Titinopathy is a group of muscle diseases caused by defects in the titin gene (TTN). With its 364 exons (gene segments), the TTN gene is the longest gene in the human body. It describes the protein titin.
… is found in the heart and skeletal muscle. It is a component of the smallest contractile unit of the musculature, the so-called sarcomere. A titin molecule connects the Z-disc on the outer edge of the sarcomere with the myosin in the middle of the sarcomere. It thus ensures that myosin and actin are parallel to each other, which allows muscle contraction. Titin ensures the elasticity and stability of the sarcomere during contraction and the resting phase of the muscle. Changes or a lack of this protein can therefore lead to muscle weakness.
Variants in the TTN gene can lead to various clinical pictures. Some of these diseases are associated with symptoms that appear in the womb or shortly after birth, while others do not develop until later in life. The diseases also progress at different rates and vary in severity. Both the skeletal and cardiac muscles can be affected. The inheritance of titinopathies, TTN-related diseases that affect the skeletal muscles, is usually recessive (both parents are carriers). Dilated cardiomyopathy, on the other hand, is inherited dominantly (one parent is sufficient to carry the trait).
The following diseases can occur due to variants in the TTN gene:
Tibial muscular dystrophy is inherited dominantly (mutation in exon 364) and only occurs in adulthood. It progresses slowly and mainly affects the lower legs.
(HMERF is inherited both dominantly and recessively and only becomes pronounced in adulthood. The cause of the disease is often a missense mutation in exon 344. HMERF is often associated with a weakening of the respiratory muscles and fatty degeneration of certain muscle areas.
Both myopathies are inherited recessively. They are usually caused by variants in exons 362-364. The first symptoms usually appear in childhood or early adulthood. Proximal myopathy is a progressive disease that primarily affects the upper and lower extremities close to the body. Distal myopathy progresses slowly and mainly affects the lower legs.
Congenital myopathy is inherited in a recessive manner. The symptoms often appear before birth. The causes are mainly truncating variants that lead to the titin protein being shortened or not produced in sufficient quantities. Symptoms include hypotonia, contractures, respiratory insufficiency, heart problems and fatty degeneration of the leg muscles. A table of typical characteristics and motor milestones can be found here: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.25241 (page 6).
Some of the congenital titinopathies belong to the centronuclear myopathies. Typical characteristics are weakness of the muscles in the face, the limbs close to the body and, in some cases, the limbs far from the body. A clear table can be found here: http://www.joshuafrase.org/uploads/2013,%20Titin%20Gene%20Found.pdf (page 3).
Congenital joint stiffness can occur even before birth. This disorder is often caused by a combination of mutations, one of which is located in a so-called ‘meta-only’ exon (these exons are only considered relevant during fetal development). It is recognizable by low fetal movements during pregnancy, symmetrical contractures and severe axial hypotonia. The heart muscles are usually not primarily affected.
Variants in the TTN gene also cause cardiomyopathies. Dominantly inherited dilated cardiomyopathy is particularly common. 15-25% of these diseases are caused by TTN variants. This leads to a progressive enlargement of the left ventricle, which reduces the heart’s pumping capacity and can cause cardiac arrhythmia. To treat these symptoms, there are drugs to regulate blood pressure, permanently implantable ventricular assist devices (VAD) or heart transplants.
There are currently no drug therapies for titinopathy. With the support of ZNM, it is hoped that research projects can be supported in the near future that will lead to treatment options for those affected.
In English-speaking countries, information on titinopathy is available from Team Titin.
The association provides
– the very good English-language overview “Recessive Titinopathy“
– the website titinmyopathy.com and
– the Facebook discussion group TeamTitin
. Team Titin is coordinated by Sarah Foye from the USA. We at ZNM – Zusammen Stark! e. V. cooperate with Sarah and have some plans for the future.
An international patient registry for congenital myopathies can be found at www.cmdir.org. Patient registries serve as a source of information for researchers, for planning clinical studies and to find out more about the course of the disease in those affected. Patients with titinopathy can also participate here.
Nora & Thomas | ttn@znm-zusammenstark.org
Judith Wartenburger
Assistant to the board of
ZNM – Together Strong! e.V
Tel.: 01515 4820534
Email: judith.wartenburger@znm-zusammenstark.org
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