Alpers’ syndrome

Alpers’ syndrome is a mitochondrial disease that is part of a larger group of conditions collectively known as mitochondrial DNA depletion disorders. It is most often caused by mistakes in the DNA of a gene called POLG (pronounced “pawl-gee”) and is part of a spectrum of POLG-related diseases. There are a number of other, extremely rare, genetic causes of Alpers’syndrome. The three major clinical features associated with Alpers’ syndrome are severe epilepsy, loss of developmental skills (developmental regression) and liver failure.

Who does it affect?

Dr Bernard Alpers first described this very rare condition in young children under the age of 3 years. Since his first description, it has now been reported to also affect older children, adolescents and young adults.

What are the clinical features?

Typically, a young infant develops normally at first and gains weight and skills appropriately. Between 6 and 12 months old seizures begin, which are often very difficult to control with anticonvulsant drugs. 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 loss of previously gained skills.

What causes Alpers’ syndrome?

Alpers’ syndrome is most often caused by a genetic mistake in a gene called POLG. This gene provides the instructions needed to make a protein called polymerase gamma, which is responsible for “reading” sequences of mitochondrial DNA (mtDNA) and using them as a template to produce more mtDNA within the mitochondria. If the polymerase gamma doesn’t work properly due to mutations within the POLG gene, this can lead to a reduction in the amount or quality of mtDNA in affected tissues. In Alpers’ syndrome, the faulty polymerase gamma does not make sufficient mtDNA in liver or brain meaning that these organs are depleted of mtDNA. Other, much rarer causes of Alpers syndrome have been reported including genetic mistakes in genes involved in the process of making mitochondrial proteins such as FARS2, NARS2 and PARS2.

How is Alpers’ syndrome inherited?

Alpers’ syndrome is inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the faulty gene to develop the condition. Typically, each parent carries one copy of the faulty gene but they do not show signs or symptoms of the condition because they also have a second, normal copy of the POLG gene, which is sufficient to maintain health. There is a 1 in 4 chance of these parents having an affected child who inherits both copies of the faulty gene (one from each parent).

Can Alpers’ syndrome be treated?

There is no specific treatment for Alpers’ syndrome 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 liver failure in Alpers’ syndrome. Liver transplant has proved unsuccessful in patients with Alpers’ syndrome.

Can Alpers’ syndrome be prevented?

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

However, once a genetic mistake in POLG has been identified, there are reproductive options that can be offered to prevent Alpers’ syndrome in the next pregnancy. For people living in the UK, reproductive advice can be discussed with the doctors at any of the 3 highly specialised mitochondrial disease centres in Newcastle, London and Oxford.

One reproductive option is prenatal testing. 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 DNA from the biopsy to see which copies have been inherited. If both faulty copies have been inherited then termination of the pregnancy is offered. This type of prenatal testing is also available for other genetic causes of Alpers’ syndrome.

Another reproductive option is preimplantation genetic diagnosis (PGD). This is an IVF-based technique that involves examining the POLG gene in DNA taken from early embryos grown in the lab to see which copies have been inherited. The aim is to identify an embryo that does not carry the genetic mistakes that cause Alpers’ syndrome. If such an embryo is identified, it can be transferred to the womb to try and establish a pregnancy.