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Last updated: 3/12/2024
Years published: 2024
NORD gratefully acknowledges Sarah Foye, President/Treasurer, Team Titin, Inc., Dr. Emily Oates, Clinical Geneticist, Senior Lecturer and Team Leader, The Sydney Childrenโs Hospital Network and The University of New South Wales, Dr. Anna Sarkozy, Consultant in Neuromuscular Diseases at the Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, London, Prof. Diane Fatkin, Molecular Cardiologist and Dr. Renee Johnson, Victor Chang Cardiac Research Institute, St Vincentโs Hospital Sydney, for the preparation of this report.
Summary
Recessive titinopathy is a condition caused by specific changes called disease-causing variants in a gene called TTN (pronounced โtitinโ). Disease-causing variants are sometimes referred to as โpathogenicโ or โlikely pathogenicโ variants on diagnostic reports. Individuals with recessive titinopathy have two disease-causing variants in TTN โ one in each copy of their TTN gene.
The most common symptoms of recessive titinopathy are muscle weakness and breathing difficulties. Some affected individuals also develop scoliosis and heart problems. The severity of the condition and rate of progression are quite variable. The reasons for this variability are not currently well understood.
Muscle biopsy findings are also variable. Structural (myopathic) differences are sometimes present. In other individuals the biopsy shows dystrophic changes suggestive of ongoing muscle breakdown and regeneration.
Introduction
A range of different recessively inherited titinopathies (recessive titinopathies) have been described to date. Three of the best characterized subtypes are autosomal recessive limb-girdle muscular dystrophy-10 (LGMDR10, previously known as type 2J), recessive distal titinopathy and congenital titinopathy. In this report, recessive titinopathies are considered clinical variations of the same disorder.
There are also several different dominantly inherited forms of titinopathy (dominant titinopathies) caused by a disease-causing variant in just one copy of the TTN gene. These conditions result in a range of muscle and heart problems that usually do not develop until adulthood. Examples include tibial muscular dystrophy (TMD), hereditary myopathy with early-onset respiratory failure (HMERF), dominant titinopathy and TTN-related dilated cardiomyopathy.
Recessive titinopathy is a muscle condition that can affect many different parts of the body. The muscle weakness caused by this condition often develops prenatally or during early childhood. However, sometimes the weakness develops later in life (later childhood, adolescence or early adulthood).
Recessive titinopathy is quite variable in terms of severity. Some affected individuals develop milder muscle weakness. Others develop much more severe weakness. For some affected individuals, the degree of weakness remains stable over many years. In others, the degree of weakness becomes more marked over time. The reasons for these differences in severity and rate of progression are not yet well understood. It is therefore difficult to predict how this condition will impact an affected individual over their lifespan (prognosis).
The most common symptoms of recessive titinopathy are:
Muscle weakness which results in difficulty moving the arms, legs, trunk, head and/or neck. Sometimes there is also weakness of the muscles of the face which can make it harder to make normal facial expressions or make the eyelids appear slightly โdroopyโ (eyelid ptosis).
Bone and joint changes such as:
o Joint tightness that can make it harder to bend certain joints, for example the hips, knees, elbows, wrists, fingers and/or feet
o Spinal changes such as spinal stiffness which makes bending forward more difficult, or a fixed curvature of the spine (scoliosis)
o Changes in the shape of the chest caused by weakness of the chest wall muscles
Feeding difficulties: Weakness of the muscles used when eating may result in difficulties chewing and swallowing.
Breathing difficulties: Weakness of the chest muscles and the main internal breathing muscle (diaphragm) that sits just under the lungs sometimes results in difficulties coughing and/or breathing. Breathing difficulties are often more pronounced during sleep when muscles are generally more relaxed. Coughing and breathing difficulties can be present from birth or develop over time.
Heart problems: The heart may not develop in the normal way during in utero development (congenital heart abnormality) or become unusually large and less efficient at pumping blood around the body with increasing age (dilated cardiomyopathy). In some affected individuals, an irregular heartbeat may develop (arrhythmia). Current evidence suggests that approximately half of all individuals with recessive titinopathy will develop a problem with their heart during their lifetime.
Recessive titinopathy is caused by specific changes called disease-causing (classified as pathogenic or likely-pathogenic) variants in a gene called TTN (โtitinโ). The TTN gene provides muscles with instructions (recipe) for how 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. Without a properly working copy of the TTN gene, the body is not able to produce enough normal titin protein. This impacts muscle function and results in the development of recessive titinopathy symptoms.
Parents of individuals with recessive titinopathy and sometimes other members of the family have one copy of the TTN gene with a disease-causing variant and one copy of the TTN gene that does not have this sort of variant and is still functioning normally. Family members who have one working copy of the TTN gene are known as recessive titinopathy carriers.
Carriers usually produce enough titin protein for their skeletal muscles (e.g. the muscles of the limbs, trunk and face) to function normally and therefore do not develop the symptoms of recessive titinopathy.
However, because recessive titinopathy carriers have one disease-causing variant they usually produce less titin protein and/or some titin protein that is not able to function in the normal way. Carriers may develop heart problems such as dilated cardiomyopathy or an irregular heartbeat (arrhythmia) at some stage in their lifetime. However, not all carriers develop heart problems, and the heart problems that do develop in recessive titinopathy carriers usually donโt develop until adulthood. The factors that determine whether a heart problem will develop are not completely understood but may include certain characteristics of the TTN variant, as well as the presence of any other heart disease risk factors.
Recessive titinopathy follows an autosomal recessive pattern of inheritance. If both parents are recessive titinopathy carriers, then, with each pregnancy, there is a 25% chance of having an affected child, a 50% chance of having a child who is a recessive titinopathy carrier like their parents and a 25% chance of having a child who is unaffected and not a carrier.
The prevalence of recessive titinopathy is unknown.
The diagnosis of recessive titinopathy requires a clinical examination by a doctor such as a neurologist or clinical geneticist, who will look for the features (symptoms and signs) of the condition as described above. An examination will determine if there is muscle weakness in the limbs, trunk, spinal, neck and face muscles as well as the breathing and heart muscles. Sometimes additional testing such as a breathing test (lung function or sleep study) or heart muscle test (for example an ECG electrical trace or heart imaging with ultrasound) is requested to check heart and lung function. Muscle imaging studies such as muscle ultrasound and/or muscle MRI may be used to determine which muscles are significantly impacted by the condition. Identifying patterns of muscle involvement can provide clues to the correct diagnosis. A muscle biopsy might also be arranged as this can provide additional clues to the correct genetic diagnosis.
Genetic testing for TTN disease-causing variants is used to confirm the diagnosis of recessive titinopathy. If the disease-causing gene variants are identified, genetic testing can be offered to other family members to find out if they have the same condition or if they are recessive titinopathy carriers. Sometimes genetic testing identifies a variant in TTN that doctors have not seen before, and it is not clear whether it causes this condition. This is called a โvariant of unknown significanceโ or VOUS or VUS. In this situation, it is unclear whether the genetic change is important or not and family testing may not be offered.
Currently, there are no available drug treatments or cures for recessive titinopathy. However expert medical teams can support the management of the day-to-day symptoms of the condition. Changes in breathing (lung function) are common, so follow up with a breathing specialist (respiratory physician/pulmonologist) is recommended. The first signs of breathing difficulties often start during sleep. Therefore, sleep studies are often used to assess breathing performance. Because there is a risk of developing heart problems, it is also important for patients to be followed regularly by a heart doctor (cardiologist). Baseline heart checks are recommended for people with recessive titinopathy and potentially also for family members. There are no clear guidelines as of yet for who needs ongoing heart screening and how frequently this needs to be done, and recommendations may differ for individual patients.
The Care of Congenital Myopathy: A Guide for Families is a free, comprehensive care guide developed for families and people with congenital myopathy 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 available in English, Spanish, Polish and Russian.
There are a few TTN specific clinical trials and studies currently being conducted:
Moderate Intensity Training in Patients With Truncating Genetic Variants in TTN
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ .
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
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: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
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/
Weston TGR, Rees M, Gautel M, Fraternali F. Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin. WIREs Mech Dis. Published online December 29, 2023. doi:10.1002/wsbm.1638
Meyer AP, Barnett CL, Myers K, Siskind CE, Moscarello T, Logan R, Roggenbuck J, Rich KA. Neuromuscular and cardiovascular phenotypes in paediatric titinopathies: a multisite retrospective study. J Med Genet. 2023 Nov 29:jmg-2023-109513. doi: 10.1136/jmg-2023-109513. Epub ahead of print. PMID: 38050027.
Skriver SV, Krett B, Poulsen NS, Krag T, Walas HR, Christensen AH, Bundgaard H, Vissing J, Vissing CR. Skeletal Muscle Involvement in Patients With Truncations of Titin and Familial Dilated Cardiomyopathy. JACC Heart Fail. 2023 Nov 8:S2213-1779(23)00695-9. doi: 10.1016/j.jchf.2023.10.010. Epub ahead of print. PMID: 37999665.
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
Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27(3):363-382. doi:10.1177/0883073812436605
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