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Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency

  • Amanda Smith
  • Skye McBride
  • Julien L. Marcadier
  • Jean Michaud
  • Osama Y. Al-Dirbashi
  • Jeremy Schwartzentruber
  • Chandree L. Beaulieu
  • Sherri L. Katz
  • FORGE Canada Consortium
  • Jacek Majewski
  • Dennis E. Bulman
  • Michael T. Geraghty
  • Mary-Ellen Harper
  • Pranesh Chakraborty
  • Matthew A. LinesEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 30)

Abstract

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined d-2- and l-2-hydroxyglutaric aciduria (dl-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient’s organic acids confirmed the d- and l-2-hydroxyglutaric aciduria typical of dl-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders.

One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.

Keywords

Citrate transporter Cytochrome c oxidase Exome sequencing Lactic acidosis Mitochondrial disease SLC25A1 

Notes

Acknowledgments

The authors gratefully acknowledge the contribution of the proband and her family, without whose participation this work could not be undertaken.

Supplementary material

References

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Amanda Smith
    • 1
    • 2
  • Skye McBride
    • 1
  • Julien L. Marcadier
    • 3
  • Jean Michaud
    • 4
  • Osama Y. Al-Dirbashi
    • 3
  • Jeremy Schwartzentruber
    • 5
  • Chandree L. Beaulieu
    • 2
  • Sherri L. Katz
    • 1
    • 6
  • FORGE Canada Consortium
  • Jacek Majewski
    • 5
  • Dennis E. Bulman
    • 2
    • 3
  • Michael T. Geraghty
    • 2
    • 3
  • Mary-Ellen Harper
    • 7
  • Pranesh Chakraborty
    • 2
    • 3
  • Matthew A. Lines
    • 2
    • 3
    Email author
  1. 1.Ottawa Hospital Research InstituteOttawaCanada
  2. 2.Children’s Hospital of Eastern Ontario Research Institute, University of OttawaOttawaCanada
  3. 3.Division of Metabolics and Newborn Screening, Department of PediatricsChildren’s Hospital of Eastern OntarioOttawaCanada
  4. 4.Department of Pathology and Laboratory MedicineChildren’s Hospital of Eastern Ontario, University of OttawaOttawaCanada
  5. 5.McGill University and Genome Quebec Innovation CentreMontrealCanada
  6. 6.Division of Respirology, Department of PediatricsChildren’s Hospital of Eastern OntarioOttawaCanada
  7. 7.Department of Biochemistry, Microbiology and ImmunologyUniversity of OttawaOttawaCanada

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