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

Am J Med Genet A. 2013 Sep;161A(9):2204-15. doi: 10.1002/ajmg.a.36059. Epub 2013 Aug 5.

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.

Keywords: MEGDEL syndrome; SERAC1; infantile hepatopathy.

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Brain / pathology
  • Carboxylic Ester Hydrolases / genetics*
  • Case-Control Studies
  • Chromosome Mapping
  • Consanguinity
  • DNA Mutational Analysis
  • Electron Transport Chain Complex Proteins / metabolism
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / genetics*
  • Homozygote
  • Humans
  • Infant, Newborn
  • Leigh Disease / diagnosis
  • Leigh Disease / genetics*
  • Liver / pathology
  • Liver / ultrastructure
  • Liver Diseases / diagnosis
  • Liver Diseases / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Metabolism, Inborn Errors / diagnosis
  • Metabolism, Inborn Errors / genetics*
  • Microsatellite Repeats / genetics
  • Mitochondria / pathology
  • Mitochondria / ultrastructure
  • Mitochondrial Diseases / diagnosis
  • Mitochondrial Diseases / genetics*
  • Mutation*
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Syndrome

Substances

  • Electron Transport Chain Complex Proteins
  • Carboxylic Ester Hydrolases
  • SERAC1 protein, human

Supplementary concepts

  • 3-Methylglutaconic Aciduria Type IV