{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:52:18Z","timestamp":1786117938316,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"HADDTS Foundation","award":["001"],"award-info":[{"award-number":["001"]}]},{"award":["001"],"award-info":[{"award-number":["001"]}],"id":[{"id":"https:\/\/ror.org\/0530jqt13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome (HADDTS; OMIM #617915) is an ultra-rare autosomal dominant disorder caused by predominantly de novo pathogenic variants in CTBP1, encoding a NAD(H)-dependent transcriptional corepressor. We reviewed all HADDTS cases reported from database inception to July 2026, searching PubMed\/MEDLINE, Google Scholar, ClinVar, DECIPHER, OMIM, preprint servers, and the HADDTS Foundation, identifying 25 peer-reviewed cases from at least 11 countries; registries indicate at least 50 known individuals. Global developmental delay and language impairment were universal (25\/25, 100%), followed by intellectual disability (24\/25, 96%), hypotonia (22\/25, 88%), ataxia and enamel defects (19\/25, 76% each), cerebellar atrophy (18\/25, 72%), feeding difficulties (15\/25, 60%), myopathy (15\/25, 60%), regression (10\/25, 40%), oculomotor apraxia (7\/25, 28%), scoliosis (6\/25, 24%), respiratory chain dysfunction (5\/25, 20%), skeletal anomalies (4\/25, 16%), and seizures (2\/25, 8%). The recurrent p.Arg342Trp (NM_001328.2; p.Arg331Trp, MANE Select NM_001012614.2) accounts for 84%, with severity from mild impairment to profound disability. In all four non-recurrent-variant carriers the canonical tetrad was incomplete; seizures and classifying skeletal anomalies occurred only in that group. Mutant CTBP1 acts dominant-negatively and heterodimerises with the essential paralog CTBP2, explaining the multisystem severity. HADDTS is a neurodevelopmental-mitochondrial overlap disorder; registries, mitochondrial evaluation, and allele-specific therapies are priorities.<\/jats:p>","DOI":"10.3390\/ijms27157065","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:45:47Z","timestamp":1786027547000},"page":"7065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delineating the CTBP1-Related Phenotypic Spectrum: A Review of HADDTS and Atypical Variants"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9502-064X","authenticated-orcid":false,"given":"Enes Ya\u011f\u0131z","family":"Akda\u015f","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linshen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Bashiri Dezfouli","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3062-459X","authenticated-orcid":false,"given":"Barbara","family":"Wollenberg","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Head and Neck Surgery, School of Medicine, Technical University of Munich (TUM), 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1797122","DOI":"10.3389\/fimmu.2026.1797122","article-title":"NAD(H)-dependent corepressor CTBP1 integrates metabolic signals to drive oncogenic programs","volume":"17","author":"Schneider","year":"2026","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10048-016-0482-4","article-title":"A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects","volume":"17","author":"Beck","year":"2016","journal-title":"Neurogenetics"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lee, S., Vijayalingam, S., Klotz, E., Dedert, C., Xu, F., Chinnadurai, G., and Ezekiel, U.R. (2025). Isogenic iPSC-derived CTBP1 mutant neuronal cells exhibit neurodevelopmental defects. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1695464"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1159\/000500942","article-title":"CTBP1 confers protection for hippocampal and cortical neurons in rat models of Alzheimer\u2019s disease","volume":"26","author":"Hu","year":"2019","journal-title":"Neuroimmunomodulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49859","DOI":"10.18632\/oncotarget.10489","article-title":"The miR-644a\/CTBP1\/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer","volume":"7","author":"Raza","year":"2016","journal-title":"Oncotarget"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.stemcr.2019.02.005","article-title":"Glycolysis Regulates Human Embryonic Stem Cell Self-Renewal under Hypoxia through HIF-2\u03b1 and the Glycolytic Sensors CTBPs","volume":"12","author":"Arthur","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13395-026-00421-w","article-title":"CtBP1 sustains activity-dependent muscle properties and dampens synaptic, contractile and metabolic changes triggered by denervation","volume":"16","author":"Cattaneo","year":"2026","journal-title":"Skelet. Muscle"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/cdd.2008.186","article-title":"C-terminal binding protein maintains mitochondrial activities","volume":"16","author":"Kim","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e187","DOI":"10.1212\/NXG.0000000000000187","article-title":"De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities","volume":"3","author":"Sommerville","year":"2017","journal-title":"Neurol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Gastaldi, L., Mart\u00edn, J.I., Sosa, L.J., Quassollo, G., Cuasolo, Y.M.P., Valente, C., Luini, A., Corda, D., C\u00e1ceres, A., and Bisbal, M. (2022). BARS influences neuronal development by regulation of post-golgi trafficking. Cells, 11.","DOI":"10.3390\/cells11081320"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e70385","DOI":"10.1111\/jnc.70385","article-title":"CTBP1 in Brain Development: A Novel Variant c. 107G> C, p.(R36P) Leads to a Distinct Neurodevelopmental Disorder","volume":"170","author":"Nishijo","year":"2026","journal-title":"J. Neurochem."},{"key":"ref_12","first-page":"327","article-title":"Developmental regression and cerebellar atrophy in a patient with congenital fiber-type disproportion and a de novo heterozygous CTBP1 variant","volume":"52","author":"Ozaki","year":"2020","journal-title":"No To Hattatsu"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12041-021-01315-0","article-title":"Exome sequencing identified a de novo frameshift pathogenic variant of CTBP1 in an extremely rare case of HADDTS","volume":"100","author":"Khamirani","year":"2021","journal-title":"J. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1097\/MCD.0000000000000321","article-title":"A further case of hypotonia, ataxia, developmental delay and tooth enamel defect syndrome due to a recurrent C-terminal binding protein 1 mutation","volume":"29","author":"Bhatia","year":"2020","journal-title":"Clin. Dysmorphol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3604592","DOI":"10.1155\/crpe\/3604592","article-title":"Hypotonia, Ataxia, Developmental Delay and Tooth Enamel Defect Syndrome (HADDTS) due to a Heterozygous de Novo Missense Variant in CTBP1 Identified via Whole Genome Sequencing","volume":"2025","author":"Marco","year":"2025","journal-title":"Case Rep. Pediatr."},{"key":"ref_16","first-page":"546","article-title":"Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant","volume":"63","author":"Wong","year":"2022","journal-title":"JIMD Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s10048-019-00578-1","article-title":"A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity","volume":"20","author":"Beck","year":"2019","journal-title":"Neurogenetics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.nmd.2023.03.007","article-title":"A pathogenic CTBP1 variant featuring HADDTS with dystrophic myopathology","volume":"33","author":"Kadhim","year":"2023","journal-title":"Neuromuscul. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sunnetci-Akkoyunlu, D., Kara, B., Ozer, T., Deniz, A., Sakarya-Gunes, A., Isik, E.B., Dogruoglu, B., Ilkay, Z., Yilmaz, M., and Sahin, S. (2025). Genetic Etiology of Developmental and Epileptic Encephalopathy in a Turkish Cohort: A Single-Center Study with Targeted Gene Panel and Whole Exome Sequencing. Genes, 16.","DOI":"10.3390\/genes16101152"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ivanov, Z., Gevezova, M., Pacheva, I., Ketev, K., Chochkova-Bukova, L., Sarafian, V., and Ivanov, I. (2026). A Rare CTBP1-Related Neurodevelopmental Disorder Is Associated with Impaired Mitochondrial Bioenergetics: A Functional Case Report. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27094003"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Liu, Y., Liu, X., Zhao, Y., and Zhang, J. (2024). A novel CTBP1 variant in a Chinese pediatric patient with a phenotype distinct from hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome. Front. Genet., 15.","DOI":"10.3389\/fgene.2024.1344682"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.5114\/fn.2026.162176","article-title":"Floppy baby syndrome as the first presentation of HADDTS associated with CTBP1 mutation","volume":"64","author":"Jurkiewicz","year":"2026","journal-title":"Folia Neuropathol."},{"key":"ref_23","unstructured":"(2026, July 31). HADDTS Foundation. Available online: https:\/\/haddtsfoundation.org."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5296","DOI":"10.1128\/MCB.22.15.5296-5307.2002","article-title":"Overlapping and unique roles for C-terminal binding protein 1 (CtBP1) and CtBP2 during mouse development","volume":"22","author":"Hildebrand","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_25","unstructured":"Karczewski, K., and Francioli, L. (2017). The Genome Aggregation Database (gnomAD), MacArthur Lab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_28","first-page":"682","article-title":"DECIPHER: Supporting the interpretation and sharing of rare disease phenotype-linked variant data to advance diagnosis and research","volume":"43","author":"Foreman","year":"2022","journal-title":"Hum. Mutat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s10048-022-00700-w","article-title":"CTBP1 and CTBP2 mutations underpinning neurological disorders: A systematic review","volume":"23","year":"2022","journal-title":"Neurogenetics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1128\/MCB.01077-07","article-title":"Role of the PLDLS-binding cleft region of CtBP1 in recruitment of core and auxiliary components of the corepressor complex","volume":"28","author":"Kuppuswamy","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vijayalingam, S., Ezekiel, U.R., Xu, F., Subramanian, T., Geerling, E., Hoelscher, B., San, K., Ganapathy, A., Pemberton, K., and Tycksen, E. (2020). Human iPSC-derived neuronal cells from CTBP1-mutated patients reveal altered expression of neurodevelopmental gene networks. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.562292"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lee, S., and Ezekiel, U.R. (2025). Using the allen brain cell atlas of the human brain to gain insights into C-Terminal-Binding protein 1 (CtBP1)\u2019s potential function. Biologics, 5.","DOI":"10.20944\/preprints202503.0508.v1"},{"key":"ref_33","unstructured":"Simons Searchlight (2025). CTBP1-Related Disorder Registry, Simons Searchlight. Available online: https:\/\/www.simonssearchlight.org\/research\/what-we-study\/ctbp1\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D925","DOI":"10.1093\/nar\/gks1173","article-title":"The NIH genetic testing registry: A new, centralized database of genetic tests to enable access to comprehensive information and improve transparency","volume":"41","author":"Rubinstein","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"103012","DOI":"10.1016\/j.scr.2022.103012","article-title":"CRISPR\/Cas9-mediated generation of hESC lines with homozygote and heterozygote p.R331W mutation in CTBP1 to model HADDTS syndrome","volume":"67","author":"Turan","year":"2023","journal-title":"Stem Cell Res."},{"key":"ref_36","unstructured":"Gezdirici, A. (2019). S-15-Diagnosing Process in a Newly Described Extremely Rare Disease by Whole Exome Sequencing Re-analysis. 13th Balkan Congress of Human Genetics, Macedonian Academy of Sciences and Arts."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100351","DOI":"10.1016\/j.jbc.2021.100351","article-title":"NAD(H) phosphates mediate tetramer assembly of human C-terminal binding protein (CtBP)","volume":"296","author":"Nichols","year":"2021","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/7065\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T14:46:46Z","timestamp":1786027606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/7065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":37,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27157065"],"URL":"https:\/\/doi.org\/10.3390\/ijms27157065","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]}}}