Lafora disease is a rare, inherited neurological condition that causes severe and progressive myoclonus epilepsy. This disorder manifests in late childhood or adolescence. It is characterized by a rapid decline in neurological function after initial symptoms appear.
Genetic Causes and Cellular Impact
Lafora disease is an autosomal recessive genetic disorder, meaning an individual must inherit a mutated copy of a specific gene from each parent to develop the condition. Both parents are carriers of one mutated gene but do not show symptoms. This inheritance pattern results in a 25% chance with each pregnancy that a child will inherit two mutated copies and develop the disease.
The disease arises from mutations in either the EPM2A gene or the NHLRC1 (also known as EPM2B) gene. The EPM2A gene provides instructions for making laforin, a dual-specificity phosphatase involved in glycogen metabolism. The NHLRC1 gene codes for malin, an E3 ubiquitin ligase that regulates laforin.
Disruptions in these genes lead to improper processing and breakdown of glycogen, the body’s stored form of glucose. Instead of forming soluble, branched glycogen molecules, abnormal, hyperphosphorylated, and poorly branched glycogen accumulates. These insoluble clumps, known as Lafora bodies, gather within the cytoplasm of various cells throughout the body, particularly neurons in the brain, liver, muscle, and skin. The accumulation of these Lafora bodies is toxic to cells, leading to progressive neurological damage.
Progression of Symptoms
Symptoms of Lafora disease emerge during late childhood or early adolescence. Initial signs often include various types of seizures, such as generalized tonic-clonic seizures, which involve stiffening and jerking movements. Myoclonic seizures, characterized by sudden, involuntary muscle jerks, are also common. Some individuals may experience occipital seizures, which can cause visual disturbances like temporary blindness or visual hallucinations.
The disease progresses rapidly, with cognitive decline often beginning within a few years of symptom onset. Patients experience a swift decline in cognitive function, progressing to severe dementia. Speech difficulties, known as dysarthria, become prominent, making communication challenging. The loss of coordination, or ataxia, affects balance and walking, often requiring assistance with movement.
Psychological symptoms accompany the neurological decline, including behavioral changes, confusion, depression, and apathy. As the disease advances, seizures become more frequent and difficult to control, sometimes leading to status epilepticus. The disease results in severe loss of physical and mental functions, leading to total disability. It is universally fatal, with most individuals succumbing to complications within a decade of first symptoms.
The Diagnostic Journey
Diagnosing Lafora disease involves a series of specialized tests, with genetic testing being the definitive method. This testing specifically looks for mutations in the EPM2A and NHLRC1 genes, which are responsible for over 95% of cases. Identifying these genetic alterations confirms the diagnosis and can also provide information for family screening.
Other tests provide supportive evidence or help rule out similar conditions. An axillary skin biopsy, for example, can detect Lafora bodies in the cells of sweat glands. These abnormal glycogen clumps can be identified under a microscope using a specific stain.
An electroencephalogram (EEG) is another diagnostic tool used to record the brain’s electrical activity. In individuals with Lafora disease, an EEG may initially show a normal background but progressively reveal abnormal brain wave patterns, such as generalized or occipital epileptiform discharges. Neuroimaging techniques, such as magnetic resonance imaging (MRI) of the brain, are performed to assess for structural changes or rule out other causes. While MRI may be unremarkable in early stages, it can show mild cerebral or cerebellar atrophy as the disease progresses.
Current Management Strategies
Presently, there is no cure for Lafora disease, and treatment focuses on managing symptoms and providing supportive care. Anti-epileptic drugs are prescribed to help control seizures, though their effectiveness often diminishes as the disease progresses. Medications such as valproate, levetiracetam, topiramate, benzodiazepines, or perampanel may be used to reduce seizure frequency and severity.
Managing the complex symptoms of Lafora disease often requires a multidisciplinary care team. Physical therapy helps to maintain mobility and strength for as long as possible, addressing issues like stiffness and coordination challenges. Occupational therapy assists individuals in adapting to their declining abilities and maintaining independence in daily activities. Speech therapy supports communication by addressing difficulties with speaking and swallowing.
Psychiatric symptoms, including depression and behavioral changes, are addressed to improve comfort and quality of life. While current therapies are largely supportive, ongoing research offers promise for future treatments. Scientists are exploring potential avenues such as gene therapy to replace mutated genes or targeted drugs to reduce brain glycogen synthesis and prevent Lafora body formation. These efforts offer hope for more effective interventions.