Alpers-Huttenlocher syndrome

Alpers-Huttenlocher syndrome is one of the most severe of a group of conditions called the POLG-related disorders. The conditions in this group feature a range of similar signs and symptoms involving muscle-, nerve-, and brain-related functions. Alpers-Huttenlocher syndrome typically becomes apparent in children between ages 2 and 4. People with this condition usually have three characteristic features: recurrent seizures that do not improve with treatment (intractable epilepsy), loss of mental and movement abilities (psychomotor regression), and liver disease.

People with Alpers-Huttenlocher syndrome usually have additional signs and symptoms. Most have problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). Neuropathy can lead to abnormal or absent reflexes (areflexia). In addition, affected individuals may develop weak muscle tone (hypotonia) that worsens until they lose the ability to control their muscles and movement. Some people with Alpers-Huttenlocher syndrome lose the ability to walk, sit, or feed themselves. Other movement-related symptoms in affected individuals can include involuntary muscle twitches (myoclonus), uncontrollable movements of the limbs (choreoathetosis), or a pattern of movement abnormalities known as parkinsonism.

Affected individuals may have other brain-related signs and symptoms. Migraine headaches, often with visual sensations or auras, are common. Additionally, people with this condition may have decreased brain function that is demonstrated as sleepiness, inability to concentrate, irritability, or loss of language skills or memory. Some people with the condition may lose their eyesight or hearing. People with Alpers-Huttenlocher syndrome can survive from a few months to more than 10 years after the condition first appears.

The prevalence of Alpers-Huttenlocher syndrome is approximately 1 in 100,000 individuals.


Most POLG gene mutations change single protein building blocks (amino acids) in the alpha subunit of pol γ. These changes result in a mutated pol γ that has a reduced ability to replicate DNA. Although the mechanism is unknown, mutations in the POLG gene often result in a reduced number of copies of mtDNA (mtDNA depletion), particularly in muscle, brain, and liver cells. MtDNA depletion causes a decrease in cellular energy, which could account for the signs and symptoms of Alpers-Huttenlocher syndrome.

A mutation in the POLG gene has not been identified in approximately 13 percent of people diagnosed with Alpers-Huttenlocher syndrome. Researchers are working to identify other genes that may be responsible for the condition.


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