{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T17:19:33Z","timestamp":1764782373370,"version":"3.41.2"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Recessive mutations in the gene encoding the histidine triad nucleotide-binding protein 1 (HINT1) are associated with axonal motor-predominant Charcot\u2013Marie\u2013Tooth (CMT) disease with neuromyotonia. A total of 24 <jats:italic>HINT1<\/jats:italic> gene mutations have been reported so far. Some of these cases had mild to moderate elevations of creatinine kinase with no earlier reports of muscle biopsy findings in these cases. In this study, we describe a patient with axonal motor-predominant neuropathy and myopathy with rimmed vacuoles, likely due to a novel <jats:italic>HINT1<\/jats:italic> gene mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case report<\/jats:title><jats:p>A 35-year-old African American man presented with insidious onset and progressive symmetric distal leg weakness followed by hand muscle atrophy and weakness since the age of 25. He had no muscle cramps or sensory complaints. His 38-year-old brother developed similar symptoms beginning in his early 30 s. On neurologic examination, the patient had distal weakness and atrophy in all limbs, claw hands, pes cavus, absent Achilles reflexes, and normal sensory examination. Electrodiagnostic studies revealed absent\/reduced compound motor action potential amplitudes distally with normal sensory responses with no neuromyotonia. His sural nerve biopsy showed a chronic non-specific axonal neuropathy, and a biopsy of the tibialis anterior muscle demonstrated myopathic features and several muscle fibers harboring rimmed vacuoles without inflammation in addition to chronic denervation changes. A homozygous variant, p.I63N (c.188T &amp;gt; A), in the <jats:italic>HINT1<\/jats:italic> gene was found in both brothers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We describe a novel, likely pathogenic, <jats:italic>HINT1<\/jats:italic> pI63N (c.188T &amp;gt; A) homozygous variant associated with hereditary axonal motor-predominant neuropathy without neuromyotonia in two African American brothers. The presence of rimmed vacuoles on muscle biopsy raises the possibility that mutations in the <jats:italic>HINT1<\/jats:italic> gene may also cause myopathy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2023.1007051","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T06:08:46Z","timestamp":1675663726000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Case report: A novel homozygous histidine triad nucleotide-binding protein 1 mutation featuring distal hereditary motor-predominant neuropathy with rimmed vacuoles"],"prefix":"10.3389","volume":"14","author":[{"given":"Nan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rocio","family":"Vazquez Do Campo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Kazamel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1002\/mus.24720","article-title":"Novel loss-of-function mutation of the HINT1 gene in a patient with distal motor axonal neuropathy without neuromyotonia","volume":"52","author":"Boaretto","year":"2015","journal-title":"Muscle Nerve."},{"key":"B2","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1093\/brain\/aww301","article-title":"Axonal neuropathy with neuromyotonia: there is a HINT","volume":"140","author":"Peeters","year":"2017","journal-title":"Brain."},{"key":"B3","first-page":"97","article-title":"Sur une forme particuli\u00e8re d'atrophie musculaire progressive souvent familiale d\u00e9butant par les pieds et les jambes et atteignant plus tard les mains","volume":"6","author":"Charcot","year":"1886","journal-title":"Rev M\u00e9d Paris."},{"journal-title":"The Peroneal Type of Progressive Muscular Atrophy","year":"1886","author":"Tooth","key":"B4"},{"key":"B5","doi-asserted-by":"publisher","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":"Lassuthova","year":"2015","journal-title":"Neurogenetics."},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","first-page":"1353516","DOI":"10.1155\/2020\/1353516","article-title":"Identification of candidate genes associated with charcot-marie-tooth disease by network and pathway analysis","volume":"2020","author":"Zhong","year":"2020","journal-title":"Biomed Res Int."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1038\/ng.2406","article-title":"Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia","volume":"44","author":"Zimon","year":"2012","journal-title":"Nat Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1984","DOI":"10.1007\/s00415-015-7851-z","article-title":"Absence of HINT1 mutations in a UK and Spanish cohort of patients with inherited neuropathies","volume":"262","author":"Horga","year":"2015","journal-title":"J Neurol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1007\/s11033-019-05238-z","article-title":"HINT1 gene pathogenic variants: the most common cause of recessive hereditary motor and sensory neuropathies in Russian patients","volume":"47","author":"Shchagina","year":"2020","journal-title":"Mol Biol Rep."},{"key":"B11","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s13023-021-01746-z","article-title":"HINT1 neuropathy in Norway: clinical, genetic and functional profiling","volume":"16","author":"Amor-Barris","year":"2021","journal-title":"Orphanet J Rare Dis."},{"key":"B12","doi-asserted-by":"publisher","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":"B13","doi-asserted-by":"publisher","first-page":"e1783","DOI":"10.1002\/mgg3.1783","article-title":"Lima EL, Amor-Barris S, De Vriendt E, Jordanova A, et al. 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