{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:34:16Z","timestamp":1760060056798,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Charcot\u2013Marie\u2013Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype\u2013phenotype correlation studies.<\/jats:p>","DOI":"10.3390\/genes16080917","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:29:02Z","timestamp":1753885742000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genotypic and Phenotypic Characterization of Axonal Charcot\u2013Marie\u2013Tooth Disease in Childhood: Identification of One Novel and Four Known Mutations"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-0262","authenticated-orcid":false,"given":"Rojan","family":"\u0130pek","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Dicle University, Diyarbak\u0131r 21280, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00fc\u015fra Eser","family":"\u00c7avdartepe","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Konya City Hospital, Konya 42020, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sevcan Tu\u011f","family":"Bozdo\u011fan","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, \u00c7ukurova University, Adana 01250, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erman","family":"Altun\u0131\u015f\u0131k","sequence":"additional","affiliation":[{"name":"Department of Neurology, Ad\u0131yaman University Training and Research Hospital, Ad\u0131yaman 02040, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9770-284X","authenticated-orcid":false,"given":"Ak\u00e7ahan","family":"Akal\u0131n","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gentics, Diyarbak\u0131r Childrens Diseases Hospital, Diyarbak\u0131r 21100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmut","family":"Yaman","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Dicle University, Diyarbak\u0131r 21280, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-9559","authenticated-orcid":false,"given":"Alper","family":"Ak\u0131n","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Dicle University, Diyarbak\u0131r 21280, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sefer","family":"Kumanda\u015f","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Pediatric Neurology Clinic, Kayseri 38040, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","unstructured":"Rowland, L.P. (2005). Peripheral neuropathies. Merrit\u2019s Neurology, Lippincott Williams and Wilkins. [12th ed.]."},{"key":"ref_2","unstructured":"Dyck, P.J., Thomas, P.K., Lambert, E.H., and Bunge, R. (1984). Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. Peripheral Neuropathy, WB Saunders."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1097\/WCO.0000000000000474","article-title":"New developments in Charcot-Marie-Tooth neuropathy and related diseases","volume":"30","author":"Pareyson","year":"2017","journal-title":"Curr. Opin. Neurol."},{"key":"ref_4","unstructured":"VarSome (2022, December 27). VarSome The Human Genomics Community. Available online: https:\/\/varsome.com\/variant\/hg38\/NEFH%20c.2434_2436del?annotation-mode=germline."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1136\/jnnp.2006.112276","article-title":"Rapid progression of late-onset axonal Charcot-Marie-Tooth disease associated with a novel MPZ mutation in the extracellular domain","volume":"78","author":"Milani","year":"2007","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.5734\/JGM.2021.18.2.83","article-title":"Analyzing clinical and genetic aspects of axonal Charcot\u2013Marie-Tooth disease","volume":"18","author":"Kwon","year":"2021","journal-title":"J. Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.nmd.2019.02.007","article-title":"Charcot-Marie-Tooth disease type 2CC due to a frameshift mutation of the neurofilament heavy polypeptide gene in an Austrian family","volume":"29","author":"Ikenberg","year":"2019","journal-title":"Neuromuscul. Disord."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.ajhg.2016.02.022","article-title":"Cryptic amyloidogenic elements in the 3-prime UTRs of neurofilament genes trigger axonal neuropathy","volume":"98","author":"Rebelo","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","unstructured":"ClinicalTrials.gov (2025, March 01). A Study of ACTX-401 for the Treatment of IGHMBP2-Related Disorders, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05152823."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3319","DOI":"10.1093\/brain\/awy280","article-title":"Development and validation of the Charcot-Marie-Tooth Disease Infant Scale","volume":"141","author":"Mandarakas","year":"2018","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.nmd.2015.07.017","article-title":"Autosomal recessive axonal polyneuropathy in a sibling pair due to a novel homozygous mutation in IGHMBP2","volume":"25","author":"Wagner","year":"2015","journal-title":"Neuromuscul. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.nmd.2016.11.008","article-title":"IGHMBP2-related clinical and genetic features in a cohort of Chinese Charcot-Marie Tooth disease type 2 patients","volume":"27","author":"Liu","year":"2017","journal-title":"Neuromuscul. Disord."},{"key":"ref_13","unstructured":"OMIM (2022, December 27). Carcot-Marie-Tooth Disease Caused Due to DYNCH1 Mutation Can Have Variable Phenotype. Available online: https:\/\/www.omim.org\/entry\/614228."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.braindev.2021.12.001","article-title":"Spinal muscular atrophy with predominant lower extremity (SMA-LED) with no signs other than pure motor symptoms at the intersection of multiple overlap syndrome","volume":"44","author":"Tekin","year":"2022","journal-title":"Brain Dev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.nmd.2018.07.002","article-title":"A recurrent de novo DYNC1H1 tail domain mutation causes spinal muscular atrophy with lower extremity predominance, learning difficulties and mild brain abnormality","volume":"28","author":"Chan","year":"2018","journal-title":"Neuromuscul. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1002\/ajmg.a.61729","article-title":"DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants","volume":"182","author":"Amabile","year":"2020","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.12998\/wjcc.v9.i30.9302","article-title":"Missense mutation in DYNC1H1 gene caused psychomotor developmental delay and muscle weakness: A case report","volume":"9","author":"Ding","year":"2021","journal-title":"World J. Clin. Cases"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/cge.13462","article-title":"MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy","volume":"95","author":"Baumann","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/ng1765","article-title":"MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion","volume":"38","author":"Spinazzola","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1086\/506913","article-title":"Navajo neurohepatopathy is caused by a mutation in the MPV17 gene","volume":"79","author":"Karadimas","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.nmd.2012.03.006","article-title":"MPV17 mutation causes neuropathy and leukoencephalopathy with multiple mtDNA deletions in muscle","volume":"22","author":"Blakely","year":"2012","journal-title":"Neuromusc. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Choi, Y.R., Hong, Y.B., Jung, S.C., Lee, J.H., Kim, Y.J., Park, H.J., Lee, J., Koo, H., Lee, J.S., and Jwa, D.H. (2015). A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. BMC Neurol., 15.","DOI":"10.1186\/s12883-015-0430-1"},{"key":"ref_23","unstructured":"OMIM (2022, December 27). Carcot-Marie-Tooth Disease Caused Due to MPV17 Mutation Can Have Variable Phenotype. Available online: https:\/\/www.omim.org\/entry\/618400."},{"key":"ref_24","unstructured":"National Center for Biotechnology Information (2025, July 16). ClinVar; Variation ID: 214660, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/variation\/214660\/."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/917\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:08Z","timestamp":1760033948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/8\/917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":24,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["genes16080917"],"URL":"https:\/\/doi.org\/10.3390\/genes16080917","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}