{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:13:25Z","timestamp":1778148805114,"version":"3.51.4"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Titin (TTN; OMIM 188840) is the largest known human sarcomeric protein, and pathogenic variants in the TTN gene cause a broad spectrum of inherited myopathies and cardiomyopathies. The extent to which TTN variants may also involve the peripheral nervous system remains poorly defined. We aimed to describe two pediatric patients carrying heterozygous truncating TTN variants with neurophysiological evidence of peripheral nerve involvement, and to review the existing literature on this underrecognized association. Pathogenic variants in the TTN gene are associated with a wide spectrum of inherited myopathies and cardiomyopathies. To date, peripheral neur opathy has not been recognized as a defining feature of TTN-related disorders, and neurophysiological investigations in affected individuals typically demonstrate normal or myopathic findings without evidence of a primary neuropathic process. Here, we report two pediatric patients with heterozygous truncating TTN variants and neurophysiological evidence of bilateral axonal involvement of the deep peroneal nerve. Methods: This case report was structured and reported according to the CARE guidelines. Genetic testing was performed using whole-exome sequencing (Blueprint Genetics Whole Exome Family Test). Nerve conduction studies and needle electromyography were performed using the Galileo NT system. Variant classification followed current ACMG guidelines. Results: The first patient, a 10-year-old girl, presented with a symptomatic distal motor phenotype characterized by bilateral pes cavus, anterior compartment muscle atrophy, areflexia, and steppage gait with onset in early childhood. The second patient, an 8-year-old boy, had subclinical bilateral axonal neuropathy identified during neurophysiological evaluation prompted by intermittent lower limb pain; his father, carrying the same variant, showed concordant neurophysiological abnormalities. In both cases, nerve conduction studies demonstrated reduced compound muscle action potential amplitudes with preserved conduction velocities and distal latencies, consistent with axonal neuropathy. Whole-exome sequencing excluded other established genetic causes of inherited neuropathy in both probands. Conclusions: Although a causal relationship cannot be established, these observations raise the possibility that peripheral nerve involvement may represent an underrecognized feature of the titinopathy spectrum. Prospective studies in larger cohorts of TTN variant carriers are needed to clarify the prevalence and pathophysiological basis of neuropathy in this context.<\/jats:p>","DOI":"10.3390\/jcm15093552","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:03:37Z","timestamp":1778144617000},"page":"3552","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Heterogeneity in Titinopathies with Peripheral Nerve Involvement in Pediatric Age: Two Case Reports"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0092-5604","authenticated-orcid":false,"given":"Carlo Alberto","family":"Cesaroni","sequence":"first","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"},{"name":"Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Pisan\u00f2","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6515-9181","authenticated-orcid":false,"given":"Massimiliano","family":"Marton","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5033-7854","authenticated-orcid":false,"given":"Stefano Giuseppe","family":"Caraffi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8856-9722","authenticated-orcid":false,"given":"Susanna","family":"Rizzi","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1501-0146","authenticated-orcid":false,"given":"Agnese","family":"Pantani","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4588-0084","authenticated-orcid":false,"given":"Diletta","family":"Ziveri","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9865-0751","authenticated-orcid":false,"given":"Marzia","family":"Pollazzon","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juha","family":"Koskenvuo","sequence":"additional","affiliation":[{"name":"Blueprint Genetics, a Quest Diagnostics Company, 02150 Espoo, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Frattini","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9321-0952","authenticated-orcid":false,"given":"Carlo","family":"Fusco","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Unit, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"},{"name":"Child Neurology and Psychiatry Unit, Pediatric Neurophysiology Laboratory, Mother and Child Department, Azienda USL-IRCCS di Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/mus.20886","article-title":"Structure-function relations of the giant elastic protein titin in striated and smooth muscle cells","volume":"36","author":"Granzier","year":"2007","journal-title":"Muscle Nerve"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1152\/physrev.00017.2009","article-title":"Muscle giants: Molecular scaffolds in sarcomerogenesis","volume":"89","author":"Ackermann","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1242\/jcs.111.11.1567","article-title":"Characterizing titin\u2019s I-band Ig domain region as an entropic spring","volume":"111","author":"Linke","year":"1998","journal-title":"J. Cell Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.jmb.2006.07.077","article-title":"Expression of distinct classes of titin isoforms in striated and smooth muscles by alternative splicing, and their conserved interaction with filamins","volume":"362","author":"Labeit","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy","volume":"366","author":"Herman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng815","article-title":"Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy","volume":"30","author":"Gerull","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1055\/s-0044-1791721","article-title":"A practical approach to diagnosing peripheral neuropathies","volume":"45","author":"Jacoby","year":"2025","journal-title":"Semin. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1038\/s41436-020-0914-2","article-title":"Genotype-phenotype correlations in recessive titinopathies","volume":"22","author":"Savarese","year":"2020","journal-title":"Genet. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/ana.25241","article-title":"Congenital Titinopathy: Comprehensive characterization and pathogenic insights","volume":"83","author":"Oates","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3233\/JND-160158","article-title":"Increasing role of titin mutations in neuromuscular disorders","volume":"3","author":"Savarese","year":"2016","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Korinthenberg, R., Trollmann, R., Plecko, B., Stettner, G.M., Blankenburg, M., Weis, J., Schoser, B., M\u00fcller-Felber, W., Lochbuehler, N., and Hahn, G. (2021). Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents-Consensus-Based Practice Guidelines. Children, 8.","DOI":"10.3390\/children8080687"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1002\/acn3.70088","article-title":"Fetal Akinesia\/Hypokinesia and Arthrogryposis of Neuromuscular Origin: Etiologic Groups, Genetics, and Phenotypic Spectrum","volume":"12","author":"Matalonga","year":"2025","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s00415-009-5372-3","article-title":"The first Italian family with tibial muscular dystrophy caused by a novel titin mutation","volume":"257","author":"Pollazzon","year":"2010","journal-title":"J. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bugiardini, E., Morrow, J.M., Shah, S., Wood, C.L., Lynch, D.S., Pitmann, A.M., Reilly, M.M., Houlden, H., Matthews, E., and Parton, M. (2018). The Diagnostic Value of MRI Pattern Recognition in Distal Myopathies. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00456"},{"key":"ref_16","unstructured":"Cameron, B., Torres-Hernandez, L., Montague, V.L., Lewis, K.A., Smith, H., Fox, J., Guo, X., Kalb, R.G., and George, L. (2024). Titin is a nucleolar protein in neurons. Res. Sq., preprint."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1038\/nn.4085","article-title":"Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD\/ALS","volume":"18","author":"Jovicic","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1126\/science.1254917","article-title":"Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells","volume":"345","author":"Kwon","year":"2014","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature13124","article-title":"C9orf72 nucleotide repeat structures initiate molecular cascades of disease","volume":"507","author":"Haeusler","year":"2014","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40478-021-01125-6","article-title":"Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization","volume":"9","author":"Nguyen","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0014-5793(98)00572-9","article-title":"Binding of a native titin fragment to actin is regulated by PIP2","volume":"429","author":"Astier","year":"1998","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Luo, Y.B., Peng, Y., Lu, Y., Li, Q., Duan, H., Bi, F., and Yang, H. (2020). Expanding the Clinico-Genetic Spectrum of Myofibrillar Myopathy: Experience From a Chinese Neuromuscular Center. Front. Neurol., 11, Erratum in Front. Neurol. 2021, 11, 636981. https:\/\/doi.org\/10.3389\/fneur.2020.636981.","DOI":"10.3389\/fneur.2020.01014"},{"key":"ref_23","first-page":"e6447","article-title":"Distrofia muscular de cinturas y extremidades autos\u00f3mica recesiva 10. Reporte de caso [Autosomal recessive limb-girdle muscular dystrophy-10. Case report]","volume":"63","year":"2025","journal-title":"Rev. Med. Inst. Mex. Seguro Soc."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gaertner, A., Bloebaum, J., Brodehl, A., Klauke, B., Sielemann, K., Kassner, A., Fox, H., Morshuis, M., Tiesmeier, J., and Schulz, U. (2021). The combined human genotype of truncating TTN and RBM20 mutations is associated with severe and early onset of dilated cardiomyopathy. Genes, 12.","DOI":"10.3390\/genes12060883"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Van Goor, D., Hyland, C., Schaefer, A.W., and Forscher, P. (2012). The role of actin turnover in retrograde actin network flow in neuronal growth cones. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030959"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3552\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:50:09Z","timestamp":1778147409000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/9\/3552"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":25,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["jcm15093552"],"URL":"https:\/\/doi.org\/10.3390\/jcm15093552","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]}}}