title: A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency.
abstract: Rhizomelic chondrodysplasia punctata (RCDP) is a group of disorders with overlapping clinical features including rhizomelia, chondrodysplasia punctata, coronal clefts, cervical dysplasia, congenital cataracts, profound postnatal growth retardation, severe intellectual disability, and seizures. Mutations in PEX7, GNPAT, and AGPS, all involved in the plasmalogen-biosynthesis pathway, have been described in individuals with RCDP. Here, we report the identification of mutations in another gene in plasmalogen biosynthesis, fatty acyl-CoA reductase 1 (FAR1), in two families affected by severe intellectual disability, early-onset epilepsy, microcephaly, congenital cataracts, growth retardation, and spasticity. Exome analyses revealed a homozygous in-frame indel mutation (c.495_507delinsT [p.Glu165_Pro169delinsAsp]) in two siblings from a consanguineous family and compound-heterozygous mutations (c.[787C>T];[1094A>G], p.[Arg263(∗)];[Asp365Gly]) in a third unrelated individual. FAR1 reduces fatty acids to their respective fatty alcohols for the plasmalogen-biosynthesis pathway. To assess the pathogenicity of the identified mutations, we transfected human embryonic kidney 293 cells with plasmids encoding FAR1 with either wild-type or mutated constructs and extracted the lipids from the cells. We screened the lipids with gas chromatography and mass spectrometry and found that all three mutations abolished the reductase activity of FAR1, given that no fatty alcohols could be detected. We also observed reduced plasmalogens in red blood cells in one individual to a range similar to that seen in individuals with RCDP, further supporting abolished FAR1 activity. We thus expand the spectrum of clinical features associated with defects in plasmalogen biosynthesis to include FAR1 deficiency as a cause of syndromic severe intellectual disability with cataracts, epilepsy, and growth retardation but without rhizomelia.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchert
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Hasan
authors.initials: H
authors.lastname: Tawamie
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Smith
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Practice for Pediatric, Kafranbel, Syria.
authors.forename: Bassam
authors.initials: B
authors.lastname: Al Hallak
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Department of Forensic Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schwarze
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.affiliation: Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
authors.forename: Francois P
authors.initials: FP
authors.lastname: Bernier
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: rami.aboujamra@uk-erlangen.de.
authors.forename: Rami
authors.initials: R
authors.lastname: Abou Jamra
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000445:Aldehyde Oxidoreductases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D001483:Base Sequence; D002386:Cataract / Q000235:genetics*; D002849:Chromatography, Gas; D003677:Deficiency Diseases / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000235:genetics*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D008055:Lipids / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D008055:Lipids; D000445:Aldehyde Oxidoreductases; C021351:hexadecanal dehydrogenase (acylating)