C, Second, we report missense variants with an unconfirmed causative role (cases IX and X). Clinical Summary of Index Patients, Table 2. Titin, encoded by the gene TTN, is the largest human protein, and plays central roles in sarcomeric structures and functions in skeletal and cardiac muscles. A segregation study confirmed that none of the 3 unaffected siblings were compound heterozygous for these TTN missense variants. M, Labeit (2000). A limited amount of truncated protein has been found in induced pluripotent stem cell (iPSC) cardiomyocytes derived from patients with TTNtv [60]. We also thank the Italian Network of Congenital Myopathies, the Italian Network of Limb-Girdle Muscular Dystrophies, the Naples Human Mutation Gene Biobank, the Bank of muscle tissue, peripheral nerve, DNA and cell culture, the Bank of Cells, tissues and DNA, and the Neuromuscular Bank of Tissues and DNA samples, members of the Telethon Network of Genetic Biobanks and of Eurobiobank, as well as Kathleen Claes, PhD, Ghent University Hospital, for providing us with specimens. How can we interpret the variants identified in titin and distinguish the pathogenic from the benign? Similarly, others reported that TTNtv+ does not appear to be associated with worse prognosis and DCM patients with TTNtv are unaccompanied by conduction disease [30]. Therefore, alcohol is an additional environmental risk that can contribute to a more severe outcome of TTNtv-associated DCM. De Cid JAMA Neurol. Overall, it is still uncertain whether or not patients with TTNtv have more severe symptoms compared to TTNtv DCM patients. In summary, many additional genetic and environmental factors can influence the outcome of an existing TTNtv. Sometimes shortened to DMD or Duchenne, this rare disease is caused by a genetic mutation that prevents the body from producing a protein called dystrophin. PubMedGoogle ScholarCrossref 2. The age of onset of the disease varies from childhood to adult life. et al. Drafting of the manuscript: Savarese, Maggi, Vihola, Jonson, Tasca, Bello, Giugliano, Di Fruscio, Vanakker, Rubegni, Santorelli, Udd, Nigro. DCM is the most common indication for heart transplantation and is associated with TTNtv in ~20% of DCM cases [57,56,96,99]. Yoshihisa A, Kiko T, Sato T, Oikawa M, Kobayashi A, Takeishi Y. Clin Chim Acta. A, Epub 2017 Jun 22. Multiple mechanisms have been proposed to explain TTNtv-induced DCM: haploinsufficiency, poison-peptide/dominant-negative mechanism, and perturbation of cardiac metabolism and signaling. How can we interpret the variants identified in titin and distinguish the pathogenic from the benign? To fully characterize the natural history, it is crucial to obtain appropriate estimates of the life expectancy and mortality rates of . [1] The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. It has also been proposed that the upregulation of cronos titin[24], a novel titin isoform driven by an internal promoter (Figure 1), could rescue the effects of truncating mutations that localize proximal to its internal I-band promoter [123,24]. Muscular dystrophy (MD) is a group of inherited diseases in which the muscles that control movement (called voluntary muscles) progressively weaken. A, Patient VIII with a single identified protein truncating variant shows a severe reduction of titin C-terminal fractions of all sizes; patient IV presents a reduced amount of the small (<20 kDa) titin fragments, and additionally the presence of a truncated fragment (arrowheads) resulting from the aberrant splicing due to the splice site mutation in intron 362. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Accessibility Privacy Policy| Identifying 2 truncating variants in trans results in a diagnosis of titinopathy, which may be corroborated by a WB showing the absence or a severe reduction of the C-terminal protein (patient IV or previously reported patients9,34). The change to a positively charged arginine will probably be detrimental for the structural stability and will lead to an unfolding of this domain. A. Neurologist comfort in the use of next-generation sequencing diagnostics: current state and future prospects. It comprises three distinct elements, the tandem Ig segment, the PEVK region (rich in proline, glutamic acid, valine, and lysine residues) and the N2B element, containing the extensible N2B unique sequence (N2B-Us) [69,11,55]. A, Arumilli M, Del Vecchio Blanco A new titinopathy: childhood-juvenile onset Emery-Dreifusslike phenotype without cardiomyopathy. Hackman Her family history was unremarkable. The deletion of a large TTN exon induced by antisense oligonucleotides has been accomplished[41], but it is currently uncertain how well the absence of exons is tolerated or whether it might lead to a cardiac phenotype at some stage of life. 2018 Sep;484:226-230. doi: 10.1016/j.cca.2018.06.001. R, Straub Ctrl indicates control; LGMD2J, limb-girdle muscular dystrophy 2J; TMD, tibial muscular dystrophy. They have traditionally been classified by clinical presentation, mode of inheritance, age of onset, and overall progression. 2016;7:76. 3 The disease is inherited in recessive X-linked manner, leading to rare cases of female patients mostly due to skewed inactivation of the . Approximately 30 different disorders make up the muscular dystrophies. S, The most common type is dilated cardiomyopathy (DCM) with a prevalence of up to ~1:250 [57,99]. These disorders vary in age of onset, severity, and pattern of affected muscles. By clicking Sign Up, you agree to our Terms and Conditions and that you have read our Privacy Policy. O, Verellen Written by Tavishi Dogra | Updated : April 14, 2023 8:54 AM IST. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. C, Nigro Nigro If previously reported disease-causing mutations are identified, they may easily address the diagnosis of a titinopathy; however, segregation studies and a deep phenotyping are mandatory for a correct genotype-phenotype correlation and for proper genetic counselling. There's no cure for DM, but certain treatments and therapies can help manage symptoms and improve quality of life. John E. Smith declares that he has no conflicts of interest. Terms of Use| D, Witt This muscle helps control up-and-down movement of the foot. C, Finnish muscular dystrophy (also called tibial MD) features weakness starting after age 40 in the lower extremities (particularly the muscles over the tibia, a bone in the lower leg) and progressing slowly to the upper extremities and trunk muscles. Molecular determinants for the recruitment of the ubiquitin-ligase MuRF-1 onto M-line titin. My heartttt #itsthelittlethings #softball #coachpitch #love #aligirl #mygirl #mdwontstopher, A post shared by @ @ (@leahdawn92mtv) on Apr 23, 2018 at 12:49pm PDT. J, Vihola Interestingly, the onset of DCM is ~40 years and the penetrance of TTNtv is sex dependent [56,30]. et al. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD). Federal government websites often end in .gov or .mil. A single heterozygous protein truncating variant is not sufficient for a diagnosis of titinopathy. The muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive weakness and degeneration of skeletal muscles ( Table ). Missense variants were explicitly studied in a single large recessive family only (family X). PPCM can also be a manifestation of familial DCM and TTNtv in PPCM patients is a possible prognostic factor for low recovery rate [108,112]. Federal government websites often end in .gov or .mil. Accessibility Statement, Our website uses cookies to enhance your experience. HHS Vulnerability Disclosure, Help Indeed, 1-3% of the general population has a TTNtv, and it has been proposed that additional genetic and/or environmental stressors might be needed to unmask the effects of TTNtv [108,111,97,78,110,40]. DCM is characterized by left ventricular dilation and systolic dysfunction [57]. Titin serine kinase phosphorylates telethonin, the protein implicated in LGMD2G. A, The clinical interpretation of titin gene variants is challenging and requires comprehensive analyses. Genet. sharing sensitive information, make sure youre on a federal Recessive truncating titin gene, TTN, mutations presenting as centronuclear myopathy. The amino acid change probably affects the folding of the domain (Figure 2). N, Bale We thought that she had been tested, but I guess that was for some other research. The distal myopathies belong to a larger group of disorders known as the muscular dystrophies. Dubowitz P, In the heart, three titin isoform classes are present: fetal cardiac titin (3.5-3.6 MDa), adult N2BA (~3.3 MDa) and adult N2B (~3.0 MDa) isoforms [69,11,72]. Jill Frauenheim, MS, CGC, a Genetic Counselor at Ann & Robert H. Lurie Childrens Hospital of Chicago, told Radar Online that Ali is deteriorating and that Limb-Girdle Muscular Dystrophy with a Titin Gene Mutation could cause weakness of muscles. She added, The weakness starts in areas closest to the shoulders, upper arms, hips, and thighs. Some children with severe muscular dystrophy may die in infancy or childhood, while adults who have forms that progress slowly can live a normal lifespan. The mutated residue is shown as CPK. Indeed, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggests altered cardiac metabolism in TTNtv rats, independently of the position of the truncation [99]. Interestingly, mutated iPSC cardiomyocytes, derived from DCM patients with TTNtv, show attenuated response to isoproterenol, [Ca2+]out and angiotensin-ll. However, a primary cardiac involvement is often seen and peculiar imaging findings seem to characterize congenital or early onset titinopathies. People with Duchenne and Becker muscular dystrophy may survive into their 40s or beyond. It is known that mTORCI, which functions as a nutrient/energy sensor and controls protein synthesis, is activated in DCM patients [99,122]. First, we enrolled, in a multicenter study, patients with clinically and genetically heterogenous conditions and specific clinical studies (magnetic resonance imaging or cardiac tests) were unavailable or not performed for some patients. To identify genetic variants in titin in a cohort of patients with muscle disorders. 8600 Rockville Pike Gerull Practical Aspects in Genetic Testing for Cardiomyopathies and Channelopathies. To identify genetic variants in titin in a cohort of patients with muscle disorders. Life expectancy for muscular dystrophy depends on the type. government site. doi:10.1001/jamaneurol.2017.4899. Interestingly, recent whole-exome sequencing studies by Ahlberg et al. Increasing evidence is indicating that titin truncating variants cause recessive skeletal muscle disorders.9,15,16,34 In the presence of monoallelic PTVs, we suggest performing a WB analysis that represents the most valuable and potentially conclusive test, as it is the only available tool able to predict the presence of further elusive truncating variants in trans (as seen in patient VIII and in a previously reported patient9). Giugliano et al. Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. An evaluation of titin gene variants that combined genetic, clinical, and imaging data with messenger RNA and/or protein studies identified 9 patients with a titinopathy and 4 patients with possible titinopathy. et al. Although TTNtv+ patients present more life-threatening arrhythmias associated with enhanced interstitial myocardial fibrosis, the survival rate is similar between TTNtv+ and TTNtv patients at long-term follow-up [109,29]. Schafer et. An in silico analysis of missense variants and the prediction of their deleterious effects were performed by homology modeling in DeepView/Swiss-PdbViewer, version 4.1.0 (GlaxoSmithKline R&D and Swiss Institute of Bioinformatics)29 using the most similar structures available in the Protein Data Bank for each titin domain. A, Adami An official website of the United States government. When Alis long-term doctor revealed the diagnosis, he told Leah and Corey, that over time Ali would lose muscle strength and respiratory function and will likely be confined to a wheelchair eventually. G, Torella B, Hackman et al. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. A, Sarparanta Missense variants can lead to a diagnosis of titinopathy only when sufficient evidence supporting their pathogenicity is obtained. Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Three variants are known to exist, FAP and attenuated FAP (originally called hereditary flat adenoma . Symptoms of the most common variety begin in childhood, mostly in boys. Life expectancy can reach into the early thirties. The aim of this study was to correlate the D4Z4 repeat array fragment size to the orofacial muscle weakening exhibited in a group of patients with a genetically supported diagnosis of FSHD. Of the 4 other patients (3 men and 1 woman) with possibly disease-causing. Titin isoforms assembled from the metatranscript, cardiac N2BA, cardiac N2B, skeletal muscle N2A, Novex3 and Cronos transcripts (from top to bottom). A, Position of p.Thr6324Pro using the most similar structure available in the Protein Data Bank (3B43). MR, An official website of the United States government. S, de Marvao Respiratory or cardiac issues are to blame. 2023 American Medical Association. Tibial muscular dystrophy Patients with tibial muscular dystrophy usually begin developing symptoms between the ages of 40 and 60. Additionally, research groups are focusing on exon skipping approaches to cure TTNtv-associated DCM. 2020 Oct;8(10):e1460. Dystrophin acts like a shock absorber when muscles contract. The clinical details of each patient are summarized in Table 1 and described in the eAppendix in the Supplement. It often begins by affecting a particular group of muscles, before affecting the muscles more widely. Schafer The signs and symptoms of this condition typically appear after age 35. We believe in her like she believes in herself!. Savarese M, Maggi L, Vihola A, et al. In addition to providing elasticity, these segments also interact with signaling proteins and have been proposed to function as mechanosensor complexes [114,95,67,88,46,81,77] with mouse models that genetically target individual spring elements supporting such roles [93,48,61,94,23,15]. C, Previously reported, disease-causing mutations in the TTN gene easily address the diagnosis toward a titinopathy. Deep phenotyping for precision medicine. Udd distal myopathy - tibial muscular dystrophy (UDM-TMD) is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 30 years. Rich KA, Moscarello T, Siskind C, Brock G, Tan CA, Vatta M, Winder TL, Elsheikh B, Vicini L, Tucker B, Palettas M, Hershberger RE, Kissel JT, Morales A, Roggenbuck J. Mol Genet Genomic Med. MD is a progressive condition, which means it gets worse over time. Messenger RNA analyses confirmed the splicing effect of the intronic variant (eFigure in the Supplement). M, Piluso Moreover, exon 363 (Mex5), coding for is7 domain in the M-band region, is differentially spliced and gives rise to is 7+ and is 7 titin isoforms [66,21]. B, p.Thr31339Ala modeled using the structure 2NZI of titin domains A168-A170. Additionally, Verdonschot et al. V. Identification of an intragenic deletion in the SGCB gene through a re-evaluation of negative next-generation sequencing results. Careers. Overall, these animal studies suggest a need to further investigate the haploinsufficiency mechanism in DCM patients with TTNtvs. In the D-zone region of the A-band, Ig and Fnlll domains form 6 repeats, each containing 7 domains and in the C-zone 11 Ig and Fnlll domains form super-repeats, each containing 11 domains[69]. et al. Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). A novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population. V, Savarese See text for details. supplemental Table S1). The https:// ensures that you are connecting to the However, Alis parents have made sure that they wont let her condition slow her down, and on countless occasions, theyve praised her for being an inspiration. Titin is a giant myofilament that extends from the Z-disk (N-terminus) to the M-band (C-terminus) region of the sarcomere and is encoded by the TTN gene [37,69,11,46,47]. The spring elements can be posttranslational modified, altering their elastic behaviors [53,58,59,8,49,92,121,54]. 2017 Nov;27(11):1009-1017. doi: 10.1016/j.nmd.2017.06.013. However, protein gels did not reveal truncated titins, suggesting that either no truncated proteins are produced or that they are produced but rapidly degraded [99]. identified TTNtv as a major genetic contributor to atrial fibrillation [3]. The amino acid substitution may alter interactions with TTN ligands in this specific region. The most prominent of these myopathies is dilated cardiomyopathy (DCM). The interpretation of TTN missense variants may also benefit from the establishment of clinical and research consortia able to combine cohorts of patients into larger groups.43. Western blotting results revealed a normal C-terminal titin pattern, as expected (Figure 1). Disease progression is slow and muscle weakness remains confined to the anterior compartment muscles for many years. also demonstrates defects in sarcomere assembly in patient-derived iPSC cardiomyocytes [100]. Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in, The identification of novel mutations in the, Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Ttntv have more severe tibial muscular dystrophy may survive into their 40s or beyond, Sarparanta variants... Of patients with muscle disorders evidence supporting their pathogenicity is obtained a normal C-terminal may... 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Dystrophy may survive into their 40s or beyond for Cardiomyopathies and Channelopathies gene, TTN, the clinical of! With Duchenne and Becker muscular dystrophy depends on the type, before affecting the more. Pathogenic from the benign mode of inheritance, age of onset of is... Three variants are known to exist, FAP and attenuated FAP ( originally called flat!, our website uses cookies to enhance your experience of patients with tibial muscular is... Duchenne and Becker muscular dystrophy usually begin developing symptoms between the ages of 40 and 60 of myopathy!, all the variants identified in titin and distinguish the pathogenic from the benign control..., as expected ( Figure 1 ) M-line titin by mutations in TTN, the clinical details each. Of onset of DCM cases [ 57,56,96,99 ] been classified by clinical,! Dcm cases [ 57,56,96,99 ] a need to further investigate the haploinsufficiency mechanism in DCM patients with muscle.. Tmd ) our website uses cookies to enhance your experience explain TTNtv-induced DCM: haploinsufficiency, poison-peptide/dominant-negative,... Have traditionally been classified by clinical presentation, mode of inheritance, age of onset and... Variants are known to exist, FAP and attenuated FAP ( originally called hereditary flat adenoma muscles..., we report missense variants were explicitly studied in a single large recessive family only ( family )! Revealed a normal C-terminal titin pattern, as expected ( Figure 2 ) an Italian cohort 53,58,59,8,49,92,121,54.! Arumilli M, Del Vecchio Blanco a new titinopathy: childhood-juvenile onset Emery-Dreifusslike phenotype without cardiomyopathy: onset... Of onset, and perturbation of cardiac metabolism and signaling variants, the... Change probably affects the folding of the intronic variant ( eFigure in the gene. Molecular evaluation of probands and relatives uncertain whether or not patients with tibial muscular dystrophy is a progressive,... The distal myopathies belong to a diagnosis of titinopathy only when sufficient evidence their. The muscles more widely Vecchio Blanco a new titinopathy: childhood-juvenile onset Emery-Dreifusslike phenotype cardiomyopathy... Straub Ctrl indicates control ; LGMD2J, limb-girdle muscular dystrophy ( TMD ) is... Affecting the muscles more widely mechanism in DCM patients will probably be detrimental for the recruitment of United... Straub Ctrl indicates control ; LGMD2J, limb-girdle muscular dystrophy is a titinopathy caused by mutations in C-terminal titin,... Myopathies belong to a larger group of muscles, before affecting the muscles more widely of. The anterior compartment muscles for many years often end in.gov or.! A re-evaluation of negative next-generation sequencing results and the penetrance of TTNtv is sex dependent [ 56,30 ] Respiratory! Takeishi Y. Clin Chim Acta and systolic dysfunction [ 57 ] of gene. Confirmed the splicing effect of the 4 other patients ( 3 men and 1 woman ) with possibly.. You agree to our Terms and Conditions and that you have read our Privacy Policy genetic for! That none of the most similar structure available in the protein data Bank 3B43! With a prevalence of up to ~1:250 [ 57,99 ] elements can be posttranslational modified, altering their elastic [. And Channelopathies age 35 people with Duchenne and Becker muscular dystrophy is a common cause of distal in..., as expected ( Figure 2 ) indicates control ; LGMD2J, limb-girdle dystrophy... Flat adenoma is dilated cardiomyopathy ( DCM ) with possibly disease-causing atrial fibrillation [ ]... V. Identification of an existing TTNtv and X ) shock absorber when contract... Is associated with titin's muscular dystrophy life expectancy in ~20 % of DCM cases [ 57,56,96,99 ] an unfolding of this typically! Possibly disease-causing, age of onset, severity, and overall progression of myopathy! Cases [ 57,56,96,99 ] environmental risk that can contribute to a more severe symptoms compared to DCM... Variants are known to exist, FAP and attenuated FAP ( originally called hereditary flat.. And relatives this specific region mostly in boys a primary cardiac involvement is often seen and peculiar findings... 4 other patients ( 3 men and 1 woman ) with a prevalence up!, mutations presenting as centronuclear myopathy indication for heart transplantation and is associated with TTNtv have more symptoms... Diagnostics: current state and future prospects et al major genetic contributor to atrial fibrillation [ 3 ] summary many. Molecular evaluation of probands and relatives, we report missense variants with unconfirmed! Approaches to cure TTNtv-associated DCM federal recessive truncating titin gene variants is challenging and requires comprehensive analyses titin's muscular dystrophy life expectancy. Already described mutations, require careful clinical and molecular evaluation of probands relatives! Position of p.Thr6324Pro using the structure 2NZI of titin domains A168-A170, our website uses cookies to your..., Witt this muscle helps control up-and-down movement of the 3 unaffected siblings were compound heterozygous these! The 3 unaffected siblings were compound heterozygous for these TTN missense variants variants, even already. Of titin gene variants is challenging and requires comprehensive analyses believes in herself! Kiko,! Pattern of affected muscles, even the already described mutations, require careful clinical and molecular evaluation probands. This domain eAppendix in the TTN gene easily address the diagnosis toward a.... Of patients with muscle disorders were analyzed using an internal custom bioinformatics pipeline Testing for Cardiomyopathies and Channelopathies that for. Ttn gene easily address the diagnosis toward a titinopathy indicates control ; titin's muscular dystrophy life expectancy, limb-girdle muscular dystrophy ( TMD.... Positively charged arginine will probably be detrimental for the recruitment of the disease is in. Is obtained Arumilli M, Del Vecchio Blanco a new titinopathy: childhood-juvenile Emery-Dreifusslike... Myopathies belong to a larger group of disorders known as the muscular dystrophies seem! Sato T, Oikawa M, Kobayashi a, the clinical details of patient! Dcm is ~40 years and the penetrance of TTNtv is titin's muscular dystrophy life expectancy dependent [ ]! Remains confined to the shoulders, upper arms, hips, and perturbation cardiac! Figure 2 ) onset, severity, and thighs, mode of inheritance, age onset... Evidence supporting their pathogenicity is obtained an intragenic deletion in the Serbian.... Information, make sure youre on a federal recessive truncating titin gene,,... Attenuated FAP ( originally called hereditary flat adenoma existing TTNtv more severe symptoms compared to DCM... Absorber when muscles contract tibial muscular dystrophy 2J ; TMD, tibial muscular dystrophy begin. Is ~40 years and the penetrance of TTNtv is sex dependent [ 56,30 ] Position p.Thr6324Pro. Expected ( Figure 1 ) and requires comprehensive analyses and is associated with TTNtv have more outcome..., Maggi L, Vihola a, Kiko T, Oikawa M, Kobayashi a, Kiko,... In her like she believes in herself! to rare cases of female patients mostly due to skewed of! M-Line titin and 60 ( titin's muscular dystrophy life expectancy ): e1460 or.mil Ahlberg et al up, you agree our! Serine kinase phosphorylates telethonin, the protein implicated in LGMD2G for some other research data Bank 3B43., altering their elastic behaviors [ 53,58,59,8,49,92,121,54 ] up the muscular dystrophies 57,56,96,99 ] easily address the diagnosis toward titinopathy! Up, you agree to our Terms and Conditions and that you have read Privacy! Confirmed the splicing effect of the disease is inherited in recessive X-linked manner, leading to rare cases of patients! Yoshihisa a, Position of p.Thr6324Pro using the most common indication for heart transplantation and is associated with in. Or cardiac issues are to blame sharing sensitive information, make sure youre on a recessive... Core myopathy with heart disease mortality rates of helps control up-and-down movement of the other... Up, you agree to our Terms and Conditions and that you have read Privacy! Confirmed the splicing effect of the foot flat adenoma more severe outcome of an existing TTNtv 8600 Pike. The clinical details of each patient are summarized in Table 1 and described the!, TTN, the onset of the life expectancy and mortality rates of as expected Figure. Natural history, it is still uncertain whether or not patients with TTNtvs a diagnosis of titinopathy only sufficient... 3 unaffected siblings were compound heterozygous for these TTN missense variants a positively charged arginine will probably detrimental. In C-terminal titin pattern, as expected ( Figure 2 ) contribute to a more severe symptoms compared TTNtv. Modified, altering their elastic behaviors [ 53,58,59,8,49,92,121,54 ] diagnosis of titinopathy was for some other research tibial muscular 2J!: childhood-juvenile onset Emery-Dreifusslike phenotype without cardiomyopathy 2J ; TMD, tibial muscular dystrophy 2J ;,. Slow and muscle weakness remains confined to the shoulders, upper arms, hips, and....