Human Genetics

, Volume 138, Issue 11–12, pp 1247–1257 | Cite as

MDH1 deficiency is a metabolic disorder of the malate–aspartate shuttle associated with early onset severe encephalopathy

  • Melissa H. Broeks
  • Hanan E. Shamseldin
  • Amal Alhashem
  • Mais Hashem
  • Firdous Abdulwahab
  • Tarfa Alshedi
  • Iman Alobaid
  • Fried Zwartkruis
  • Denise Westland
  • Sabine Fuchs
  • Nanda M. Verhoeven-Duif
  • Judith J. M. JansEmail author
  • Fowzan S. AlkurayaEmail author
Original Investigation


The reversible oxidation of l-malate to oxaloacetate is catalyzed by NAD(H)-dependent malate dehydrogenase (MDH). MDH plays essential roles in the malate–aspartate shuttle and the tricarboxylic acid cycle. These metabolic processes are important in mitochondrial NADH supply for oxidative phosphorylation. Recently, bi-allelic mutations in mitochondrial MDH2 were identified in patients with global developmental delay, epilepsy and lactic acidosis. We now report two patients from an extended consanguineous family with a deleterious variant in the cytosolic isoenzyme of MDH (MDH1). The homozygous missense variant in the NAD+-binding domain of MDH1 led to severely diminished MDH protein expression. The patients presented with global developmental delay, epilepsy and progressive microcephaly. Both patients had normal concentrations of plasma amino acids, acylcarnitines, lactate, and urine organic acids. To identify the metabolic consequences of MDH1 deficiency, untargeted metabolomics was performed on dried blood spots (DBS) from the patients and in MDH1 knockout HEK293 cells that were generated by Crispr/Cas9. Increased levels of glutamate and glycerol-3-phosphate were found in DBS of both patients. In MDH1 KO HEK293 cells, increased levels of glycerol-3-phosphate were also observed, as well as increased levels of aspartate and decreased levels of fumarate. The consistent finding of increased concentrations of glycerol-3-phosphate may represent a compensatory mechanism to enhance cytosolic oxidation of NADH by the glycerol-P-shuttle. In conclusion, MDH1 deficiency is a new metabolic defect in the malate–aspartate shuttle characterized by a severe neurodevelopmental phenotype with elevated concentrations of glycerol-3-phosphate as a potential biomarker.



Malate dehydrogenase


Malate–aspartate shuttle


Tricarboxylic acid


Dried blood spot


Liquid chromatography–mass spectrometry and tandem mass spectrometry


Glycerol 3-phosphate


Glycerol phosphate



We thank the patients and families for their enthusiastic participation. We also thank the Genotyping and Sequencing Core Facilities at KFSHRC for their technical help. We also thank Marjolein Bosma, Birgit Schiebergen-Bronckhorst, Johan Gerrits and Yuen Fung Tang for their technical assistance. This work was supported by King Salman Center for Disability Research (85721 to FSA); and Metakids (2017-075 to JJMJ).

Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest.

Supplementary material

439_2019_2063_MOESM1_ESM.docx (97 kb)
Supplementary material 1 (DOCX 96 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Melissa H. Broeks
    • 1
  • Hanan E. Shamseldin
    • 2
  • Amal Alhashem
    • 3
  • Mais Hashem
    • 2
  • Firdous Abdulwahab
    • 2
  • Tarfa Alshedi
    • 2
  • Iman Alobaid
    • 2
  • Fried Zwartkruis
    • 4
  • Denise Westland
    • 1
  • Sabine Fuchs
    • 5
  • Nanda M. Verhoeven-Duif
    • 1
  • Judith J. M. Jans
    • 1
    Email author
  • Fowzan S. Alkuraya
    • 2
    Email author
  1. 1.Section Metabolic Diagnostics, Department of GeneticsUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Department of GeneticsKing Faisal Specialist Hospital and Research CenterRiyadhSaudi Arabia
  3. 3.Department of PediatricsPrince Sultan Military Medical CityRiyadhSaudi Arabia
  4. 4.Department of Molecular Cancer Research, Center for Molecular MedicineUniversity Medical Center UtrechtUtrechtThe Netherlands
  5. 5.Section Metabolic Diseases, Department of Child Health, Wilhelmina Children’s HospitalUniversity Medical Center UtrechtUtrechtThe Netherlands

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