Behavioral & Cognitive Disorders
Fragile X syndrome
Nov. 21, 2022
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Lafora disease is a severe form of progressive myoclonus epilepsy characterized by the onset of seizures or cognitive decline during late childhood or adolescence with a progressive course, usually ending in death 5 to 10 years after the initial symptoms. Lafora disease is caused by mutations in the EPM2A or EPM2B genes, encoding the laforin phosphatase and the malin ubiquitin ligase, respectively, two cytoplasmically active enzymes that regulate glycogen construction. Pathologically, the disease is characterized by the presence of polyglucosan intracellular inclusion bodies called Lafora bodies in neurons and other tissues. Despite improved patient diagnosis, prenatal diagnosis, and genetic counseling for this devastating disease, treatment is primarily palliative, aiming at seizure reduction. In this article, the author summarizes the clinical manifestations and rapidly expanding information on the genetic basis and metabolic derangements of Lafora disease and some promising results from the treatment of animal models.
• Lafora disease is an autosomal recessive progressive myoclonus epilepsy characterized by the accumulation of insoluble abnormal glycogen deposits in the brain and peripheral tissues. Clinically it manifests with cortical myoclonus, other types of epileptic seizures, progressive intellectual decline, ataxia, and early death.
• Onset of symptoms is in the second decade of life, typically between the ages of 11 and 18 years. Death usually occurs 2 to 10 years after onset (mean 5 years).
• The pathological hallmark of Lafora disease is the presence of cytoplasmic polyglucosan inclusions, the Lafora bodies.
• The disease is caused by mutations in either the EPM2A gene, encoding the protein phosphatase laforin, or the EPM2B gene, encoding the ubiquitin ligase malin.
• The MRI shows subtle or no abnormalities, and the EEG is grossly abnormal even in early stages. Biopsy or genetic studies are required for a definitive diagnosis.
• Management is only supportive and palliative, limited to symptomatic management of the epileptic seizures, myoclonus, and intercurrent complications. There are promising therapies in development in preclinical stages that soon may proceed to clinical trials.
The neuropathological features typically found in Lafora disease were first described by Gonzalo Rodríguez Lafora in 1911 (39; 39).
Gonzalo Rodriguez-Lafora (1886-1971) was a neurologist and pathologist at the Provincial Hospital in Madrid. He was born and died in Madrid and worked there except for a few years of study in Germany and France and 3 years in W...
It was soon established that the presence of typical Lafora inclusion bodies in the pathological material was associated with a progressive neurologic disorder with myoclonus, different types of seizures, and dementia. This triad of symptoms characterizes a group of diseases categorized as progressive myoclonic epilepsies (07; 28; 57; 48). Lafora disease is recognized as one of the major causes of progressive myoclonus epilepsy with well-defined clinical and pathological characteristics. The Commission on the Classification and Terminology of the International League Against Epilepsy (ILAE) classified Lafora disease in the group of symptomatic generalized epilepsies with known or suspected metabolic cause (Commission on the Classification and Terminology of the International League Against Epilepsy 1989). In the ILAE Task Force report, Lafora disease is classified among “diseases frequently associated with epileptic seizures or syndromes” (21). Another ILAE report classifies all “progressive myoclonus epilepsies” amongst epilepsies with adolescence-adult onset together with juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with generalized tonic-clonic seizures alone, autosomal dominant epilepsy with auditory features, and other familial temporal lobe epilepsies (05).
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