Alpers syndrome

Other Names: Alpers disease; Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis; Alpers progressive infantile poliodystrophy; Poliodystrophia cerebri progressiva; Progressive cerebral poliodystrophy; Diffuse cerebral degeneration in infancy; Alpers-Huttenlocher syndrome; Neuronal degeneration of childhood with liver disease, progressive; PNDC; Infantile poliodystrophy

Alpers syndrome is a progressive neurologic disorder that begins during childhood and is complicated in many instances by serious liver disease.The conditions in this group feature a range of similar signs and symptoms involving muscle-, nerve-, and brain-related functions.

Epidemiology

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

Cause

Alpers-Huttenlocher syndrome is caused by mutations in the POLG gene. This gene provides instructions for making one part, the alpha subunit, of a protein called polymerase gamma (pol γ). Pol γ functions in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. Pol γ "reads" sequences of mtDNA and uses them as templates to produce new copies of mtDNA in a process called DNA replication.

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Areflexia(Absent tendon reflexes)
• Ataxia
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Choreoathetosis
• Coma
• Developmental regression(Loss of developmental milestones)
• Focal-onset seizure(Seizure affecting one half of brain)
• Global developmental delay
• Microcephaly(Abnormally small skull)
• Muscular hypotonia(Low or weak muscle tone)
• Myoclonus
• Progressive spasticity
• Spastic paraparesis

5%-29% of people have these symptoms

• Blindness

Diagnosis

Establishing the diagnosis of a POLG-related disorder relies on clinical findings and identification of biallelic POLG pathogenic variants for all phenotypes except adPEO, for which identification of a heterozygous POLG pathogenic variant is diagnostic.

Treatment

Treatment is symptomatic and supportive. Anticonvulsants may be used to treat the seizures, but at times the seizures do not respond well to therapy, even at high doses. Therefore, the benefit of seizure control should be weights against what could be excessive sedation from the anticonvulsant. Valproate should not be used since it can increase the risk of liver failure. Physical therapy may help to relieve spasticity and maintain or increase muscle tone.

Prognosis

The prognosis for individuals with Alpers' disease is poor. Those with the disease usually die within their first decade of life. Continuous, unrelenting seizures often lead to death. Liver failure and cardiorespiratory failure due to brain, spinal cord, and nerve involvement may also occur.

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