{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:50:50Z","timestamp":1791978650149,"version":"4.4.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The PIKfyve-FIG4-VAC14 lipid kinase complex generates phosphoinositide PI(3,5)P2. Pathogenic variants in VAC14 and FIG4 cause neurodevelopmental disorders and PIKFYVE has been linked to autosomal dominant fleck corneal dystrophy.<\/jats:p>\n                  <jats:p>We searched for the underlyging, genetic cause of a neurodevelopmental disorder in five affected individuals from three families using exome- or genome sequencing. Cranial MRI images and clinical phenotypes were analyzed. Size, number and acidity of cellular vacuoles were investigated in patient-derived fibroblasts from family 1 using LysoSensor acidophilic probes. Levels of PI(3,5)P2 were quantified in patient-derived fibroblasts from family 1 using high-performance liquid chromatography-tandem mass spectrometry. Pikfyve-mutant zebrafish larvae were injected with wildtype-mRNA or mutant mRNA harboring the PIKFYVE missense variant identified in family 3. Pikfyve-mutant zebrafish larvae were treated with metformin, bafilomycin A1, or rapamycin.<\/jats:p>\n                  <jats:p>We identified biallelic PIKFYVE variants in five affected individuals with hypomyelinating leukodystrophy, brain hyperintensities of inferior olives, thalami, long tracts, and optic nerves. Clinically, they presented with intellectual disability, spasticity, muscular weakness, and nystagmus. Additional features included feeding difficulties, auditory dysfunction, insulin resistance, microcephaly, peripheral neuropathy, and mild creatine kinase elevations.<\/jats:p>\n                  <jats:p>We detected four distinct PIKFYVE variants: three loss-of-function variants (family 1 &amp; 2), and one p.Arg1156Pro missense variant (family 3). The pathogenicity of the p.Arg1156Pro variant was confirmed by phenotypic rescue of pikfyve-mutant zebrafish larvae injected with wildtype-mRNA but not with p.Arg1156Pro mRNA. Consistent with the role of PIKfyve in maintaining endolysosomal homeostasis, patient-derived fibroblasts of family 1 accumulated enlarged, hyperacidic vacuoles and showed a reduced PI(3,5)P2 production upon hyperosmotic stimulation. Exposing pikfyve-mutant zebrafisch larvae to the mTORC1 inhibitor and TRPML1 activator rapamycin attenuated cellular vacuolization, highlighting potential therapeutic approaches.<\/jats:p>\n                  <jats:p>Our findings establish PIKFYVE deficiency as a novel cause of hypomyelinating leukodystrophy and endolysosomal dysfunction.<\/jats:p>","DOI":"10.1093\/brain\/awag355","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:41:07Z","timestamp":1791891667000},"source":"Crossref","is-referenced-by-count":0,"title":["Biallelic variants in\n                    <i>PIKFYVE<\/i>\n                    cause a hypomyelinating leukodystrophy with endolysosomal dysfunction"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0719-1607","authenticated-orcid":false,"given":"Luisa","family":"Averdunk","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]},{"name":"Westdeutsches Zentrum f\u00fcr Kinder- und Jugendgesundheit (WZKJ) (West German center of child and youth health), University Children's Hospital of Cologne , 50924 Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Gro\u00df","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B","family":"Hamacher","sequence":"additional","affiliation":[{"name":"Center for Advanced Imaging, Heinrich Heine University D\u00fcsseldorf , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke , NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diran","family":"Herebian","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shekeeb","family":"Mohammad","sequence":"additional","affiliation":[{"name":"Children\u2019s hospital at Westmead clinical school, Faculty of Medicine and Health, University of Sydney , Westmead 2145, New South Wales ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexej","family":"Knaus","sequence":"additional","affiliation":[{"name":"Institute of Genomic Statistics and Bioinformatics, University of Bonn , 53127 Bonn ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Seibt","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Schaper","sequence":"additional","affiliation":[{"name":"Center of Rare Diseases, Medical Faculty, Heinrich-Heine-University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinrich","family":"Sticht","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg , 91054 Erlangen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Bryen","sequence":"additional","affiliation":[{"name":"Centre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney , Sydney, NSW 2010 ,","place":["Australia"]},{"name":"Centre for Population Genomics, Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Kathrin","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Core Facility for Electron Microscopy, Medical Faculty, Heinrich Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Langener","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology, University Hospital RWTH Aachen , 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenika","family":"De Simone","sequence":"additional","affiliation":[{"name":"Edwards Family Division of Genetics and Rare Diseases, Ann & Robert H. Lurie Children's Hospital of Chicago , Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina","family":"Markshausen","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Lenk","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Michigan , Ann Arbor, MI 48109 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujal","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University-University Hospital D\u00fcsseldorf , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Sandaradura","sequence":"additional","affiliation":[{"name":"Sydney Children's Hospitals Network - Westmead , Sydney, New South Wales 2145 ,","place":["Australia"]},{"name":"Children's Hospital Westmead Clinical School, University of Sydney , Sydney, New South Wales 2145 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Guthoff","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical Faculty, Heinrich Heine University , 40225 D\u00fcsseldorf ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-5607","authenticated-orcid":false,"given":"Richard J","family":"Leventer","sequence":"additional","affiliation":[{"name":"Centre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney , Sydney, NSW 2010 ,","place":["Australia"]},{"name":"Centre for Population Genomics, Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Department of Paediatrics, University of Melbourne , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Royal Children\u2019s Hospital , Melbourne, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rotem","family":"Orbach","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke , NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Rius","sequence":"additional","affiliation":[{"name":"Centre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney , Sydney, NSW 2010 ,","place":["Australia"]},{"name":"Centre for Population Genomics, Murdoch Children\u2019s Research Institute , Melbourne, VIC 3052 ,","place":["Australia"]},{"name":"Department of Paediatrics, University of Melbourne , Melbourne, VIC 3052 ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Morton","sequence":"additional","affiliation":[{"name":"Sydney Children's Hospitals Network - 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