Exercise Intolerance as a Clinical Red Flag For Childhood-Onset Mitochondrial Diseases : A Narrative Review

Abstract

Background: Childhood-onset mitochondrial diseases comprise a clinically and genetically heterogeneous group of inherited disorders in which impaired oxidative phosphorylation predominantly affects tissues with high energy demands. Exercise intolerance is a common but nonspecific manifestation that may be overlooked or attributed to other conditions, contributing to delayed diagnosis. This narrative review aims to summarize the current evidence regarding exercise intolerance as a potential clinical red flag for childhood-onset mitochondrial diseases.

Methods: A narrative literature review was conducted using the PubMed/MEDLINE database. English-language articles published between 2010 and 2026 were identified using keywords related to mitochondrial diseases, exercise intolerance, diagnosis, and pediatric populations. Additional relevant studies were identified through backward citation searching.

Results: Current evidence suggests that exercise intolerance frequently represents one of the earliest manifestations of childhood-onset mitochondrial diseases. Its diagnostic significance increases when accompanied by neurological or multisystem manifestations together with supportive laboratory or neuroimaging abnormalities, warranting further metabolic and genetic evaluation.

Conclusions: Exercise intolerance should be recognized as an important clinical red flag for childhood-onset mitochondrial diseases, particularly when associated with additional neurological or multisystem features. Early clinical recognition followed by appropriate metabolic and genetic evaluation may reduce diagnostic delay, facilitate molecular diagnosis, and improve patient management.