- Donate
- Understanding Rare Disease
- Living with a Rare Disease
- Community Support
- Advancing Research
- Driving Policy
- Get Involved
- Rare Disease News
- Resource Library
- About Us
- For Clinicians & Researchers
- For Patient Organizations
Last updated: 5/23/2024
Years published: 2024
NORD gratefully acknowledges Sarah Foye, President, Team Titin, Inc., Joelle Robinson, DO candidate, Touro College of Osteopathic Medicine, Bjarne Udd, MD, PhD, Professor, Tampere Neuromuscular Center and Folkhรคlsan Research Center, Helsinki, Finland, Jennifer Roggenbuck, MS, CGC, Associate Professor, The Ohio State University Wexner Medical Center, Columbus, Ohio, Diane Fatkin, Professor Molecular Cardiologist, Dr. Renee Johnson, PhD, FHGSA, Victor Chang Cardiac Research Institute, St Vincentโs Hospital Sydney, and Dr. Leslie Hayes, MD, Boston Childrenโs Hospital for the preparation of this report.
Summary
Dominant titinopathy is a group of progressive conditions caused by disease-causing variants in the TTN gene. This gene makes a protein called titin, which is essential for the structure and function of the heart and skeletal muscles. Everyone has two copies of the TTN gene. Individuals with dominant titinopathy have one disease-causing TTN gene variant.
The most common symptoms of dominant titinopathy depend on whether the most affected muscle groups are cardiac versus skeletal. For people with heart muscle disease, this includes shortness of breath, palpitations, fatigue, or explained weight gain or leg swelling. For people who mainly have skeletal muscle involvement, there can be trouble walking or weakness in arm, leg or breathing muscles, limited range of motion of a joint (contractures) or curvature of the spine (scoliosis). The age of onset for dominant titinopathy can vary with most patients being diagnosed during adulthood. The severity of the condition and rate of progression are also hugely variable. The mechanisms that underlie this variability are not completely understood and appear to involve factors such as the location and type of genetic change as well as additional patient-related factors such as other illnesses and lifestyle.
There is wide diversity with the dominant titinopathy subtypes. Researchers do not fully understand all its forms and new ones continue to emerge. This diversity and complexity are a result of the giant size of the TTN gene. Researchers are still working to understand if some dominant forms are truly dominant, psuedodominant or a result of a combination of variants in 2 different genes (e.g. SRPK3 and TTN).
The diagnosis of dominant titinopathy requires the identification of heart or skeletal muscle dysfunction, together with genetic testing to identify a TTN gene variant. Clinical and genetic screening of family members may also be indicated. There are no specific treatments for this disorder and standard medical management is based on the presence and severity of heart and/or skeletal muscle dysfunction.
Introduction
There are several different dominantly inherited forms of titinopathy (dominant titinopathies) that can result from single disease-causing variants in just one copy of the TTN gene. These result in a range of heart and muscle problems that can typically develop in adulthood. Examples include:
Dilated Cardiomyopathy
DCM is one of the most common forms of dominant titinopathy. This is a primary disorder of the heart which is characterized by enlargement and reduced pumping action of the left (ยฑ right) ventricle. The clinical presentation of TTN-related DCM can include symptoms and signs of heart failure, such as shortness of breath, fatigue and leg swelling. However, some patients with DCM have no symptoms and the diagnosis is made during routine heart testing. Affected individuals may experience palpitations, dizzy spells or blackouts if there are abnormal heart rhythms coming from the atria or ventricles. DCM can occur at any age in people who have a TTN gene variant, but mostly occurs in mid-adult life. If untreated, DCM progresses, and some individuals may need implantable cardioverter-defibrillators or heart transplants. Many individuals have DCM as an isolated finding; however, DCM may also develop over time in people who initially present with skeletal muscle dysfunction.
Skeletal Myopathy
Dominant titinopathies can affect skeletal muscle in different ways. Some people can show severe symptoms, while some may not. Dominant titinopathy can present at any time, but skeletal features most often appear in adolescence. Symptoms usually start in the hands and feet (distal weakness) and later affect the large muscles closer to the body. Symptoms include muscle weakness, difficulty walking, difficulty moving the hands and feet and limitations in the range of motion of joints (contractures). Fatigue is also commonly seen. Oftentimes people will lift their foot high off the ground when moving (steppage gait) or have unusually high arches (pes cavus). As symptoms get worse, it may be difficult to breathe or hold oneself upright. Sometimes eating or chewing may be affected as well. A muscle enzyme called creatine kinase (CK) is sometimes elevated though it can be normal. Some of the sub-types of skeletal myopathy have specific clinical features (outlined below).
Hereditary Myopathy with Early Respiratory Failure (HMERF)
HMERF typically presents with variable breathing difficulties (respiratory insufficiency) beginning in middle age. There are problems with breathing muscles that can make it difficult to complete daily activities such as exercising, walking up stairs, or sleeping through the night. Another common first sign is a difficulty flexing ankles or โfoot dropโ, which may lead to falls. Many people experience weakness in the muscles around the hips (pelvic girdle weakness). Some patients also find it difficult to flex their fingers, quadriceps and neck. There may be changes in the size of the calf muscles. CK is typically mildly elevated but can be normal. The variants in TTN that are typically associated with HMERF fall in a particular region of the gene called the 119th fibronectin-3 domain.
Tibial Muscular Dystrophy (TMD, Udd Myopathy)
Tibial muscular dystrophy presents around the ages of 40 or 50 years with thinning and weakness of the muscles on the anterior shin that lift the foot. This โfoot dropโ can lead to increased falls and tripping. Over time, thigh and pelvic girdle muscles may also become weaker, leading to a โwaddling gaitโ, but arms remain unaffected. TMD does not lower the expected lifespan of someone with the disease. CK levels are typically normal or slightly elevated. There is a higher incidence of this disease in the Finnish population due to a common TTN variant known to cause TMD.
Other Dominant Titinopathies
Other single TTN variants have led to a spectrum of muscle disorders. There are some early onset clinical presentations with neonatal or infant weakness with early contractures (sometimes called arthrogryposis) and some later onset presentations similar to those described above. Some patients have cardiac disease, but not all.
Dominant titinopathies are caused by disease-causing (classified as pathogenic or likely-pathogenic) variants in the TTN gene. The TTN gene provides instructions to make a very large protein called titin. The titin protein is important for muscles to function properly. Together with other proteins the body makes, titin helps muscle to contract and relax in the correct way. Disease-causing variants in the TTN gene alter the amount and/or function of the titin protein produced by the gene. The gene variants that cause dominant titinopathies typically result in a shortened (or truncated) titin protein and are called โtruncating TTN variantsโ. More recent research has identified patients with a particular type of genetic change in the structure of the TTN DNA called a โcopy number variationโ.
The genetic variants causing dominant titinopathy follow an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) gene variant that arises in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Truncating variants in the TTN gene are the most common genetic cause of DCM, occurring in 10-25% of patients. The prevalence of dominant skeletal muscle titinopathy is unknown in populations other than Finland where 1/2,000 of the original population carry the founder gene variant called FINmaj.
Patients suspected of having DCM need to have a detailed medical history and physical examination to determine the extent of disease and identify any additional factors that may be contributing to heart dysfunction. It is important to take a three-generation family history to see if other relatives are affected and to determine if there is a likely pattern of inheritance in the family. The diagnosis of DCM is made by cardiac imaging techniques such as echocardiography or cardiac magnetic resonance imaging. A baseline electrocardiogram is required and additional tests such as 24-hour holter monitoring may be needed to look for cardiac arrhythmias.
Diagnosis of skeletal muscle titinopathy requires a clinical examination by a physician (often a neurologist) who will look for the signs and symptoms described above. Testing will be done to determine if there is muscle weakness in the limbs, trunk, spinal, neck and face muscles as well as the breathing muscles and heart muscle. Sometimes additional testing such as a breathing test (pulmonary function test or sleep study) is requested to check lung function. A muscle biopsy may also be done although the findings may be variable. Structural (myopathic) differences are sometimes present. In other individuals the biopsy shows dystrophic changes suggestive of ongoing muscle breakdown and regeneration. In addition, muscle imaging studies such as muscle ultrasound and/or muscle magnetic resonance imaging are sometimes used to assess which muscles are significantly impacted by the disorder. Identifying patterns of muscle involvement can help to establish the correct diagnosis since findings are distinct and very different in the different forms of dominant titinopathies.
Genetic testing for TTN gene variants is needed when there is a clinical suspicion of a dominant titinopathy. Variants in TTN can be identified through multi-gene panels or by whole exome or genome sequencing. If a disease-causing variant is identified in the patient, genetic testing can be offered to other affected and unaffected family members to find out if they have the same condition or are at risk of developing the condition in the future. Interpretation of genetic test results is not always straightforward and not all TTN gene variants cause disease. Variants that are classified as โpathogenicโ or โlikely pathogenicโ are considered to have a strong likelihood of causing disease. However, it is not uncommon for a genetic change to be called a โvariant of unknown significanceโ or VUS. In this situation, it is unclear whether the genetic change causes the disease or not and family testing may not be offered.
Finding a TTN variant does not specifically change the clinical management of TTN-related DCM. Patients are treated with standard drugs and devices for heart failure according to the extent of heart muscle dysfunction and presence of arrhythmias. At present, there is a lack of evidence for preventative therapies in people who carry a TTN gene variant but who have not yet been diagnosed with DCM.
There are clinical practice guidelines for heart problems like cardiomyopathy, heart failure and arrhythmias. Based on the most recent ESC and AHA Heart Failure clinical guidelines, the Global Heart Hub Heart Failure Patient Council developed a Heart Failure Friendly Guide designed to support individuals who have been newly diagnosed with heart failure, those who are living with the condition and their caregivers. This guide is available in English, Lithuanian, Spanish (LATAM) and Romanian.
Currently, there are no available drug treatments or cures for dominant skeletal muscle titinopathy. The best care for someone with titinopathy involves managing the day-to-day symptoms with the support of a medical team. Changes in breathing (lung function) are common, so follow-up with a breathing specialist (respiratory physician or pulmonologist) is recommended. The first signs of breathing difficulties are often during sleep; therefore, sleep studies are often used to assess breathing performance. Braces, supports and treatments such as occupational and physical therapy may assist in day-to-day living. Stretching, bracing and sometimes surgery can be used to prevent or address contractures. Because there is a risk of developing heart problems in people with skeletal myopathy, it is also important for patients to be followed regularly by a heart doctor (cardiologist). Baseline and ongoing heart checks are recommended for people with dominant titinopathy and other relatives with a TTN gene variant, even if they do not have symptoms. Counseling or psychological support can help patients and their families adjust to the diagnosis.
The Care of Congenital Myopathy: A Guide for Families is a free, comprehensive care guide developed for families and people with congenital myopathy (CM) in response to community requests for useful information. This guide is based on the Consensus Statement on Standard of Care for Congenital Myopathies published in 2012 by Wang and colleagues in the Journal of Child Neurology. This guide is available in English, Spanish, Polish and Russian.
There are a few TTN specific clinical trials and studies currently being conducted:
Registry: Congenital Muscle Disease International Registry
Moderate Intensity Training in Patients With Truncating Genetic Variants in TTN
Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation
Information on all current clinical trials can be found online at https://clinicaltrials.gov/
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website.
For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Perrin A, Mรฉtay C, Savarese M, et al. Titin copy number variations associated with dominant inherited phenotypes. J Med Genet. 2024;61(4):369-377. Published 2024 Mar 21. doi:10.1136/jmg-2023-109473
Heymans S, Lakdawala NK, Tschรถpe C, Klingel K. Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches. Lancet. 2023;402(10406):998-1011. doi:10.1016/S0140-6736(23)01241-2
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2022 May 3;145(18):e1033] [published correction appears in Circulation. 2022 Sep 27;146(13):e185] [published correction appears in Circulation. 2023 Apr 4;147(14):e674]. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
Lv X, Zhao B, Xu L, et al. Clinical, pathological, and molecular genetic analysis of 7 Chinese patients with hereditary myopathy with early respiratory failure. Neurol Sci. 2022;43(5):3371-3380. doi:10.1007/s10072-021-05783-1
Vissing CR, Rasmussen TB, Dybro AM, et al. Dilated cardiomyopathy caused by truncating titin variants: long-term outcomes, arrhythmias, response to treatment and sex differences. J Med Genet. 2021;58(12):832-841. doi:10.1136/jmedgenet-2020-107178
Akhtar MM, Lorenzini M, Cicerchia M, et al. Clinical phenotypes and prognosis of dilated cardiomyopathy caused by truncating variants in the TTN gene. Circ Heart Fail. 2020;13(10):e006832. doi:10.1161/CIRCHEARTFAILURE.119.006832
Palmio J, Leonard-Louis S, Sacconi S, et al. Expanding the importance of HMERF titinopathy: new mutations and clinical aspects. J Neurol. 2019;266(3):680-690. doi:10.1007/s00415-019-09187-2
Tharp CA, Haywood ME, Sbaizero O, Taylor MRG, Mestroni L. The giant protein titinโs role in cardiomyopathy: genetic, transcriptional, and post-translational modifications of TTN and their contribution to cardiac disease. Front Physiol. 2019;10:1436. Published 2019 Nov 28. doi:10.3389/fphys.2019.01436
Oates EC, Jones KJ, Donkervoort S, et al. Congenital titinopathy: comprehensive characterization and pathogenic insights. Ann Neurol. 2018;83(6):1105-1124. doi:10.1002/ana.25241
Fatkin D, Huttner IG. Titin-truncating mutations in dilated cardiomyopathy: the long and short of it. Curr Opin Cardiol. 2017;32(3):232-238. doi:10.1097/HCO.0000000000000382
Roberts AM, Ware JS, Herman DS, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7(270):270ra6. doi:10.1126/scitranslmed.3010134
Pfeffer G, Barresi R, Wilson IJ, et al. Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. J Neurol Neurosurg Psychiatry. 2014;85(3):331-338. doi:10.1136/jnnp-2012-304728
Herman DS, Lam L, Taylor MR, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012;366(7):619-628. doi:10.1056/NEJMoa1110186
INTERNET
Udd B, Hackman P. Udd Distal Myopathy โ Tibial Muscular Dystrophy. 2005 Feb 17 [Updated 2020 Jan 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1323/ Accessed May 1, 2024.
NORD strives to open new assistance programs as funding allows. If we donโt have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDโs mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/