title: Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.
abstract: 3-Methylglutaconic aciduria (3-MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3-MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3-MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2-6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the disease MEGDHEL syndrome.
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Sarig
authors.forename: Dorit
authors.initials: D
authors.lastname: Goldsher
authors.forename: Janna
authors.initials: J
authors.lastname: Nousbeck
authors.forename: Dana
authors.initials: D
authors.lastname: Fuchs-Telem
authors.forename: Ksenya
authors.initials: K
authors.lastname: Cohen-Katsenelson
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Iancu
authors.forename: Irena
authors.initials: I
authors.lastname: Manov
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008107:Liver Diseases / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D008928:Mitochondria / Q000473:pathology / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome
chemical_list: D045222:Electron Transport Chain Complex Proteins; D002265:Carboxylic Ester Hydrolases; C576043:SERAC1 protein, human
keywords: MEGDEL syndrome; SERAC1; infantile hepatopathy