Lafora disease

C P Panayiotopoulos MD PhD (Dr. Panayiotopoulos of St. Thomas' Hospital has no relevant financial relationships to disclose.)
Originally released April 26, 1995; last updated January 12, 2017; expires January 12, 2020

This article includes discussion of Lafora disease, Lafora body disease, Lafora progressive myoclonus epilepsy, and myoclonic epilepsy of Lafora. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Lafora disease is a progressive and fatal autosomal recessive disorder characterized by recurrent myoclonic and other types of seizure as well as relentlessly progressive intellectual and neurologic deterioration. Survival is short, less than 10 years after onset, which is usually in the first half of the second decade of life. Lafora disease is caused by mutations in the EPM2A or EPM2B genes, encoding the laforin phosphatase and the malin ubiquitin ligase, respectively, 2 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.

Key points

 

• Lafora disease is autosomal recessive progressive myoclonic epilepsy manifesting with cortical myoclonus, other types of epileptic seizures, progressive intellectual decline, and ataxia.

 

• 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.

 

• Diagnostic findings on MRI and neurophysiological testing are not definitive, and biopsy or genetic studies may be required.

 

• Management is only supportive and palliative, limited to symptomatic management of the epileptic seizures, myoclonus, and intercurrent complications.

Historical note and terminology

The neuropathological features typically found in Lafora disease were first described by Lafora in 1911 (Lafora 1911; Lafora and Glueck 1911).

Image: Dr. Gonzalo Lafora
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, other types of seizure, and dementia. This triad of symptoms characterizes a group of diseases categorized as progressive myoclonic epilepsies (Berkovic et al 1991; Genton et al 2005; Shahwan et al 2005; Panayiotopoulos 2010). Lafora disease is recognized as 1 of the major causes of progressive myoclonic 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” (Engel 2001). The new 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 (Berg et al 2010).

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