The disease

Lafora disease is a severe, hereditary form of progressive myoclonic epilepsy. The disease usually begins with epileptic seizures in late childhood or adolescence, and affects men and women equally.

Other signs and symptoms include difficulty walking, muscle spasms (myoclonus) and dementia. Affected individuals also experience rapid cognitive deterioration that begins around the same time as the attacks. The disease is often fatal within 10 years of onset. Most cases are caused by changes (mutations) in the EPM2A gene or the NHLRC1(EPM2B) gene and are inherited in an autosomal recessive manner. Treatment is based on the signs and symptoms present in each individual.

The signs and symptoms of Lafora disease usually appear in late childhood or adolescence. Before the onset of symptoms, affected children appear to have normal development, although some may have isolated febrile or non-febrile convulsions during infancy or early adolescence.

Recurrent epileptic seizures are the most common feature of Lafora disease. Several types of seizures have been reported, including generalised tonic-clonic seizures, occipital seizures (which can cause temporary blindness and visual hallucinations) and myoclonic seizures. These seizures are considered ‘progressive’ because they generally worsen and become more difficult to treat over time.

With the onset of seizures, people with Lafora disease often begin to show signs of cognitive decline. This can include behavioural changes, depression, confusion, ataxia (difficulty controlling muscles), dysarthria and eventually dementia. By their mid-twenties, those most affected lose the ability to carry out activities of daily living, have continuous bursts of myoclonus, and require tube feeding and comprehensive care.

Like most illnesses, symptoms vary from person to person. People with the same disease may not have all the symptoms listed.

Most cases of Lafora disease are caused by mutations in the EPM2A gene or the NHLRC1 (or EPM2B) gene. Both genes are located on chromosome 6. The EPM2A gene makes the protein called Laforin and the EPM2B gene makes the protein called Malin. These genes code for proteins that play an essential role in the survival of nerve cells (neurons) in the brain. Although proteins are thought to have many functions in the body, one important role is to help regulate the production of a complex sugar called glycogen (an important source of energy stored in the body). Mutations in the EPM2A gene or the NHLRC1 gene interfere with the production of functional proteins, leading to the formation of Lafora bodies (aggregates of abnormal glycogen that cannot be broken down and used as fuel) in cells. An accumulation of Lafora bodies appears to be particularly toxic to the cells of the nervous system and leads to the signs and symptoms of Lafora disease. Some cases of Lafora disease are caused by one or more as yet unidentified genes.

Lafora disease is transmitted in an autosomal recessive fashion. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person generally each carry a mutated copy of the gene and are known as carriers. Carriers generally show no signs or symptoms of the disease. When two carriers of an autosomal recessive disease have children, each child has a 25% (1 in 4) chance of having the disease, a 50% (1 in 2) chance of being a carrier like each parent, and a 25% chance of not being a carrier.

A diagnosis of Lafora disease is often suspected on the basis of the presence of characteristic signs and symptoms. Additional tests may then be carried out to confirm the diagnosis and exclude other conditions that may cause similar features. For example, a skin biopsy may be performed to detect the ‘Lafora bodies’ (abnormal glycogen aggregates that cannot be broken down and used as fuel) found in most people with the disease. Genetic testing for mutations in the EPM2A gene or the NHLRC1 gene may be used to confirm the diagnosis in some cases. An EEG and MRI of the brain are generally recommended in all people with recurrent seizures and are useful for investigating other conditions in the differential diagnosis.

Unfortunately, there is currently no cure or means of slowing the progression of Lafora disease. Treatment is purely symptomatic and is based on the signs and symptoms present in each individual. It is the neurologist who is best placed to prescribe a treatment tailored to the individual’s situation.

Treatment should avoid drugs that may aggravate myoclonus (e.g. phenytoin).

Unfortunately, the long-term outlook for people with Lafora disease is poor. There is currently no cure for the disease, and it is considered to be progressive, meaning that symptoms worsen over time. On average, sufferers survive for around 10 years after the onset of symptoms.