Multiple mitochondrial DNA deletion syndrome

Multiple mitochondrial DNA deletion syndrome (also known as mitochondrial DNA depletion/deletion syndrome or progressive external ophthalmoplegia with mitochondrial DNA deletions) is a group of genetic disorders characterized by the accumulation of multiple deletions in mitochondrial DNA (mtDNA) within affected tissues. These deletions impair the function of mitochondria — the energy-producing structures in cells — leading to progressive dysfunction of organs with high energy demands. The condition primarily affects the nervous system, skeletal muscles, and eyes, though the liver, heart, and other organs may also be involved depending on the specific genetic subtype. Key clinical features vary by subtype but commonly include progressive external ophthalmoplegia (weakness of the eye muscles causing drooping eyelids and limited eye movement), proximal muscle weakness, exercise intolerance, sensory or sensorimotor neuropathy, ataxia (impaired coordination), sensorineural hearing loss, and dysphagia. Some forms present with more severe neurological involvement including seizures, cognitive decline, or parkinsonism. The disorder can present from childhood through adulthood, with adult-onset forms being more common in certain subtypes. Multiple mitochondrial DNA deletion syndrome is caused by pathogenic variants in nuclear genes responsible for mitochondrial DNA maintenance, including POLG, TWNK (previously C10orf2), RRM2B, SLC25A4 (ANT1), TYMP, DGUOK, TK2, and others. Inheritance can be autosomal dominant or autosomal recessive depending on the gene involved. There is currently no cure for this condition. Treatment is supportive and symptomatic, focusing on management of ptosis (eyelid surgery), physical therapy for muscle weakness, hearing aids for hearing loss, and monitoring for cardiac or hepatic complications. Coenzyme Q10 supplementation and other mitochondrial cofactors are sometimes used, though evidence for their efficacy remains limited.

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