Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome

Sci Rep. 2016 Jan 29;6:19544. doi: 10.1038/srep19544.


Phelan-McDermid Syndrome (PMS), which is defined by a deletion within 22q13, demonstrates significant phenotypic variation. Given that six mitochondrial genes are located within 22q13, including complex I and IV genes, we hypothesize that mitochondrial complex activity abnormalities may explain phenotypic variation in PMS symptoms. Complex I, II, II + III and IV activity was measured in 51 PMS participants. Caretakers completed questionnaires and provided genetic information through the PMS foundation registry. Complex activity was abnormal in 59% of PMS participants. Abnormalities were found in complex I and IV but not complex II + III and II activity, consistent with disruption of genes within the 22q13 region. However, complex activity abnormalities were not related to specific gene deletions suggesting a "neighboring effect" of regional deletions on adjacent gene expression. A specific combination of symptoms (autism spectrum disorder, developmental regression, failure-to-thrive, exercise intolerance/fatigue) was associated with complex activity abnormalities. 64% of 106 individuals in the PMS foundation registry who did not have complex activity measured also endorsed this pattern of symptoms. These data suggest that mitochondrial abnormalities, specifically abnormalities in complex I and IV activity, may explain some phenotypic variation in PMS individuals. These results point to novel pathophysiology mechanisms and treatment targets for PMS patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chromosome Deletion
  • Chromosome Disorders / enzymology
  • Chromosome Disorders / genetics*
  • Chromosome Disorders / pathology*
  • Chromosomes, Human, Pair 22 / enzymology
  • Chromosomes, Human, Pair 22 / genetics
  • Citrate (si)-Synthase / genetics
  • Electron Transport / genetics
  • Female
  • Gene Deletion
  • Genes, Mitochondrial
  • Humans
  • Male
  • Mitochondria / pathology*
  • Registries
  • Young Adult


  • Citrate (si)-Synthase

Supplementary concepts

  • Telomeric 22q13 Monosomy Syndrome