Macrocytosis in Mitochondrial DNA Deletion Syndromes

Acta Haematol. 2023;146(3):220-225. doi: 10.1159/000529311. Epub 2023 Feb 10.


Large single mitochondrial DNA (mtDNA) deletion syndrome is a rare inborn error of metabolism with variable heteroplasmy levels and clinical phenotype among affected individuals. Chronic progressive external ophthalmoplegia (CPEO) is the most common phenotype in adults with this form of mitochondrial disease [J Intern Med. 2020;287(6):592-608 and Biomed Rep. 2016;4(3):259-62]. The common CPEO clinical manifestations are ptosis and ophthalmoplegia. More variable phenotypic manifestations of CPEO (CPEO plus) include involvement of the peripheral nervous system and myopathy. Here, we describe a 62-year-old female with CPEO and the major mtDNA deletion present at 40% heteroplasmy, who had a coexistent previously undescribed CPEO phenotypic feature of persistent unexplained macrocytosis without anemia. Building on this case, we reviewed other major mtDNA deletion cases seen in our Adult Metabolic Diseases Clinic (AMDC) at the University of British Columbia, Vancouver, Canada, from 2016 to 2022. The major mtDNA deletion cases (n = 26) were compared with mtDNA missense variants identified in the clinic over the same period who acted as the comparison group (n = 16). Of these, the most frequent diagnosis was maternally inherited diabetes and deafness and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. Ten out of 26 (38%) of mtDNA deletion patients had macrocytosis with elevated mean corpuscular volume (MCV), median (interquartile range) of 108 fL (102-114 fL). Seven of the patients with macrocytosis had no pertinent etiology. None of the comparison group had macrocytosis. There was a significant difference (p = 0.000) between the MCV and MCH in the mtDNA deletion group compared to the comparison group. This communication sheds light on the association of macrocytosis with the mtDNA deletion syndrome. It would be of great interest to determine if the association is found in other mitochondrial disease clinic populations.

Keywords: Chronic progressive external ophthalmoplegia; Macrocytosis; Maternally inherited diabetes and deafness; Mitochondrial DNA deletion syndromes; Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes.

Publication types

  • Case Reports
  • Review
  • News

MeSH terms

  • Anemia*
  • DNA, Mitochondrial / genetics
  • Female
  • Humans
  • Ophthalmoplegia* / diagnosis
  • Ophthalmoplegia* / genetics
  • Ophthalmoplegia, Chronic Progressive External* / genetics


  • DNA, Mitochondrial

Supplementary concepts

  • Noninsulin-dependent diabetes mellitus with deafness