Mitochondrial DNA depletion syndrome, myopathic form

Mitochondrial DNA depletion syndrome, myopathic form (also known as MDS, myopathic form or mitochondrial DNA depletion syndrome 2, myopathic type) is a rare, severe genetic disorder characterized by a marked reduction in mitochondrial DNA (mtDNA) copy number primarily affecting skeletal muscle. This leads to impaired mitochondrial respiratory chain function and progressive muscle weakness. The condition predominantly affects the muscular system, though other organs may also be involved to varying degrees. It is caused by pathogenic variants in genes essential for mitochondrial DNA maintenance, most commonly TK2 (thymidine kinase 2), which encodes an enzyme critical for mitochondrial nucleotide metabolism. The myopathic form typically presents in infancy or early childhood with progressive muscle weakness (myopathy), hypotonia (reduced muscle tone), difficulty feeding, and motor regression — meaning children may lose previously acquired motor skills such as walking or sitting. Affected individuals often develop respiratory insufficiency due to weakness of the breathing muscles, which can be life-threatening. Elevated serum creatine kinase levels and ragged red fibers on muscle biopsy are characteristic findings. Some patients may also develop mild involvement of other organs, but the predominant clinical picture is skeletal muscle disease. Currently, there is no definitive cure for this condition. Management is primarily supportive and includes respiratory support (including mechanical ventilation when needed), physical therapy, nutritional support, and monitoring for complications. Deoxynucleoside substrate therapy (specifically oral deoxynucleosides such as deoxythymidine and deoxycytidine) has shown promise in clinical studies for TK2-related myopathic MDS, with some patients demonstrating stabilization or improvement in motor and respiratory function. Early diagnosis and intervention are important for optimizing outcomes.

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