Background Gross Pathology Histopathology & Immunohistochemistry Reference

BACKGROUND AND CLINICAL INFORMATION: Head

Summary: Lafora body disease is an autosomal recessive stimulus-sensitive progressive myoclonic epilepsy with onset in the late childhood or adolescence. Unverricht (classic) type is associated with earlier onset and more severe symptoms. Lundborg type is associated with later onset and less severe symptoms. Clinical features include generalized seizures, myoclonus, visual deterioration, psychoses, and rapid intellectual decline with the development of dementia. Pathologically it is associated with neuronal inclusions (Lafora bodies) in the cerebral and cerebellar cortex and in brain stem nuclei. Inclusions are also seen in other organs including liver, muscle, and skin. Lafora body is an insoluble form of carbohydrate that contains 80-90% of glucose and are related to abnormal glycogenoses.

Genetics:

Mutation in the EPM2A gene on chromosome 6q24 which codes for a putative protein tyrosine phosphatase gene. EPM2A transcripts are detected in many different tissues including brain. EPM2A is composed of 4 exons and about 130 kB in length.
EPM2A must not be confused with EPM1 gene that is on 21q22.3 and is associated with Unverricht-Lundborg disease.

Molecular pathology: About 14 different mutations in 24 families are now known. The extent of mutation heterogeneity makes it difficult to screen for the mutation, both for prenatal and postnatal diagnosis.

Biochemistry:

Lafora body disease is a generalized storage disorder possibly related to abnormal glycogenoses. The responsible biochemical defect has not been identified.
The lafora bodies are composed of glucose polymer (polyglycosan) that is chemically but not structurally related to glycogen.
Lafora bodies contain 80%-93% of glucose, the only saccharide detected, and 6% protein. Enzymatic analyses reveal that Lafor bodies acontain glucose polymers linked with alpha-1:4 and alpha-1:6 bonds.
Although the storage material in Lafora disease is histochemically, ultrastructurally, and biochemically similar to polysaccharide that accumulates in branching enzyme activity (type IV glycogenosis), branching enzyme activity was normal in brain and muscle from one patient.

Clinical features:

Unverricht (classic) type: begins between 6-19 years of age (mean: 11 years). First manifestations are decreased scholastic performance, behavior disorders, or seizures. Generalized tonoic/clonic and clonic seizures appears and myoclonic jerks develop later. Visual deterioration is common. Full blown myoclonic epilepsy develop as the disease progress. Within 1 to 2 years after the onset of seizures, dementia develops. Death occurs within 2-10 years as a result of heart failure, or aspiration pneumonia.
Lundborg type: this has more protracted clinical course. Grand mal seizures are the first manifestation. Myoclonias and dementia are slowly progressive and death usually occurs after the age of 40 years.
Liver function test is usually normal.
Diagnostic test: biopsy of axillary skin.

GROSS PATHOLOGY: Head

Mild diffuse cortical atrophy.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Lafora bodies: Lafora bodies variesin size from 1 to 30 micron in diameter and one or more Lafora bodies may be present in the cytoplasm. They may be found in nerve cell processes and apparently free in the neuropil. They have a concentric target like lamination, PAS positive, diastases resistant, and Alcian blue positive. The core is more strongly stained than the rim. Lafora bodies are also basophilic, and variably metachromatic (with methyl violet or toluidine blue) inclusion bodies. They are also found in liver, striated muscles, sweat glands.

Skin: Lafora bodies are seen in the cytoplasm of myoepithelial cells, eccrine and apocrine sweat duct cells.

Brain: Lafora bodies are found in the cytoplasm of neurons. When found in the perikarya, they displace the nucleus and Nissl substance to the side. They are scattered in the cerebral cortex and has the highest density in the central region an prefrontal motor cortex. Other cerebral deep gray matter are less severely affected and areas of high density include substantia nigra, dentate nuclei, superior olive, pontine reticular nuclei, and basal ganglia. Only occasional inclusions are found in the spinal cord.

EM: Lafora bodies, except those in striated muscles, do not have a limiting membrane. The core contains a dense bundle of fibrils about 6-8 nm in diameter. Between the fibrils are dense granular structures about 15-50 nm in diameter.

REFERENCES: Head

Minassian BA, Ianzano L, Delgado-Escueta AV, Scherer SW. Identification of new and common mutations in the EPM2A gene in Lafora disease. Neurology 2000 54:488-90.

Ganesh S, Amano K, Delgado-Escueta AV, Yamakawa K. Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A. Biochem Biophys Res Commun 1999 257:24-8.

Serratosa JM, Gomez-Garre P, et al. A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet 1999 8:345-52.

Labauge P, Beck C, et al. Lafora disease is not linked to the Unverricht-Lundborg locus. Am J Med Genet 1995 60:80-4.

NeuroLearn NeuroHelp Metabolic For Comment: KarMing-Fung@ouhsc.edu

Background Gross Pathology Histopathology & Immunohistochemistry Reference