{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T06:35:40Z","timestamp":1762929340589,"version":"3.45.0"},"reference-count":12,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"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. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Biallelic variants in\n                      <jats:italic>KCTD7<\/jats:italic>\n                      have been associated with progressive myoclonic epilepsy (PME), a rare autosomal recessive disorder characterized by early-onset epilepsy, cognitive decline, myoclonus, and ataxia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Whole-exome sequencing was first performed in the elder sister to identify candidate variants, followed by in silico pathogenicity prediction. Sanger sequencing was then used to validate the variants in both parents and the younger brother.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We report two siblings with progressive myoclonic epilepsy (PME) carrying compound heterozygous\n                      <jats:italic>KCTD7<\/jats:italic>\n                      variants: c.334C\u202f&amp;gt;\u202fT (p.Arg112Cys), a paternally inherited variant previously reported in homozygous form and currently classified as likely pathogenic, and c.640C\u202f&amp;gt;\u202fT (p.Arg214Trp), a novel maternally inherited variant currently classified as of uncertain significance. Both patients presented between 2 and 3\u202fyears of age with gait instability, myoclonic seizures, and developmental regression. EEG revealed background slowing, multifocal spike\u2013slow wave discharges, and electrical status epilepticus during sleep. Brain MRI findings were initially unremarkable despite progressive neurological deterioration. Whole-exome sequencing and Sanger validation confirmed the variants and their segregation. In silico tools predicted both variants to be deleterious, and structural modeling using PyMOL and I-Mutant 3.0 demonstrated that both variants likely disrupt local residue interactions and reduce protein stability. Both patients received antiepileptic therapy and immunomodulatory treatment, including intravenous methylprednisolone and immunoglobulin. The proband achieved seizure control and improved gait following immunotherapy, though cognitive deficits persisted. The younger sibling exhibited a more severe disease course, with progressive cognitive decline, speech and visual impairment, and loss of independent ambulation, despite partial seizure control. These findings expand the genetic and phenotypic spectrum of KCTD7-related PME and suggest that immunotherapy may confer partial clinical benefit in selected cases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This case expands the variant spectrum of\n                      <jats:italic>KCTD7<\/jats:italic>\n                      -related disorders and emphasizes the utility of comprehensive genetic testing in early-onset neurodegenerative epileptic syndromes. Functional studies are needed to clarify the clinical significance of the novel\n                      <jats:italic>KCTD7<\/jats:italic>\n                      variant.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2025.1670008","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T06:31:14Z","timestamp":1762929074000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Compound heterozygous KCTD7 variants in two siblings presenting with myoclonic epilepsy and ataxia"],"prefix":"10.3389","volume":"19","author":[{"given":"Jingjing","family":"Song","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenlin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luoxiao","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shitao","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liping","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenhui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.seizure.2023.04.013","article-title":"Developmental and\/or epileptic encephalopathy with spike-and-wave activation in sleep in Saudi Arabia: Electroclinical, etiologic, genetic, and outcome multicenter study","volume":"107","author":"Alsini","year":"2023","journal-title":"Seizure"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1007\/s12035-011-8194-0","article-title":"Progressive myoclonic epilepsy-associated gene KCTD7 is a regulator of potassium conductance in neurons","volume":"44","author":"Azizieh","year":"2011","journal-title":"Mol. Neurobiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1007\/s00415-012-6545-z","article-title":"A compound heterozygous missense mutation and a large deletion in the KCTD7 gene presenting as an opsoclonus-myoclonus ataxia-like syndrome","volume":"259","author":"Blumkin","year":"2012","journal-title":"J. Neurol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1080\/01677063.2021.1892095","article-title":"Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy","volume":"35","author":"Burke","year":"2021","journal-title":"J. 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Genet."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1002\/ana.25351","article-title":"KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect","volume":"84","author":"Metz","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"3109","DOI":"10.1093\/brain\/aww244","article-title":"Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport","volume":"139","author":"Moen","year":"2016","journal-title":"Brain"},{"key":"ref10","doi-asserted-by":"publisher","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. 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