Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy

Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy (also known as RRM2B-related mitochondrial DNA depletion syndrome or mtDNA depletion syndrome 8A) is an extremely rare and severe genetic disorder caused by pathogenic variants in the RRM2B gene, which encodes the p53-inducible small subunit of ribonucleotide reductase. This enzyme is essential for maintaining the mitochondrial deoxyribonucleotide pool required for mitochondrial DNA (mtDNA) replication. Deficiency leads to a critical reduction in mtDNA copy number (mtDNA depletion) in affected tissues, impairing mitochondrial oxidative phosphorylation and energy production. The disease primarily affects the brain, skeletal muscles, and kidneys. Key clinical features include severe encephalomyopathy presenting in infancy with hypotonia, muscle weakness, psychomotor regression or developmental delay, seizures, lactic acidosis, and failure to thrive. A distinguishing feature of this form is the presence of renal tubulopathy, which can manifest as proximal renal tubular dysfunction (Fanconi-like syndrome) with electrolyte imbalances, aminoaciduria, and phosphaturia. Additional findings may include respiratory insufficiency, feeding difficulties, and sensorineural hearing loss. Brain imaging may show progressive cerebral and cerebellar atrophy. The prognosis is generally poor, with most affected infants experiencing rapid neurological decline. There is currently no curative treatment. Management is supportive and multidisciplinary, focusing on seizure control, nutritional support, correction of metabolic and electrolyte abnormalities related to renal tubular dysfunction, and respiratory support as needed. Genetic counseling is recommended for affected families.

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