Wellcome Trust Centre For Mitochondrial Research

What is Alpers Disease?

Alpers disease is a mitochondrial disease that affects the brain and liver. Mitochondria work as tiny batteries within cells providing them with energy. Cells cannot function properly without this energy supply and in the case of Alpers disease this leads to severe epilepsy, loss of developmental skills and liver failure.

Why is it called Alpers?

Dr Bernard Alpers was the pathologist who, in 1931, first identified a particular pattern of brain involvement in children with severe epilepsy. He had no idea that mitochondria were involved, nor did Dr Peter Huttenlocher who, in 1976, described the key clinical and pathological features of Alpers disease. Sometimes other names are used to describe Alpers disease including: Alpers-Huttenlocher Syndrome (AHS), Progressive Neuronal Degeneration of Childhood (PNDC) or, less commonly, Progressive Sclerosing Poliodystrophy. These all refer to the same condition and are not different diagnoses. Doctors tend to call the condition “Alpers” even though Huttenlocher made a significant contribution to describing the disease.

Who is affected?

Alpers syndrome is a rare condition that generally affects young children (6 months to 3 years), but some older children and young adults may be affected by severe epilepsy and liver disease due to a defect in the same gene that causes Alpers. Typically, a young infant develops normally at first and gains weight and skills appropriately. At around 12 months old seizures begin and these are often very difficult to control. Seizures may be generalized, where they involve all four limbs, or focal, where a single limb or one side of the body jerks repeatedly. The jerks are sometimes referred to as ‘myoclonic jerks’. The onset of these seizures is associated with a slowing in development and often there is a loss of previously gained skills (regression).

What causes Alpers?

Alpers is one possible outcome when the tiny batteries known as mitochondria do not work properly. More specifically, Alpers is caused by a fault in Polymerase Gamma, an enzyme that allows the mitochondrion to make its own DNA (mtDNA). This defect was not discovered until 2004 when researchers found faults in a gene called POLG, which contains the genetic code for Polymerase Gamma. In Alpers syndrome the faulty Polymerase Gamma does not make sufficient mtDNA in liver or brain – these organs are depleted of mtDNA.

How is Alpers inherited?

We inherit two copies of a gene, one from each parent. If one copy, say from the father, is faulty, then this usually isn’t a problem, as the other normal copy from the mother will work perfectly well. Parents of children with Alpers syndrome carry one faulty copy and one normal copy of POLG. One faulty copy doesn’t cause either parent any problems because their back-up copy works fine. However, if their child inherits both faulty copies of POLG then no back-up copy is available and Polymerase Gamma does not function properly, leading to depletion of mtDNA in brain and liver. If both parents have a single faulty copy (the faults may not be the same in both parents) then the risk of a child inheriting both faulty copies and having Alpers disease is 1 in 4. This risk for these parents will stay the same for each pregnancy.

Can Alpers be treated?

There is no specific treatment for Alpers disease, but symptoms can be relieved to an extent with anticonvulsants. It is important that Sodium Valproate is avoided as this commonly used anticonvulsant can bring on the liver failure. Liver transplant has proved unsuccessful in patients with Alpers disease.

Can Alpers be prevented?

If the genetic faults are present, then there is nothing that can be taken during pregnancy or given to the infant that will prevent Alpers occurring.

However, once the faults in POLG have been identified, it is possible to offer prenatal testing in the next pregnancy. This form of prevention is only suitable for those people who would consider termination and would usually be done after 10-12 weeks of the pregnancy by chorionic villus biopsy. The POLG gene is examined in this biopsy to see which copies have been inherited. If both faulty copies have been inherited then termination of the pregnancy is offered. In the UK there are 3 centres in Newcastle, London and Oxford that offer this genetic testing service.

Research Questions

We know that Alpers disease is caused by faults in the POLG gene, but at present there is much we do not understand about Alpers such as:

  • How common is Alpers?
  • Why are the liver and brain cells of young children particularly affected?
  • Why do some mutations in POLG lead to milder problems with a later onset?
  • How do the mutations in POLG lead to cells not working properly?
  • Why are some parts of the brain more affected than others?
  • How does Alpers compare to other forms of mtDNA depletion involving liver and brain?

These are just some of the questions that researchers are, or will be, trying to answer so that we can understand the mechanisms that cause Alpers syndrome. Only through understanding the mechanisms of a disease can we begin to plan effective treatments.