Mitochondrial DNA depletion syndrome, hepatocerebral form

Mitochondrial DNA depletion syndrome, hepatocerebral form (also known as hepatocerebral mitochondrial DNA depletion syndrome) is a severe inherited disorder characterized by a marked reduction in mitochondrial DNA (mtDNA) copy number in affected tissues, primarily the liver and brain. This condition belongs to a group of mitochondrial DNA depletion syndromes (MDS) and can be caused by mutations in several nuclear genes involved in mitochondrial DNA maintenance, including POLG, DGUOK, MPV17, TWNK (C10orf2), and SUCLG1. These genes encode proteins essential for mitochondrial DNA replication or nucleotide metabolism, and their dysfunction leads to progressive loss of mtDNA and impaired mitochondrial energy production. The hepatocerebral form typically presents in the neonatal or early infantile period with progressive liver failure, which may include jaundice, hepatomegaly, elevated liver enzymes, coagulopathy, and hypoglycemia. Neurological involvement is also prominent and may include hypotonia, developmental delay or regression, nystagmus, psychomotor retardation, and seizures. Additional features can include lactic acidosis, failure to thrive, and feeding difficulties. The severity and specific clinical presentation can vary depending on the underlying genetic cause, but the prognosis is generally poor, with many affected children dying in infancy or early childhood due to progressive hepatic failure or neurological deterioration. Currently, there is no curative treatment for mitochondrial DNA depletion syndrome, hepatocerebral form. Management is primarily supportive and symptomatic, including nutritional support, management of liver dysfunction, and treatment of seizures. Liver transplantation has been attempted in some patients, particularly those with DGUOK or MPV17 mutations, but outcomes are variable and neurological progression may continue despite successful transplantation. Emerging therapies, including nucleoside supplementation strategies, are under investigation but remain experimental. Genetic counseling is recommended for affected families.

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