Alpers-Huttenlocher syndrome

Alpers-Huttenlocher syndrome (also known as Alpers syndrome, Alpers disease, or progressive neuronal degeneration of childhood with liver disease) is a severe, autosomal recessive mitochondrial DNA depletion disorder most commonly caused by biallelic pathogenic variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. The disease primarily affects the brain and liver, leading to a characteristic clinical triad of refractory seizures (often epilepsia partialis continua), psychomotor regression, and hepatic dysfunction that can progress to liver failure. Onset typically occurs in infancy or early childhood, though later presentations have been reported. The neurological deterioration is progressive and includes intractable seizures, loss of previously acquired developmental milestones, cortical visual impairment, hypotonia, spasticity, and eventual severe encephalopathy. Liver involvement ranges from elevated transaminases to fulminant hepatic failure, which may be triggered or worsened by exposure to valproic acid — a medication that is strictly contraindicated in this condition. Additional features may include feeding difficulties, failure to thrive, and movement abnormalities such as ataxia or myoclonus. There is currently no cure for Alpers-Huttenlocher syndrome, and treatment remains supportive and symptomatic. Seizure management is particularly challenging, as the epilepsy is often refractory to standard antiepileptic drugs, and valproate must be avoided due to the risk of precipitating fatal hepatotoxicity. Nutritional support, physical therapy, and management of liver complications are important components of care. Liver transplantation has been considered in some cases but remains controversial due to the progressive neurological decline. The prognosis is poor, with most affected individuals surviving months to a few years after symptom onset, though the clinical course can be variable.

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