What is Lafora Disease?
Progressive myoclonic epilepsies are uncommon hereditary disorders that can affect people of all ages, though they’re often seen in late childhood or adolescence. These conditions lead to consistent jitters (known as myoclonus), seizures, dementia, problems with bodily movement (or ataxia), and, in severe cases, can be fatal. Included in this group of conditions are many diseases, such as Unverricht-Lundborg disease, Lafora disease, and neuronal ceroid lipofuscinoses, all of which are quite rare.
Lafora disease, for instance, is a severe type of progressive myoclonus epilepsy, usually showing symptoms during adolescence in previously healthy individuals. Unfortunately, this disease often leads to death within 10 years of the appearance of symptoms. Lafora disease is generally caused by specific genetic mutations that lead to an abnormal accumulation of a substance called glycogen in the brain and other tissues. This excess glycogen forms clumps known as Lafora bodies. The presence of Lafora bodies in a tissue sample can confirm the diagnosis of Lafora disease.
Common characteristics of Lafora disease include uncontrollable jitters and seizures that are sensitive to light, sudden drops in body muscle control, difficulty with planning physical movements (or apraxia), inability to see due to problems in the brain (or cortical blindness), swiftly progressing dementia, and mental health issues. This disease can be identified through a combination of patient symptoms, abnormal electrical brain activity, tissue sample analysis, and genetic testing. Unfortunately, there is currently no way to prevent or cure Lafora disease. The treatment mainly focuses on managing symptoms and providing supportive care. Antiepileptic drugs can be used to control jitters and seizures, but over time, patients may become resistant to these medications, which can result in worsening of the disease and increased seizures, leading to a decline in neurological function.
What Causes Lafora Disease?
Lafora disease is a type of brain disorder that people inherit from their parents. This means both parents must carry a gene for the disease, even though they don’t show any symptoms themselves. The disease is caused by issues with two specific genes named EPM2A and EPM2B, located on a particular part of the human chromosome. These genes control the production of two proteins, laforin and malin. When these genes have certain changes or mutations, they can’t function properly.
Studies have shown that these two proteins, laforin and malin, work together in the body. Their main role is to prevent the formation of excessively long chains of glucose (a type of sugar molecule) in certain complex carbohydrates (like glycogen). If either laforin or malin isn’t working correctly, it leads to the formation of abnormally long glucose chains, causing water to be pushed out. Over time, these changes can result in the creation of unusual structures called Lafora bodies in almost all body tissues.
More research has revealed that certain changes in the EPM2A gene can result in a slower progression of Lafora disease. For example, certain specific mutations like F321C and G279C show minor functional defects and are linked with a slow rate of disease progression. This knowledge can help doctors and researchers identify and classify new EPM2A gene mutations quickly, aiding the future treatment of Lafora disease patients.
Patients with Lafora disease have mutations in the genes that control either laforin or malin protein. As a result, they develop abnormal glycogen (a type of stored sugar) deposits in nearly all their body tissues. These deposits are strange because they resemble plant starch more than human glycogen.
Recently, scientists found another gene named PRMD8 that’s linked to Lafora disease. This gene controls the movement of laforin and malin proteins to the cell’s command center, the nucleus. When PRMD8 has a mutation, laforin and malin can’t get to the nucleus, leading to a deficiency within the rest of the cell and this is associated with early development of Lafora disease.
Risk Factors and Frequency for Lafora Disease
Lafora disease is mainly diagnosed in people from the Mediterranean, Northern African, or Central Asian regions, specifically countries like Spain, France, Italy, India, and Pakistan. More than 250 families around the globe have been found to have this disease, due to mutations in the EPM2A and EPM2B genes which are responsible for certain proteins in the body. It is estimated to affect around 4 in 1,000,000 people, but it’s believed that the actual number might be more, especially in developing countries due to a higher rate of misdiagnosis or lack of diagnosis.
A study in Germany looked into Lafora disease’s prevalence and characteristics. It was found that people with new variations of the disease usually started showing symptoms in their teenage years and followed the standard disease progression. This study suggested that in Germany, about 1.69 in 10 million people have Lafora disease.
Signs and Symptoms of Lafora Disease
Lafora disease is a severe kind of epilepsy that gets progressively worse over time. Symptoms often appear during adolescence and tend to get worse over the course of a decade, sometimes resulting in a vegetative state or death. This severe progression of the disease is often due to complications from brain degeneration and extreme, uncontrollable seizures.
Some of the common symptoms of Lafora disease include:
- Seizures
- Jerky movements (myoclonus)
- Decreasing intellectual capabilities
- Problems with movement and coordination
- Muscle stiffness or spasticity
- Difficulty speaking clearly
- Loss of vision
- Mental health problems, particularly in the later stages of the disease
One of the early signs of Lafora disease is a decline in cognitive abilities, including issues with speech. As the disease progresses, patients may become stiffer and show changes in behavior, including depression and lack of interest or enthusiasm. Often, jerky movements are responsible for early disability and dependence on a wheelchair.
These jerky movements can occur while at rest but usually disappear during sleep. They may become worse with physical action, exposure to light, or emotional excitement. Seizures, ranging from myoclonic (jerky movements) to occipital (which may cause visual disturbances), are common. Some patients may even experience seizures that resemble migraines with visual disturbances.
Testing for Lafora Disease
Lafora disease is a condition that is usually confirmed using a distinct staining method known as Periodic acid-Schiff stain. The presence of certain types of particles called polyglucosan is a key indicator of this disease. Lafora bodies, which are abnormal structures, typically accumulate in the patient’s skin, muscle, liver, and brain tissues. A biopsy, which is a procedure that involves taking a small sample of tissue for examination, can confirm the diagnosis. The axillary skin region, located under the armpit, is the most common and accessible site for biopsy.
The diagnosis can be confirmed through examination of the affected tissue. Observing Lafora bodies and finding mutations in specific genes during this examination is usually enough for a diagnosis. Genetic tests may be used if the patient comes from a family where parents are related by blood, or if Lafora bodies are observed in tissue samples.
Electroencephalogram (EEG, a test that measures electrical activity in the brain) may show normal patterns in the early stages of the disease, but as the disease progresses, certain abnormal patterns can be seen. These patterns often appear as irregular and generalized spikes, which may be provoked by exposing the patient to light stimulation at low frequency.
Brain imaging usually shows normal results at the time of diagnosis, but a specific type of brain scan (fluorodeoxyglucose positron emission tomography or FDG-PET) can show decreased brain activity in specific areas, early in the disease. This scan uses a small amount of radioactive sugar substance and a special camera to take pictures of brain activity and function. One study concludes that this scan seems to be highly sensitive in evaluating patients with Lafora disease at any stage and might show correlation with disease progression.
Lastly, examining the patient’s eye (retina) might offer a non-invasive way to evaluate the disease. Certain characteristics found in the retina might suggest a patient has Lafora disease, and this could be a crucial way to track the progression of the disease. Some patients showed reduced thickness in the retina and changes in cells responsible for vision, which are conditions that could be attributed to the negative impact of the disease on nervous tissues.
Treatment Options for Lafora Disease
It’s unfortunate, but at this time there is no cure for Lafora disease. Care for those with Lafora disease mostly involves managing seizures and enhancing the quality of their everyday life. Since Lafora disease can lead to many different types of seizures, different kinds of anti-epileptic medications like levetiracetam, sodium valproate, topiramate, and benzodiazepines are often considered.
One of the preferred treatments for the seizures is valproate. However, it should be avoided in patients with suspected mitochondrial disorders as it may lead to problems in energy production and cause high ammonia blood levels. Clonazepam is effective in treating a particular type of seizure called myoclonic seizures and can be used in Lafora disease usually in conjunction with other treatments. Phenobarbital is another anti-epileptic drug that can be used. However, care is needed if it is being paired with valproate to avoid toxicity. Piracetam is a medication that has been found effective in treating myoclonic seizures, with few side effects and is generally well tolerated.
Levetiracetam is another powerful anti-epileptic drug with few side effects. It’s proven effective in the treatment of generalized seizures and myoclonus (a sudden, brief, involuntary muscle jerk) in several studies. Brivaracetam works similarly to levetiracetam and has shown great potential in treating myoclonus. These medications work by suppressing the excessive electrical activity in the brain that leads to seizures.
Perampanel is a particular type of medication that typically treats hard-to-control seizures but is also effective for generalized epilepsy. Its effectiveness in treating Lafora disease was demonstrated by 2 case studies, in one of which it served as a primary treatment and in the other as an add-on medication. In both cases, perampanel led to significant reductions in seizure frequency and improved neurological and cognitive functioning.
Topiramate is another medication frequently used to treat seizures in patients with Lafora disease. Zonisamide is a medication effective in treating a wide variety of epilepsies and has shown promising results in treating patients with Lafora disease. However, the effectiveness of zonisamide typically decreases over time. Patients with Lafora disease are usually advised to avoid the use of other sodium channel blockers, including phenytoin, carbamazepine, and oxcarbazepine.
Other ways to manage seizures include vagal nerve stimulation, which has been found effective in reducing seizure frequency in a few cases of Lafora disease. A low carbohydrate-high cholesterol ketogenic diet, though helpful in some forms of epilepsy, has been found ineffective for treating Lafora disease.
Metformin, a medication typically used to treat type 2 diabetes, has been found beneficial as a neuroprotective agent in Lafora disease. Starting metformin treatment early appears to improve neurological symptoms and slow the progression of the disease.
New technologies are being explored to potentially help treat Lafora disease. These include using antibodies as targeting molecules or cell-penetrating tools, delivering missing enzymes to cells to help manage glycogen storage disorders like Lafora, and using liposomes to deliver needed genes to cells.
Though we currently do not have a cure for Lafora disease, these approaches with medications and new technologies bring hope for better management and improved quality of life for those living with the disease.
What else can Lafora Disease be?
When a doctor is considering a diagnosis of Lafora disease, they also need to rule out several other conditions that might show similar symptoms. These includes:
- Juvenile myoclonic epilepsy: This is a common type of epilepsy that typically starts during the teen years. It’s often described as contracting and stretching movements (myoclonic) and convulsive seizures (tonic-clonic). It usually responds well to medication, but sometimes a patient’s resistance to medication can lead to a misdiagnosis.
- Myoclonic epilepsy with ragged red fibers: This is another type of epilepsy.
- Schizophrenia: This is a mental disorder that affects a person’s ability to think, feel, and behave clearly.
- Sialidosis: This is a rare genetic disorder.
- Subacute sclerosing panencephalitis: This is a progressive and deadly brain disorder.
- Unverricht-Lundborg disease: This is the most common form of epilepsy characterized by myoclonus (contracting and stretching movements), generalized seizures, intellectual disability, ataxia (loss of full control of body movements), and dysarthria (slurred or slow speech). An electroencephalogram (EEG), a test that measures electrical activity in the brain, might show a dominant rhythm in the back of the brain with a mild slowing and abnormal electrical activities in the front. Brain MRI could show mild shrinking of the cerebellum (part of the brain that controls movement), and a glucose metabolic imaging (FDG-PET) might reveal low metabolic activity in certain parts of the brain.
