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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. Diagnosis

There is a clearly distinguishable clinical pattern from Unverricht-Lundborg disease, with the major distinctions being:

  1. Later age of onset, and shorter duration of illness.
  2. Focal occipital seizures in half the casesand visual impairment87.
  3. Significant and progressive cognitive impairment 48. Inheritance

Lafora body disease follows an AR pattern of inheritance 50. Myoclonus

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. 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. Pathophysiology

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. 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. 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 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 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. Management

Control of seizures should be attempted with antimyoclonic drugs, especially valproic acid, clonazepam, and piracetam48



    48.   Berkovic SF. Progressive myoclonus epilepsies: specific causes and diagnosis. New Eng.J.Med. 1986;315:296-305.

    49.   Dreifus FE. In: Pediatric Epileptology:  Classification  and  Management of  seizures in  a  child. Boston: John Wright 1983: 109-19.

    50.   Roger J, Dravet C, Bureau M, Dreifuss FE, Wolf P. Progressive Myoclonic Epilepsy in Childhood and Adolescence. In: Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey 1985: 302-10.

    51.   Berkovic, S. F., Andermann, F., Karpati, G., Carpenter, S., Andermann, E., and Shoubridge, E. Mitochondrial Encephalomyelopathies:A Solution to the Enigma of the Ramsay Hunt Syndrome. Neurology 37(Suppl 1), 125. 1987.
Ref Type: Abstract

    52.   Marsden CD, Obeso JA. Viewpoints on the Ramsay Hunt syndrome: 1. The Ramsay Hunt syndrome is a useful clinical entity. Movement Disorders 1989;4:6-12.

    53.   Andermann F, Berkovic S, Carpenter S, Andermann E. The Ramsay Hunt syndrome is no longer a useful diagnostic category. Movement Disorders 1989;4:13-7.

    54.   May DL, White HH. Familial myoclonus, cerebellar ataxia, and deafness. Specific genetically-determined disease. Arch.Neurol. 1968;19:331-8.

    55.   Harding AE. Ramsay Hunt syndrome, Unverricht-Lundborg disease, or what? Movement Disorders 1989;4:18-9.

    56.   Tassinari, C. A, Michelucci, R, Genton, P, Pellissier, J. F, and Roger, J. Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies. Journal of Neurology, Neurosurgery & Psychiatry 52, 262-265. 1989.
Ref Type: Journal (Full)

    57.   Berkovic SF, Andermann F. Ramsay Hunt syndrome: to bury or to praise [letter; comment]. Journal of Neurology, Neurosurgery & Psychiatry 1990;53:89-90.

    58.   Marsden CD, Harding AE, Obeso JA, Lu CS. Progressive myoclonic ataxia (the Ramsay Hunt syndrome). Archives of Neurology 1990;47:1121-5.

    59.   Malafosse A, Lehesjoki AE, Genton P, Labauge P, Durand G, Tassinari CA, Dravet C, Michelucci R, de la Chapelle A. Identical genetic locus for Baltic and Mediterranean myoclonus. Lancet 1992;339:1080-1.

    60.   Marseilles Consensus Group. Classification of Progressive Myoclonus Epilepsies and Related Disorders. Ann.Neurol. 28(1), 113-116. 1990.
Ref Type: Journal (Full)

    61.   Obeso JA, Rothwell JC, Marsden CD. The spectrum of cortical myoclonus. From focal reflex jerks to spontaneous motor epilepsy. Brain 1985;108:193-24.

    62.   Berkovic SF, So NK, Andermann F. Progressive myoclonus epilepsies: clinical and neurophysiological diagnosis. [Review] [103 refs]. Journal of Clinical Neurophysiology 1991;8:261-74.

    63.   Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R. Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol.Scand. 1974;50:307-32.

    64.   Lundborg H. Der Erbgang der progressiven myoklonus-Epilepsie. In: Zeitschrift Fur die gesamte Neurologie un. 1912: 353-8.

    65.   Norio R, Koskiniemi M. Progressive myoclonus epilepsy: genetic and nosological aspects with special reference to 107 Finnish patients. Clin.Genet. 1979;15:382-98.

    66.   Andermann, F. Unverricht-Lunborg Disease. Gilman, S. . 2002.  MedLink Neurology.
Ref Type: Electronic Citation

    67.   Genton P, Michelucci R, Tassinari CA, Roger J. The Ramsay Hunt syndrome revisited: Mediterranean myoclonus versus mitochondrial encephalomyopathy with ragged-red fibers and Baltic myoclonus. Acta Neurologica Scandinavica 1990;81:8-15.

    68.   Lehesjoki AE, Koskiniemi M, Sistonen P, Miao J, Hastbacka J, Norio R, de la Chapelle A. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proceedings of the National Academy of Sciences of the United States of America 1991;88:3696-9.

    69.   Berkovic SF, Andermann F, Carpenter S, Wolfe LS. Progressive Myoclonic Epilepsies: Specific causes and diagnosis. New England Journal of Medicine 1986;315:296-305.

    70.   Norio, R. Personal Communication. #254800 MYOCLONUS EPILEPSY OF UNVERRICHT AND LUNDBORG. Online Mendelian Inheritance in Man . 1978.
Ref Type: Electronic Citation

    71.   Virtaneva K, D'Amato E, Miao J, Koskiniemi M, Norio R, Avanzini G, Franceschetti S, Michelucci R, Tassinari CA, Omer S, Pennacchio LA, Myers RM, Dieguez-Lucena JL, Krahe R, de la Chapelle A, Lehesjoki AE. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. Nature Genetics 1997;15:393-6.

    72.   Book, J. A. Personal Communication #254800 MYOCLONUS EPILEPSY OF UNVERRICHT AND LUNDBORG. Online Mendelian Inheritance in Man . 1978.
Ref Type: Electronic Citation

    73.   Koskiniemi, M, Donner, M, Majuri, H, Haltia, M, and Norio, R. Progressive Myoclonic Epilepsy-A clinical and pathological study. Acta Neurologica Scandinavica 50, 307-322. 1974.
Ref Type: Journal (Full)

    74.   Leino E, Partanen J, Helkala EL, Riekkinen PJ. Clinical stages of progressive myoclonus epilepsy in adult patients. Acta Neurol Scand 1982;65:19-29.

    75.   Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ. "Baltic" myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet 1983;2:838-42.

    76.   Iivanainen M, Himberg JJ. Valproate and clonazepam in the treatment of severe progressive myoclonus epilepsy. Arch.Neurol. 1982;39:236-8.

    77.   Cochius J, Carpenter S, Andermann E, Rouleau G, Nousiainen U, Kalviainen, R, Farrell K, Andermann F. Sweat gland vacuoles in Unverricht-Lundborg disease: a clue to diagnosis? Neurology 1994;44:2372-5.

    78.   Matthews WB, Howell DA, Stevens DL. Progressive myoclonus epilepsy without Lafora bodies. Journal of Neurology, Neurosurgery & Psychiatry 1969;32:116-22.

    79.   Haltia M, Kristensson K, Sourander P. Neuropathological studies in three Scandinavian cases of progressive myoclonus epilepsy. Acta Neurol Scand 1969;45:63-77.

    80.   Pennacchio LA, Lehesjoki AE, Stone NE, Willour VL, Virtaneva K, Miao J, D'Amato E, Ramirez L, Faham M, Koskiniemi M, Warrington JA, Norio R, de, la Chapelle A, Cox DR, Myers RM. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1) [see comments]. Science 1996;271:1731-4.

    81.   Lafreniere RG, Rochefort DL, Chretien N, Rommens JM, Cochius JI, Kalviainen R, Nousiainen U, Patry G, Farrell K, Soderfeldt B, Federico, A, Hale BR, Cossio OH, Sorensen T, Pouliot MA, Kmiec T, Uldall P, Janszky J, Pranzatelli MR, Andermann F, Andermann E, Rouleau GA. Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nature Genetics 1997;15:298-302.

    82.   Obeso JA, Artieda J, Rothwell JC, Day B, Thompson P, Marsden CD. The treatment of severe action myoclonus. Brain 1989;112 ( Pt 3):765-77.

    83.   Henry TR, Leppik IE, Gumnit RJ, Jacobs M. Progressive myoclonus epilepsy treated with zonisamide. Neurology 1988;38:928-31.

    84.   Selwa LM. N-acetylcysteine therapy for Unverricht-Lundborg disease. Neurology 1999;52:426-7.

    85.   Roger R. Progressive Myoclonic Epilepsy in Childhood and Adolescence. In: J.Roger CDMBFEDaPW, ed. Epileptic syndromes in infancy, childhood and adolescence. London: John Libbey 1985: 302-10.

    86.   Van Heycop ten Ham MW. Lafora disease: a form of progressive myoclonic epilepsy. In: Vinken PJ, Bruyn GW, eds. Amsterdam: North Holland 1974: 382-422.

    87.   Roger J, Pellissier JF, Bureau M, Dravet C, Revol M, Tinuper P. [Early diagnosis of Lafora disease. Significance of paroxysmal visual manifestations and contribution of skin biopsy]. Rev.Neurol.(Paris) 1983;139:115-24.

    88.   Wilner, A. N., Andermann, F., and Andermann, E. Lafora body disease. Gilman, S. Medlink Neurology . 3-17-2004.  Medlink Corporation. 3-17-0040.
Ref Type: Electronic Citation

    89.   Tinuper P, Aguglia U, Pellissier JF, and Gastaut H. Visual ictal phenomena in a case of Lafora disease proven by skin biopsy. Epilepsia 24, 214-218. 1983.
Ref Type: Journal (Full)

    90.   Kaufman MA, Dwork AJ, Willson NJ, John S, Liu JD. Late-onset Lafora's disease with typical intraneuronal inclusions. Neurology 1993;43:1246-8.

    91.   Kraus-Ruppert R, Ostertag B, Hafner H. A study of the late form (type Lundborg) of progressive myoclonic epilepsy. J.Neurol.Sci. 1970;11:1-15.

    92.   Robitaille Y, Carpenter S, Karpati G, DiMauro SD. A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora's disease and normal ageing. Brain 1980;103:315-36.

    93.   Schnabel R, Gootz M. Zur Substruktur Der Myoklonuskorper Bei Progressiver Myoklonusepilepsie (Typ Unverricht). Acta Neuropath. 1971;18.

    94.   Minassian BA. Progressive myoclonus epilepsy with polyglucosan bodies: Lafora disease. Adv.Neurol 2002;89:199-210.

    95.   Carpenter S, Karpati G, Andermann F, Jacob JC, Andermann E. Lafora's disease: peroxisomal storage in skeletal muscle. Neurology 1974;24:531-8.

    96.   Vanderhaeghen, J. J. Correlation between Ultrastructure and Histochemistry of Lafora Bodies. Acta Neuropath 17, 24-36. 1971.
Ref Type: Journal (Full)

    97.   Harriman DGF, Millar JHD. Progressive Familial Myoclonic Epilepsy in Three Families: Its clinical features and pathological basis. Brain 1955;78:325-49.

    98.   Chan EM, Ackerley CA, Lohi H, Ianzano L, Cortez MA, Shannon P, Scherer SW, Minassian BA. Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Hum.Mol.Genet. 2004;13:1117-29.

    99.   Carpenter S, Karpati G. Sweat gland duct cells in Lafora disease: diagnosis by skin biopsy. Neurology 1981;31:1564-8.

  100.   Busard HL, Gabreels-Festen AA, Renier WO, Gabreels FJ, Stadhouders AM. Axilla skin biopsy: a reliable test for the diagnosis of Lafora's disease. Ann.Neurol. 1987;21:599-601.

  101.   Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, Minassian BA. Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology 2003;61:1611-4.

  102.   Janeway R, Ravens JR, Pearce LA, Odor DL, Suzuki K. Progressive myoclonus epilepsy with Lafora inclusion bodies. I. Clinical, genetic, histopathologic, and biochemical aspects. Arch Neurol 1967;16:565-82.

  103.   Schwarz, G. A. and Yanoff, M. Lafora's Disease: Distinct Clinico-Pathologic Form of Unverricht's Syndrome. Arch Neurol 12, 172-188. 1965.
Ref Type: Journal (Full)

  104.   Davison C, Keschner M. Myoclonus Epilepsy. Arch Neurol Psych 1940;43:524-45.

  105.   van Heycop ten Ham MW, De Jager H. Progressive Myoclonus Epilepsy with Lafora Bodies. Clinico-Pathological Features. Epilepsia 1963;4:119.

  106.   Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, Dunham I, Gardner R, Fong CY, Carpenter S, Jardim L, Satishchandra P, Andermann E, Snead OC3, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nature Genetics 1998;20:171-4.

  107.   Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC, Avanzini G, Elia M, Ackerley CA, Jovic NJ, Bohlega S, Andermann E, Rouleau GA, Delgado-Escueta AV, Minassian BA, Scherer SW. Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat.Genet. 2003;35:125-7.