Evidence map›Paper›PMID 41696790›Full record

ArticleAnnals of neurology2026

The Clinical Spectrum and Neurodevelopmental Pathogenesis of KPTN-Related Disorder in a Mouse Model.

Lettie E Rawlins, Philip H Iffland, John Page, Rebecca Z Flessner, Soad M Elziny, Irina Sbornova, Janice K Babus, Sophie R Bruckmeier, Ria Parikh, Merel Verhoeven and 14 more

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Article in Annals of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

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5 · Who and what money

Authors and funding

24 authors.

Lettie E RawlinsUniversity of Exeter Medical School, Exeter, UK.
Philip H IfflandDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.ORCID 0000-0003-2203-188X
John PageDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Rebecca Z FlessnerDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Soad M ElzinyDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Irina SbornovaDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Janice K BabusDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Sophie R BruckmeierDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Ria ParikhDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
Merel VerhoevenDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
James FashamUniversity of Exeter Medical School, Exeter, UK.ORCID 0000-0002-7614-9202
Joseph S LeslieUniversity of Exeter Medical School, Exeter, UK.
Richard CaswellUniversity of Exeter Medical School, Exeter, UK.ORCID 0000-0003-0713-4602
Nishanka UbeyratnaUniversity of Exeter Medical School, Exeter, UK.
Olivia WengerNew Leaf Center, Clinic for Special Children, Mount Eaton, OH, USA.
Ethan M ScottNew Leaf Center, Clinic for Special Children, Mount Eaton, OH, USA.
John SchreiberChildren's National Medical Center, Washington, DC, USA.ORCID 0000-0003-0615-2497
Steffen SyrbeCenter for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany.
Annick Klabunde-CherwonCenter for Child and Adolescent Medicine, Heidelberg University, Heidelberg, Germany.
Martina OwensExeter Genomics Laboratory (NHS South West Genomic Laboratory Hub), Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Andrew H CrosbyUniversity of Exeter Medical School, Exeter, UK.
Emma L BapleUniversity of Exeter Medical School, Exeter, UK.ORCID 0000-0002-6637-3411
Peter B CrinoDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.ORCID 0000-0002-6232-3740
KPTN ConsortiumKPTN Consortium.

Funding

KPTN Loss and Megalencephaly: mTOR Activation as Therapeutic TargetR37NS125632 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI Peter B Crino · 2022 to 2026
$1.7M
The Role of GATOR1 in Cortical MalformationsR01NS099452 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI CRINO, PETER B · 2017 to 2021
$1.7M
NINDS NIH HHS R01 NS099452NINDS NIH HHS R01NS099452NINDS NIH HHS R37 NS125632NINDS NIH HHS R37NS125632Wellcome Trust
6 · The paper itself

Abstract

objectivePathogenic variants in Kaptin (KPTN) cause KPTN-related disorder (KRD). KPTN modulates mTOR signaling activation within the KICSTOR complex in response to cellular amino acid levels. We define the clinical spectrum and investigate the developmental pathogenesis of KRD.

methodsWe report the genotype and clinical phenotype of 71 KRD individuals (28 female subjects, ages 1 to 55 years) including 48 newly identified KRD individuals. The effects of Kptn knockout on brain development were assayed in vitro and in vivo.

resultsWe defined 15 novel KPTN variants. Intellectual disability (ID) was identified in all KRD individuals. Macrocephaly and epilepsy were observed in 46% and 47%, respectively. Neuroimaging revealed megalencephaly but no overt structural abnormalities. Ketotic hypoglycemia and endocrinopathies were identified in KRD. Increased head size was detected in unaffected parents heterozygous for KPTN variants. Two KRD individuals with drug-resistant epilepsy were treated with the mTOR inhibitor sirolimus but did not exhibit improved seizure control. CRISPR/Cas9 Kptn knockout in vitro induced mTOR activation and an mTOR-dependent increase in cell size. Kptn-/- mice exhibited increased cortical mTOR signaling that was reduced by rapamycin. Heterotopic neurons were identified in the subcortical white matter in the Kptn -/- mouse. Focal CRISPR/Cas9 Kptn knockout in cortex via in utero electroporation resulted in white matter heterotopic neurons. Electroencephalogram (EEG) did not detect ictal or inter-ictal abnormalities.

interpretationKRD is a multisystem neurodevelopmental disorder associated with ID, macrocephaly, epilepsy, mTOR signaling hyperactivation, and in a mouse model, subtle structural alterations in cerebral cortical cytoarchitecture. ANN NEUROL 2026;99:1287-1302.

Indexed as

Intellectual DisabilityNeurodevelopmental DisordersAdolescentAnimalsChildChild, PreschoolDisease Models, AnimalEpilepsyFemaleHumansInfantMaleMegalencephalyMiceMice, KnockoutTOR Serine-Threonine KinasesTOR Serine-Threonine Kinases

Identifiers

PMID41696790
PMCPMC13092776

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LicenceCC BY-NC-ND
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.