{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T20:41:56Z","timestamp":1791578516039,"version":"4.3.4"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,4,14]],"date-time":"2015-04-14T00:00:00Z","timestamp":1428969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>FBXL4<\/jats:italic>\n                    deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of\n                    <jats:italic>FBXL4<\/jats:italic>\n                    deficiency has been established in 28 individuals. This paper retrospectively reviews proxy\u2010reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal\/early\u2010onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow\u2010up 46 months), three children were lost to follow\u2010up. All survivors developed severe psychomotor retardation. Brain imaging was non\u2010specific in neonates but a later\u2010onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the\n                    <jats:italic>FBXL4<\/jats:italic>\n                    gene albeit with no clear delineation of a genotype\u2010phenotype correlation. Treatment with \u201cmitochondrial medications\u201d did not prove effective. In conclusion, a clinical pattern of early\u2010onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of\n                    <jats:italic>FBXL4<\/jats:italic>\n                    . Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.\n                  <\/jats:p>","DOI":"10.1007\/s10545-015-9836-6","type":"journal-article","created":{"date-parts":[[2015,4,13]],"date-time":"2015-04-13T04:28:45Z","timestamp":1428899325000},"page":"905-914","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to\n                    <i>FBXL4<\/i>\n                    mutations"],"prefix":"10.1002","volume":"38","author":[{"given":"Martina","family":"Huemer","sequence":"first","affiliation":[{"name":"Department of Pediatrics Landeskrankenhaus Bregenz Carl\u2010Pedenz\u2010Str. 2 Bregenz 6900 Austria"},{"name":"Division of Metabolism University Children's Hospital Z\u00fcrich Z\u00fcrich Switzerland"},{"name":"radiz \u2013 Rare Disease Initiative Z\u00fcrich University Z\u00fcrich Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Karall","sequence":"additional","affiliation":[{"name":"Clinic for Pediatrics I, Inherited Metabolic Disorders Medical University of Innsbruck Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schossig","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology Medical University of Innsbruck Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose E.","family":"Abdenur","sequence":"additional","affiliation":[{"name":"Division of Metabolic Disorders CHOC Children's Orange CA USA"},{"name":"Department of Pediatrics University of California at Irvine (UCI) Irvine CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Al Jasmi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine and Health Sciences United Arab Emirates University Al Ain United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Biagosch","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Technische Universit\u00e4t M\u00fcnchen Munich Germany"},{"name":"Institute of Human Genetics Helmholtz Zentrum M\u00fcnchen Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Distelmaier","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Heinrich\u2010Heine\u2010University D\u00fcsseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Freisinger","sequence":"additional","affiliation":[{"name":"Klinikum am Steinenberg Childrens\u2019 Hospital Reutlingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett H.","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias B.","family":"Haack","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics Technische Universit\u00e4t M\u00fcnchen Munich Germany"},{"name":"Institute of Human Genetics Helmholtz Zentrum M\u00fcnchen Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Hauser","sequence":"additional","affiliation":[{"name":"Childrens\u2019 Hospital Central California Madera California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"Hertecant","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Tawam Hospital Al Ain UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Ebrahimi\u2010Fakhari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Hospital Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassiliki","family":"Konstantopoulou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Medical University of Vienna Vienna 1090 Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Leydiker","sequence":"additional","affiliation":[{"name":"Division of Metabolic Disorders CHOC Children's Orange CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"Lourenco","sequence":"additional","affiliation":[{"name":"Neurogenetics Unit. Department of Neurology University of Sao Paulo Sao Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Scholl\u2010B\u00fcrgi","sequence":"additional","affiliation":[{"name":"Clinic for Pediatrics I, Inherited Metabolic Disorders Medical University of Innsbruck Innsbruck Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekkehard","family":"Wilichowski","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescent Medicine, Division of Pediatric Neurology University Medical Center G\u00f6ttingen, Georg August University G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole I.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department.of Child Neurology VU University Medical Center, and Neuroscience Campus Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia 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