Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome.

Richard E Frye,Devin Cox,Marie Tippett,Shirish Damle,Stephen Kahler,John Slattery,Doreen Granpeesheh,Agustin Legido,Michael J Goldenthal

doi:10.1038/srep19544

Abstract

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.

Highlights

Phelan-McDermid Syndrome (PMS) is a genetic syndrome defined by a deletion in the 22q13 chromosomal region and a variety of clinical findings including physical dysmorphology, medical conditions such as seizures, both growth failure and overgrowth, hypotonia, gastrointestinal disturbances and neurodevelopmental disorders such as developmental delays and autism spectrum disorder (ASD)[1]
In this study we demonstrated that 59% of individuals with PMS had abnormalities in electron transport chain (ETC) complex activity, thereby supporting our hypothesis that disruption of mitochondrial genes in the 22q13 region may disrupt mitochondrial function
We predicted that Complex I and Complex IV abnormalities would be more common than expected in PMS individuals while abnormalities in Complex II and II + III would not

Summary

Results

Complex I activity variance was significantly greater in PMS participants as compared to the control group but mean Complex I activity for PMS participants was not different than the control group. PMS participants demonstrated significantly lower Complex IV activity [t(50) = 4.81, p < 0.0001] than age-matched controls [Mean (SD): PMS 0.24 (0.12); Controls 0.35 (0.11)] but the variance was not significantly different between groups. Neither the mean nor variance in Citrate Synthase was significantly different between the PMS participants and age-matched controls. These findings confirm differences in Complex I and Complex IV activity between PMS participants and controls found in the previous analysis.

Participants with Any Complex Affected

Discussion

Methods