Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome

Area of Science:

• Genetics
• Biochemistry
• Neuroscience

Background:

• Phelan-McDermid Syndrome (PMS) is characterized by deletions in the 22q13 region.
• Significant phenotypic variability exists among individuals with PMS.
• Six mitochondrial genes, including those for complex I and IV, are located within 22q13.

Purpose of the Study:

• To investigate if mitochondrial complex activity abnormalities contribute to the phenotypic variation in PMS.
• To identify potential links between specific gene deletions and mitochondrial dysfunction.
• To correlate mitochondrial complex activity with a distinct set of PMS symptoms.

Main Methods:

• Mitochondrial complex I, II, II+III, and IV activity assays were performed on 51 PMS participants.
• Genetic information and phenotypic data were collected via questionnaires and the PMS foundation registry.
• Symptom patterns were analyzed in relation to measured complex activities and compared to registry data.

Main Results:

• Abnormal mitochondrial complex activity was observed in 59% of PMS participants.
• Complex I and IV activities were frequently abnormal, while complex II and II+III activities were not.
• A specific symptom cluster (autism spectrum disorder, developmental regression, failure-to-thrive, exercise intolerance/fatigue) was associated with abnormal complex activity.
• This symptom cluster was present in 64% of registry individuals without measured complex activity.

Conclusions:

• Mitochondrial complex I and IV activity abnormalities are implicated in the phenotypic variability of Phelan-McDermid Syndrome.
• The findings suggest a potential "neighboring effect" of deletions on adjacent gene expression influencing mitochondrial function.
• These results highlight novel pathophysiology mechanisms and potential therapeutic targets for PMS.