Tibial muscular dystrophy (TMD) is a type of muscular dystrophy characterized by weakness and wasting (atrophy) in the tibialis anterior muscle in the lower leg, which helps with dorsiflexion (action of pulling the foot toward the shin). People with TMD experience progressive difficulty in walking and foot drop (inability to lift the front part of the foot).

In general, the symptoms of TMD starts to appear in mid-life, after ages 35 to 40. But in some cases, it may go unnoticed even in the elderly.

What causes TMD?

TMD is caused by mutations in the titin (TTN) gene. The titin protein encoded by this gene plays an important role in the contraction and relaxation of muscles. It is the largest protein in the sarcomeres, the basic units of a muscle.

Titin functions as a molecular blueprint that specifies and coordinates the precise assembly of the structural, regulatory, and contractile proteins that compose the sarcomere. It also acts as a molecular spring that helps maintain the integrity of muscles during contraction, relaxation, and stretching. Finally, it serves as a mechano-sensor that integrates various signaling pathways that induce the contraction, relaxation, or stretching of muscles.

Mutations in the TTN gene alter the structure and function of the titin protein and disrupt its interactions with other sarcomere-related proteins. This causes the muscles to weaken and waste away over time. The mutations may also disrupt the signaling function of titin.

Research has shown that a biological pathway in the muscles of people with TMD, called the unfolded protein response (UPR) pathway, is overactive. This pathway controls the turnover and degradation of proteins within the muscle cells, so that its overactivity results in the degeneration and loss of muscle fibers.

How is TMD inherited?

Everyone has two copies of each gene, one inherited from the mother and one from the father. TMD is inherited in an autosomal dominant fashion, which means that one mutated copy of the gene is sufficient to cause the disorder.

People with TMD have a 50 percent chance of passing on the disease onto their children, and a 50 percent chance of having children unaffected by the disease.

Types of titin mutations

Several mutations in the TTN gene associated with TMD have been identified. The first reported TTN mutation was an 11 “letter” change in the last part of the gene. This changes four amino acids at the end of the titin protein. (Amino acids are building blocks of proteins encoded by nucleotides, or letters, contained in the DNA). Because it was first identified in several Finnish families, the mutation is called FINmaj.

Several other mutations have since been reported in families from Italy, Belgium, Spain, France, and Finland. These mutations include:

  • Missense mutations, which are single-letter changes in the DNA that change the amino acid sequence of the titin protein
  • Nonsense mutations, which are als0 a single letter change but ones that introduce a premature stop signal in the DNA. This causes the cell’s protein-making machinery to stop making titin protein midway.
  • Deletions, or missing letters, that result in a frameshift, thus changing the whole amino acid sequence of the titin protein. (The genetic code contained inside the DNA is read in letters of three by the protein-making machinery of the cell. If one letter is missing — or added — the whole reading frame of the DNA sequence is changed).

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