Years published: 2023
NORD gratefully acknowledges Bryce Murray, BS, Kendall Schmidt, BS, Brianna Tucker, BA, MaryAnn Campion, EdD, MS, and Rebecca J. Levy MD, PhD, Stanford University, for the preparation of this report.
Lafora disease is a rare neurological condition. Early symptoms include neurological issues beginning during adolescence from 8-19 years of age. These issues can include trouble in school, frequent headaches and seizures. Lafora disease occurs when the body does not properly process glycogen, which is a source of stored energy. When glycogen is not processed properly, it builds up in the body and forms clumps called “Lafora bodies” that interfere with proper function of the brain and other physical systems.
Lafora disease is an autosomal recessive genetic condition caused by changes (pathogenic variants or mutations) in the genes EPM2A or EPM2B (also called NHLRC1).
Progressive myoclonic epilepsies are a group of rare neurological conditions characterized by myoclonus, generalized epilepsy and neurological decline or neurodegeneration. Myoclonus is a rapid movement of a muscle or group of muscles that appears like a twitch or jerk. Some forms of myoclonus have brain electrical changes on testing called an electroencephalogram (EEG) that makes them similar to a brief seizure. Lafora disease is classified as a progressive myoclonic epilepsy condition. Lafora disease was first described in 1911 by Gonzalo Lafora.
Lafora disease is characterized by an onset of symptoms between 8-19 years of age, with the peak symptom onset being between 14-16 years. There are also extremely rare cases of early onset Lafora disease in patients as young as 5 years. Most affected individuals do not have symptoms until adolescence and then may start to have headaches, trouble learning in school and, most characteristically, seizures. The most common type of seizure in Lafora disease is myoclonic seizures, which look like jerking or brief shaking movements. Other seizure types include tonic-clonic seizures (stiffening of muscles followed by jerking or shaking), absence seizures (“staring spells”), atonic seizures (the body becomes limp), and complex partial seizures (“staring spells” with jerking or repetitive movements in one part of the body). Focal occipital seizures that present as blindness or hallucinations are possible. Over time, seizures typically increase in severity and become more difficult to control. Status epilepticus (prolonged or back-to-back seizures) may occur.
Motor and movement symptoms can include difficulty with balance, walking, coordination and spasticity. Cognitive and psychiatric features can include difficulty speaking, behavioral changes, depression, apathy and progressive dementia.
Progression of Lafora disease leads to intractable myoclonus, loss of physical functions and severe cognitive decline. Within 6 years of disease onset, around half of individuals affected by Lafora disease will lose the ability to voluntarily move their body and/or cognitively interact with their surroundings. Despite this, 50% of affected individuals survive more than 11 years after presentation of first symptoms. Some affected children have shown a later onset, slower progression of symptoms and live longer than what is typical for most patients with Lafora disease.
Lafora disease is caused by changes (pathogenic variants or mutations) in the EPM2A or EPM2B (also called NHLRC1) genes. EPM2A encodes the protein laforin, which is a phosphatase that forms a complex with the ubiquitin ligase, malin, encoded by EPM2B. The malin-laforin complex aids in monitoring and preventing excessive elongation of glycogen branch chains. When elongation is uncontrolled, glycogen branch chains cause glycogen molecules to precipitate into “Lafora bodies,” or abnormal glycogen particles which cannot be broken down and instead form accumulations that damage cells. These Lafora bodies build up throughout the nervous system as well as in tissues such as muscle, liver and skin.
Lafora disease occurs when harmful variants in the EPM2A or EPM2B gene cause improper glycogen regulation by the malin-laforin complex. Over time, the buildup of Lafora bodies interferes with nervous system functioning, resulting in seizures, motor and cognitive decline characteristic of Lafora disease. More research is needed to help understand how different harmful variants in the EPM2A and EPM2B genes specifically impact glycogen processing regulation.
Lafora disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Lafora disease typically affects adolescent females and males equally and has been reported at higher frequencies in populations from the Mediterranean (Spain, France, Italy), Northern Africa, India and Pakistan. The disease prevalence from reported cases is around 4 per 1,000,000 people; however, this number may be an underestimate due to unreported or undiagnosed cases.
The diagnostic process for individuals with Lafora disease can occur in multiple ways. The first symptoms that bring a patient to a physician are usually focal or myoclonic seizures. Neurological findings typically start at 8-19 years of age. Lafora disease can be diagnosed with a skin biopsy that shows Lafora bodies in the cells of a patient’s sweat ducts. Molecular genetic testing for pathogenic variants in the EPM2A or EPM2B genes confirms the diagnosis.
Clinical Testing and Work-Up
Doctors may suggest an electroencephalogram (EEG) or magnetic resonance imaging (MRI) of the brain to check for other disorders and screen for seizures.
There is no cure yet for Lafora disease, so current treatment is focused on managing symptoms.
Medical care may involve a team of specialists, including a neurologist (a physician who specializes in the diagnosis and treatment of medical conditions affecting the brain and nervous system) and a geneticist (a physician who specializes in the diagnosis and treatment of genetic conditions). Physical therapy or occupational therapy may be considered to help maintain good muscular condition and preserve the ability to walk for as long as possible.
Symptoms are typically managed using a combination of medications. Many different anti-seizure medications (ASM) are used to treat the seizures and myoclonus associated with Lafora disease, with some evidence for particular benefit from valproic acid and perampanel. Another type of medication that may be used are benzodiazepines. Seizure emergencies can involve myoclonic clusters (multiple jerking movements of a muscle or muscles) or myoclonic status epilepticus (myoclonic seizures that last for over 15 minutes); these emergencies may require urgent medical evaluation.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the patient and family may also be helpful.
There is evidence that metformin, a medication primarily used to treat type 2 diabetes, is helpful for patients with Lafora disease, particularly when started early in disease development. Metformin has been designated an orphan drug for Lafora disease by the U.S. Food and Drug Administration (FDA) but is not yet approved to treat Lafora disease.
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