder causes weakness and atrophy of tibialis anterior, extensor digitorum longus, extensor hallucis longus.
TMD is most common in Finland, which is estimated to be 15:100,000 individuals due to founder effect.
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, patients experience weakness in long toe extensors, which causes foot drop.In atypical cases, there's proximal lower limb weakness with/without posterior calf muscle weakness.
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. Serum creatine kinase values are usually normal or slightly raised, also in MRI/CT of the leg, shows fatty degeneration of tibialis anterior.Cause
TMD is caused by a specific mutations in a gene TTN, which encodes protein titin. TMD associated mutations are located on the last exon Mex6. Finnish patients usually have a unique 11-bp indel mutation, which changes 4 amino acid residues.TMD cases have been documented in other countries, including France, Italy, and Belgium, with their own unique mutations.
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.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. This causes distortion of pathways, that are related to controlling turnover and degradation, leading to muscle fibre loss.