Brain Pathology Case of the Month - April 2007

DIAGNOSIS:   Diagnosis: Lafora body disease

DISCUSSION:

The clinical and histopathological features were first described by Gonzalo Lafora, a Spanish neurologist, in 1911, while working with Alzheimer in Munich (12,13). The characteristic clinical presentation is the onset of myoclonus and multiple seizure types in a previously normal child. The mean age of onset is 14 years and ranges from 10 to 17 years (17). Cognitive decline is prominent, while ataxia, dyskinesias and spasticity develop later.

The EEG is characterized by background slowing and generalized polyspikes, which may be more prominent in the posterior head regions . (11,16).

The differential diagnosis of this presentation includes the progressive myoclonic epilepsies such as Unverricht-Lundborg disease (EPM1), early onset Dentato-Pallido-Luysian Atrophy, Sialidosis, Spielmeyer-Vogt disease (Neuronal Ceroid Lipofuscinosis type 3), and MERRF (myoclonic epilepsy with ragged red fibers). Other causes of seizures and progressive neurological deterioration in this age group include Homocystinuria, X-linked Adrenoleukodystrophy, Gaucher disease type 3, and Hallervorden-Spatz disease (14). Lafora body disease is differentiated clinically from EPM1 by the rapid decline in cognition.

Pathological appearance: On macroscopic examination, the brain will appear normal or atrophic. Microscopic examination will demonstrate Lafora bodies in the cytoplasm of neurons and astrocytes in the cortex, thalamus, cerebellum and subcortical nuclei. Lafora bodies are also present is other body tissues, including the myoepithelial cells of apocrine glands and eccrine gland duct cells.

Lafora bodies consist of polyglucosans (polymers of sulphated polysaccharides) and have a deep staining core (PAS-positive) with a speculated outline surrounded by a zone of intermediate stain intensity (4). The ultrastructural appearance of the Lafora body from our case is shown in Figure 3.

Normal apocrine gland or duct cells in the axilla may contain PAS-positive bodies that can lead to a misdiagnosis of Lafora body disease. In skin taken from outside the axilla or genital regions, however, apocrine cells are absent, and Lafora bodies are present in eccrine duct cells, decreasing the risk of a false positive diagnosis (1).

Research in the genetics and proteomics of Lafora body disease had advanced rapidly since the gene was found in 1998. Mutations in the EPM2A gene cause up to 80% of Lafora body disease and are inherited in an autosomal recessive manner. The gene has been localized to the long arm of chromosome 6 (6q24), and encodes for a dual phosphatase 331 amino acid protein, laforin, normally located at the plasma membrane and rough endoplasmic reticulum (15). Various mutations (mostly deletions) result in loss of function of the laforin protein (9,10). The overexpressed non-functional protein aggregates with glycogen-microsomal complexes (18,5), and may cause cell death by non-apoptotic neuronal degeneration (7). A second gene causing Lafora body disease, NHLRC1, was identified in 2003 on chromosome 6p22.3 (3), and encodes for malin, an E3 ubiquitin ligase involved in proteolysis cascades.

The classic presentation of Lafora body disease described above has recently been demonstrated to be associated with a mutation in exon 4 of the EPM2A gene. A clinical variant consisting of early childhood onset dyslexia and learning disorder followed later by epilepsy and neurological deterioration, is associated with a mutation in exon 1 of the EPM2A gene (2,6), and in one case of an EPM2B gene mutation. Patients usually die within 2-10 years after onset of the disease. The EPM2B mutation is associated with a slower progression of disease with or without a late onset of disease (8).

Genetic testing is available; however, the number of mutations is large, and gene sequencing is necessary. The current standard of diagnosis remains a skin biopsy.

REFERENCES:

  1. Andrade DM, Ackerley CA, Minett TS, Teive HA, Bohlega S, Scherer SW, Minassian BA (2003) Skin biopsy in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls. Neurology 61(11):1611-4
  2. Annesi G, Sofia V, Gambardella A, Candiano IC, Spadafora P, Annesi F, Cutuli N, De Marco EV, Civitelli D, Carrideo S, Tarantino P, Barone R, Zappia M, Quattrone A (2004) A novel exon 1 mutation in a patient with atypical lafora progressive myoclonus epilepsy seen as childhood-onset cognitive deficit. Epilepsia 45:294-295
  3. 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 (2003) Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nature Genet 35: 125-127
  4. Ellison D, Love S, Chimelli L, Harding BN, Lowe J, Vinters HV (2000) Miscellaneous pediatric disorders. In: Neuropathology, Ellison D, Love S (Ed.). Mosby: London.
  5. Fernandez-Sanchez ME, Criado-Garcia O, Heath KE, Garcia-Fojeda B, Medrano-Fernandez I, Gomez-Garre P, Sanz P, Serratosa JM, Rodriguez de Cordoba S (2003) Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum Mol Genet 12:3161-3171
  6. Ganesh S, Delgado-Escueta AV, Suzuki T, Francheschetti S, Riggio C, Avanzini G, Rabinowicz A, Bohlega S, Bailey J, Alonso ME, Rasmussen A, Thomson AE, Ochoa A, Prado AJ, Medina MT, Yamakawa K (2002) Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet 11:1263-1271
  7. Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai DS, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K (2002) Targeted disruption of the EPM2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Molec Genet 11: 1251-1262
  8. Gomez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, de Cordoba SR, Serratosa JM (2005) Lafora disease due to EPM2B mutations: A clinical and genetic study. Neurology 64(6):982-986
  9. Gomez-Garre, P.; Sanz, Y.; Rodriguez de Cordoba, S.; Serratosa, J. M (2000) Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora: high degree of allelic heterogeneity and prevalence of deletions. Europ J Hum Genet 8: 946-954
  10. Ianzano L, Young EJ., Zhao XC, Chan EM, Rodriguez MT, Torrado MV, Scherer SW, Minassian BA (2004) Loss of function of the cytoplasmic isoform of the protein laforin (EPM2A) causes Lafora progressive myoclonus epilepsy. Hum Mutat 23:170-176
  11. Koskiniemi M, Toivakka E, Donner M (1974) Progressive myoclonus epilepsy: electroencephalographical findings. Acta Neurol Scand 50:333-359.
  12. Lafora GR (1911) Uber das Vorkommen amyloider Korperchen im Innern der Ganglienzellen; zugleich ein zum Studium der amyloiden Substanz im Nervensystem. Virchows Arch 205:295-303
  13. Lafora GR, Glueck B (1911) Beitrag zur Histopathologie der myoklonischen Epilepsie. Z. Gesamte Neurol Psychiatr 6:1-14
  14. Leary LD, Nordli Jnr. DR, DeVivo DC (2000). Epilepsy in the setting of inherited, metabolic, and mitochondrial disorders. In: The Treatment of Epilepsy, Wyllie E (Ed.), Chapter 41, pp. 637-656. Lippincott, Williams & Wilkins: Philadelphia.
  15. 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 OC 3rd, Lopes-Cendes I, Tsui LC, Delgado-Escueta AV, Rouleau GA, Scherer SW (1998) Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nature Genet 20: 171-174
  16. Ponsford S, Pye IF, Elliot EJ (1993) Posterior paroxysmal discharge: an aid to early diagnosis in Lafora disease. J Royal Soc Med 86:597-599.
  17. Van Heycop Ten Ham MW (1975) Lafora disease, a form of progressive myoclonus epilepsy. In: The epilepsies: Handbook of clinical neurology, Vinken PJ, Bruyn GW, eds. Chapter 15, pp. 382-422, Elsevier: Amsterdam
  18. Wang J, Stuckey JA, Wishart MJ, Dixon JE (2002) A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen. J Biol Chem 277: 2377-238

Contributed by Widdess-Walsh P, Prayson RP, Cohen B, Lachhwani D

International Society of Neuropathology