Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension

Am J Med Genet A. 2020 Apr;182(4):755-761. doi: 10.1002/ajmg.a.61491. Epub 2020 Jan 22.


Pulmonary hypertension (pHTN) is a severe, life-threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population.

Keywords: abnormal pulmonary development; iron sulfur clusters; ketogenic diet; multiple mitochondrial dysfunctions syndrome 1; pulmonary hypertension.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / genetics*
  • Developmental Disabilities / etiology*
  • Developmental Disabilities / pathology
  • Female
  • Humans
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / pathology
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / complications*
  • Mitochondrial Diseases / genetics
  • Mutation*
  • Prognosis


  • Carrier Proteins
  • NFU1 protein, human

Supplementary concepts

  • Multiple Mitochondrial Dysfunctions Syndrome