title: A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13.
abstract: Mitochondrial DNA depletion syndromes (MTDPS) represent a clinically and genetically heterogeneous group of autosomal recessive disorders, caused by mutations in genes involved in maintenance of mitochondrial DNA (mtDNA). Biallelic mutations in FBXL4 were recently described to cause encephalomyopathic MTDPS13. The syndrome has infantile onset and presents with hypotonia, feeding difficulties, a pattern of mild facial dysmorphisms, global developmental delay and brain atrophy. Laboratory investigations reveal elevated blood lactate levels, unspecific mitochondrial respiratory chain (MRC) enzyme deficiencies and mtDNA depletion. We report a novel missense variant, c.1442T > C (p.Leu481Pro), in FBXL4 (NM_012160.4) in a Norwegian boy with clinical, biochemical and cerebral MRI characteristics consistent with MTDPS13. The FBXL4 c.1442T > C (p.Leu481Pro) variant was not present in public databases, 149 Norwegian controls nor an in-house database containing whole exome sequencing data from 440 individuals, and it was predicted in silico to be deleterious to the protein function. Activities of MRC enzymes were normal in muscle tissue (complexes I-IV) and cultured skin fibroblasts (complexes I-V) from the patient, but mtDNA depletion was confirmed in muscle, thus supporting the predicted pathogenicity of the FBXL4 c.1442T > C (p.Leu481Pro) variant. On clinical indication of mitochondrial encephalomyopathy, sequencing of FBXL4 should be performed, even when the activity levels of the MRC enzymes are normal.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: tuva.baroy@medisin.uio.no.
authors.forename: Tuva
authors.initials: T
authors.lastname: Barøy
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: p.j.c.ramane@medisin.uio.no.
authors.forename: Christeen Ramane J
authors.initials: CR
authors.lastname: Pedurupillay
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: ybliksru@ous-hf.no.
authors.forename: Yngve T
authors.initials: YT
authors.lastname: Bliksrud
authors.affiliation: Department of Clinical Neurosciences for Children, Women and Children's Division, Oslo and University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: marasmus@ous-hf.no.
authors.forename: Magnhild
authors.initials: M
authors.lastname: Rasmussen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: asbjorh@student.matnat.uio.no.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: magnusdv@medisin.uio.no.
authors.forename: Magnus D
authors.initials: MD
authors.lastname: Vigeland
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: timothy.hughes@medisin.uio.no.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hughes
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Maaike.Brink@radboudumc.nl.
authors.forename: Maaike
authors.initials: M
authors.lastname: Brink
authors.affiliation: Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Richard.Rodenburg@radboudumc.nl.
authors.forename: Richard
authors.initials: R
authors.lastname: Rodenburg
authors.affiliation: Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: bnedrega@ous-hf.no.
authors.forename: Bård
authors.initials: B
authors.lastname: Nedregaard
authors.affiliation: Department of Clinical Neurosciences for Children, Women and Children's Division, Oslo and University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: petter.stromme@medisin.uio.no.
authors.forename: Petter
authors.initials: P
authors.lastname: Strømme
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: eirik.frengen@medisin.uio.no.
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: doriana.misceo@medisin.uio.no.
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
mesh_terms: D002648:Child; D004272:DNA, Mitochondrial / Q000235:genetics*; D059472:Exome / Q000235:genetics; D044783:F-Box Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics; D017237:Mitochondrial Encephalomyopathies / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology*; D020125:Mutation, Missense; D009664:Norway / Q000453:epidemiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D044783:F-Box Proteins; D044767:Ubiquitin-Protein Ligases; C561936:FbxL4 protein, human
keywords: FBXL4; MTDPS13; Mitochondrial disorder; c.1442T>C; mtDNA depletion; p.Leu481Pro