A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13

Tuva Barøy; Christeen Ramane J Pedurupillay; Yngve T Bliksrud; Magnhild Rasmussen; Asbjørn Holmgren; Magnus D Vigeland; Timothy Hughes; Maaike Brink; Richard Rodenburg; Bård Nedregaard; Petter Strømme; Eirik Frengen; Doriana Misceo

doi:10.1016/j.ejmg.2016.05.005

A novel mutation in FBXL4 in a Norwegian child with encephalomyopathic mitochondrial DNA depletion syndrome 13

Eur J Med Genet. 2016 Jun;59(6-7):342-6. doi: 10.1016/j.ejmg.2016.05.005. Epub 2016 May 13.

Authors

Affiliations

¹ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: tuva.baroy@medisin.uio.no.
² Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: p.j.c.ramane@medisin.uio.no.
³ Department of Medical Biochemistry, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: ybliksru@ous-hf.no.
⁴ 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.
⁵ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: asbjorh@student.matnat.uio.no.
⁶ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: magnusdv@medisin.uio.no.
⁷ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: timothy.hughes@medisin.uio.no.
⁸ 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.
⁹ 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.
¹⁰ Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: bnedrega@ous-hf.no.
¹¹ 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.
¹² Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: eirik.frengen@medisin.uio.no.
¹³ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0407, Oslo, Norway. Electronic address: doriana.misceo@medisin.uio.no.

PMID: 27182039
DOI: 10.1016/j.ejmg.2016.05.005

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.

Keywords: FBXL4; MTDPS13; Mitochondrial disorder; c.1442T>C; mtDNA depletion; p.Leu481Pro.

Publication types

Case Reports

MeSH terms

Child
DNA, Mitochondrial / genetics*
Exome / genetics
F-Box Proteins / genetics*
Fibroblasts / metabolism
Fibroblasts / pathology
Humans
Male
Metabolism, Inborn Errors / genetics
Mitochondrial Encephalomyopathies / epidemiology
Mitochondrial Encephalomyopathies / genetics*
Mitochondrial Encephalomyopathies / pathology
Muscle, Skeletal / pathology*
Mutation, Missense
Norway / epidemiology
Ubiquitin-Protein Ligases / genetics*

Substances

DNA, Mitochondrial
F-Box Proteins
Ubiquitin-Protein Ligases
FbxL4 protein, human