{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:04:12Z","timestamp":1792789452530,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["grant-RC 2024-2025"],"award-info":[{"award-number":["grant-RC 2024-2025"]}]},{"name":"5\u00d71000 voluntary contributions","award":["grant-RC 2024-2025"],"award-info":[{"award-number":["grant-RC 2024-2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Autosomal recessive inherited pathogenetic variants in the histidine triad nucleotide-binding protein 1 (HINT1) gene are responsible for an axonal Charcot-Marie-Tooth neuropathy associated with neuromyotonia, a phenomenon resulting from peripheral nerve hyperexcitability that causes a spontaneous muscle activity such as persistent muscle contraction, impaired relaxation and myokymias. Methods: Herein, we describe two brothers in whom biallelic HINT1 variants were identified following a multidisciplinary approach. Results: The younger brother came to our attention for clinical evaluation of moderate intellectual disability, language developmental delay, and some behavioral issues. His elder brother presented mild intellectual disability, hyperactivity, tiptoe walking, and gait ataxia. At first evaluation, motor impairment with frequent falls, pes cavus, and distal hyposthenia with reduced osteotendinous reflexes were found in both. Grip myotonic phenomenon was also noted. Blood tests revealed mildly elevated creatine kinase, and neurophysiology investigations revealed predominantly axonal polyneuropathy. Muscle MRI highlighted fibro-adipose infiltration, prevalent in the lower limbs. Gene panel testing detected a heterozygous HINT1 variant (c.355C&gt;T\/p.(Arg119Trp)) on the paternal allele. A further in-depth analysis using Integrative Genomics Viewer and Optical Genome Mapping led us to identify an additional variant in HINT1 represented by a complex rearrangement located in the region 5\u2032UTR-exon 1-intron 1, not previously described. Conclusions: This complex rearrangement could have been overlooked if the clinical picture had not been evaluated as a whole (from a clinical, neurophysiological, and neuroimaging point of view). Neuropsychiatric manifestations (intellectual disability, hyperactivity, etc.) are part of the picture of HINT1-related neuromyotonia.<\/jats:p>","DOI":"10.3390\/genes15111483","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T04:53:05Z","timestamp":1731991985000},"page":"1483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Small Complex Rearrangement in HINT1-Related Axonal Neuropathy"],"prefix":"10.3390","volume":"15","author":[{"given":"Alessandra","family":"Tessa","sequence":"first","affiliation":[{"name":"Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariapaola","family":"Schifino","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9407-3195","authenticated-orcid":false,"given":"Eliana","family":"Salvo","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Trovato","sequence":"additional","affiliation":[{"name":"Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Cesana","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6169-4382","authenticated-orcid":false,"given":"Silvia","family":"Frosini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Pasquariello","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8056-5690","authenticated-orcid":false,"given":"Giada","family":"Sgherri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Battini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-7712","authenticated-orcid":false,"given":"Maria Clara","family":"Bonaglia","sequence":"additional","affiliation":[{"name":"Cytogenetics Laboratory, Scientific Institute, IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[{"name":"Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8588-0323","authenticated-orcid":false,"given":"Guja","family":"Astrea","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, IRCCS Stella Maris Foundation, 56128 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"ref_1","first-page":"39","article-title":"Charcot-Marie-Tooth disease and related genetic neuropathies","volume":"18","author":"Patzko","year":"2012","journal-title":"Continuum"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e1783","DOI":"10.1002\/mgg3.1783","article-title":"HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report","volume":"9","author":"Madeiro","year":"2021","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1111\/cge.14198","article-title":"HINT1 neuropathy: Expanding the genotype and phenotype spectrum","volume":"102","author":"Morel","year":"2022","journal-title":"Clin. Genet."},{"key":"ref_4","first-page":"868","article-title":"Axonal neuropathy with neuromyotonia: There is a HINT","volume":"140","author":"Peeters","year":"2017","journal-title":"Brain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1055\/s-0035-1570493","article-title":"A Novel Variant in the HINT1 Gene in a Girl with Autosomal Recessive Axonal Neuropathy with Neuromyotonia: Thorough Neurological Examination Gives the Clue","volume":"47","author":"Rauchenzauner","year":"2016","journal-title":"Neuropediatrics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/ejhg.2013.231","article-title":"Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy","volume":"22","author":"Zhao","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.bbr.2011.02.012","article-title":"Increased anxiety-related behaviour in Hint1 knockout mice","volume":"220","author":"Varadarajulu","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5181925","DOI":"10.1155\/2017\/5181925","article-title":"HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator","volume":"2017","author":"Liu","year":"2017","journal-title":"Neural Plast."},{"key":"ref_9","unstructured":"O\u2019Brien, M. (1976). Aids to Examination of the Peripheral Nervous System, Her Majesty\u2019s Stationary Office. Memorandum No. 45."},{"key":"ref_10","unstructured":"Wechsler, D. (2024, November 14). Wechsler Intelligence Scale for Children, 4th ed.; WISC-IV; 2003. Available online: https:\/\/psycnet.apa.org\/doiLanding?doi=10.1037%2Ft15174-000."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kreutzer, J.S., DeLuca, J., and Caplan, B. (2011). Child Behavior Checklist. Encyclopedia of Clinical Neuropsychology, Springer.","DOI":"10.1007\/978-0-387-79948-3"},{"key":"ref_12","unstructured":"March, J.S. (2024, November 14). Multidimensional Anxiety Scale for Children, 2nd ed.; MASC2. Available online: https:\/\/psycnet.apa.org\/doiLanding?doi=10.1037%2Ft05050-000."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"D\u2019Amore, A., Tessa, A., Casali, C., Dotti, M.T., Filla, A., Silvestri, G., Antenora, A., Astrea, G., Barghigiani, M., and Battini, R. (2018). Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.00981"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"ACMG Laboratory Quality Assurance Committee. 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_15","doi-asserted-by":"crossref","unstructured":"Bonaglia, M.C., Salvo, E., Sironi, M., Bertuzzo, S., Errichiello, E., Mattina, T., and Zuffardi, O. (2023). Case Report: Decrypting an interchromosomal insertion associated with Marfan\u2019s syndrome: How optical genome mapping emphasizes the morbid burden of copy-neutral variants. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1244983"},{"key":"ref_16","first-page":"817","article-title":"Analysis of HINT1 gene variant in a case with neuromyotonia and axonal neuropathy","volume":"36","author":"Xu","year":"2019","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/ng.2406","article-title":"Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia","volume":"44","author":"Baets","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1007\/s12035-020-02265-x","article-title":"Human HINT1 Mutant Proteins that Cause Axonal Motor Neuropathy Exhibit Anomalous Interactions with Partner Proteins","volume":"58","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ejmg.2018.07.009","article-title":"Novel mutations in HINT1 gene cause the autosomal recessive axonal neuropathy with neuromyotonia","volume":"62","author":"Wang","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10048-014-0427-8","article-title":"Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom","volume":"16","author":"Mazanec","year":"2015","journal-title":"Neurogenetics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13023-021-01746-z","article-title":"HINT1 neuropathy in Norway: Clinical, genetic and functional profiling","volume":"16","author":"Brauteset","year":"2021","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1385\/JMN:31:03:221","article-title":"Meta-analysis of 12 genomic studies in bipolar disorder","volume":"31","author":"Elashoff","year":"2007","journal-title":"J. Mol. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e87","DOI":"10.1038\/tp.2012.13","article-title":"Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients","volume":"2","author":"Guest","year":"2012","journal-title":"Transl. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Barbier, E., and Wang, J.B. (2009). Anti-depressant and anxiolytic like behaviors in PKCI\/HINT1 knockout mice associated with elevated plasma corticosterone level. BMC Neurosci., 10.","DOI":"10.1186\/1471-2202-10-132"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.schres.2008.08.006","article-title":"Is the histidine triad nucleotide-binding protein 1 (HINT1) gene a candidate for schizophrenia?","volume":"106","author":"Chen","year":"2008","journal-title":"Schizophr. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rozevska, M., Rots, D., Gailite, L., Linde, R., Mironovs, S., Timcenko, M., Linovs, V., Locmele, D., Micule, I., and Lace, B. (2023). The most common European HINT1 neuropathy variant phenotype and its case studies. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1084335"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.nmd.2019.05.001","article-title":"Autosomal recessive axonal neuropathy caused by HINT1 mutation: New association of a psychiatric disorder to the neurologic phenotype","volume":"29","author":"Scarpini","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.nmd.2020.01.003","article-title":"Response to \u201cAutosomal recessive axonal neuropathy caused by HINT1 mutation: New association of a psychiatric disorder to the neurological phenotype\u201d","volume":"30","author":"Rossi","year":"2020","journal-title":"Neuromuscul. Disord."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"363","DOI":"10.4103\/0028-3886.375403","article-title":"HINT1-Associated Axonal Neuropathy with Neuromyotonia","volume":"71","author":"Reddy","year":"2023","journal-title":"Neurol. India"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1002\/mus.24774","article-title":"A case of neuromyotonia and axonal motor neuropathy: A report of a HINT1 mutation in the United States","volume":"52","author":"Jerath","year":"2015","journal-title":"Muscle Nerve"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Jiang, N., Campo, R.V.D., and Kazamel, M. (2023). Case report: A novel homozygous histidine triad nucleotide-binding protein 1 mutation featuring distal hereditary motor-predominant neuropathy with rimmed vacuoles. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1007051"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1483\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:34:52Z","timestamp":1760114092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/11\/1483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":31,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["genes15111483"],"URL":"https:\/\/doi.org\/10.3390\/genes15111483","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]}}}