Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency

Mitochondrial DNA depletion syndrome, hepatocerebral form due to DGUOK deficiency (also known as DGUOK-related mitochondrial DNA depletion syndrome or deoxyguanosine kinase deficiency) is a severe inherited metabolic disorder caused by mutations in the DGUOK gene, which encodes the mitochondrial enzyme deoxyguanosine kinase. This enzyme is essential for the salvage pathway of mitochondrial deoxyribonucleoside triphosphates, which are building blocks needed for mitochondrial DNA (mtDNA) replication. When DGUOK is deficient, cells cannot maintain adequate copies of mtDNA, leading to mtDNA depletion and impaired mitochondrial respiratory chain function, particularly in the liver and brain. The disease primarily affects the liver and the central nervous system (hepatocerebral form). Most affected infants present in the neonatal or early infantile period with progressive liver failure, including hepatomegaly, jaundice, coagulopathy, and elevated liver enzymes. Neurological features include hypotonia, nystagmus, psychomotor regression or developmental delay, and in some cases seizures. Additional findings may include lactic acidosis, hypoglycemia, and elevated blood lactate and tyrosine levels. Some patients may also develop renal tubular dysfunction. The disease typically follows a rapidly progressive course, and many affected children do not survive beyond the first year of life without intervention. Currently, there is no curative treatment for DGUOK deficiency. Management is primarily supportive and symptomatic, including nutritional support, management of liver failure complications, and treatment of metabolic crises. Liver transplantation has been attempted in some patients; however, outcomes are variable and often poor, particularly in patients with significant neurological involvement, as transplantation does not address the progressive neurodegeneration. Genetic counseling is recommended for affected families. Research into potential therapies, including nucleoside supplementation strategies, is ongoing but remains experimental.

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