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In 1911 Lafora & Glueck found amyloid-like inclusions in the neurons of patients with PME, establishing the pathological hallmark of the disease which bears Lafora’s name. The illness is characterized by the onset of generalized tonic-clonic seizures and/or myoclonus between the ages of 6 and 19 years85, typically around the 14th year of life62. Rapid and severe mental deterioration occurs, often with psychotic symptoms50. Survival is short, and the mean age of death is 20 years, less than 2 to 10 years after onset86.
There is a clearly distinguishable clinical pattern from Unverricht-Lundborg disease, with the major distinctions being:
- Later age of onset, and shorter duration of illness.
- Focal occipital seizures in half the casesand visual impairment87.
- Significant and progressive cognitive impairment 48.
Lafora body disease follows an AR pattern of inheritance 50.
At first, as with many forms of PME, the myoclonic seizures can mimic juvenile myoclonic epilepsy. The myoclonus is constant, and jerks may be massive and synchronous, usually limited to one or more muscle groups 88. Jerks are also described as being asynchronous and asymmetrical86. The myoclonic jerks are not associated with loss of consciousness and are aggravated by voluntary movement. With progression, myoclonus increases in intensity and becomes quite severe and multifocal, precipitated by posture or action85.
1.6.2.4 Clinical Manifestations
Seizures are predominantly clonic, tonic-clonic and myoclonic50 and can be preceded by increasing myoclonus86. Paroxysmal visual manifestations that are epileptic in nature may be an early sign of the disease89, and visual disturbance and blindness occur in a minority86. Dysarthria and cerebellar symptoms have been described frequently86. After a few years, there may be a rapid onset of dementia, and some cases may present with dementia 69.
A few cases of a possible adult-onset form of the disease with a more benign course have been described, with a 30 year course in one patient 90. Although typical Lafora inclusion bodies were found in these cases, it is unclear if they represent the same disease. Of note, in Lafora body disease, inclusions are found in the neuronal perikarya, and in late-onset Lafora body disease there are inclusions in both axons and perikarya 90;91, a similar distribution to adult polyglucosan body disease92.
Lafora bodies have the properties of an acid mucopolysaccharide, are periodic acid-Schiff (PAS) positive, and are a polyglucosan protein complex 93. Polyglucosans are glucose polymers, similar to glycogen, but lacking its branched structure94. The bodies vary in size from 1 to 30 mm in diameter, and cells may contain single or multiple bodies24. Deposits generally appear free in the cytoplasm of neurons95. The histological appearance is that of a concentric-lamellar target-like structure, with a basophilic core surrounded by a pale eosinophilic zone, containing dark radial stria 24. At the electron microscope level, the bodies consist of filamentous and granular components, located in neuronal cell processes and perikarya 96 .
There are similarities between Lafora bodies, corpora amylacea, deposits found in type IV glycogenosis and intra-axonal bodies seen with normal ageing 92. The bodies have been found throughout the nervous system, with dentate nucleus, substantia nigra, thalamus, and pons being the main locations, and are also seen in the retina and spinal nerves 73. In addition, Lafora bodies are present in non-neuronal tissue, such as muscle and liver 97.
A unique biochemical pathway of glycogen metabolism appears to exist: this is made up of laforin, E3 ubiquitin ligase, and three proteins which interact with laforin. Laforin appears to bind polyglucosan accumulations and promotes their elimination98.
1.6.2.6 Special Investigations
Skin biopsies show Lafora bodies in the eccrine ducts of sweat glands99. Biopsies from the axilla show bodies in the myoepithelial cells of the acini of the apocrine glands100. However, biopsies from apocrine glands may be a source of confusion, since apocrine glands normally contain PAS positive inclusions 101.
1.6.2.7 Pathology
LBs are an intracytoplasmic inclusion of neurons, varying in size from 1-30 mm, with a variable number of inclusions per cell. Typically on H & E staining there is a dense basophilic core and a pale periphery, with the centre staining intensely with Periodic-acid Schiff 97;102and Alcian blue102;103 Most other reports emphasize the presence of diffuse LBs and report moderate neuronal loss 90;103 104;105
1.6.2.8 Genetics
The gene locus is located at chromosome 6q24, and the gene is currently termed: Epilepsy, progressive myoclonus type 2A, with the gene symbol being EPM2A. The gene product is the laforin protein, which is characterized by a carbohydrate-binding domain and a tyrosine phosphatase domain106. In addition, the EPM2B (also termed NHLRC1) gene has been recently identified, and encodes for the E3 ubiquitin ligase107.
1.6.2.9 Epidemiology
Lafora body disease is a rare disorder and there are no accurate estimates of its prevalence. In a review of PME from the Montreal Neurologic Institute, an epilepsy referral centre, 12 (14.2%) of 84 patients with PME had Lafora body disease53.
1.6.2.10 Management
Control of seizures should be attempted with antimyoclonic drugs, especially valproic acid, clonazepam, and piracetam48.
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