Brain Pathology Case of the Month - April 2009

DIAGNOSIS  

- Progressive myoclonus epilepsy Lafora-type (LD, OMIM# 254780), confirmed also by genetic testing, revealing a homozygous missense mutation (c.205C>G, P69A) in the EPM2B (NHLRC1) gene.

DISCUSSION

LD is the most common and severe form of adolescent-onset progressive myoclonus epilepsies (PMEs), a group of devastating inherited neurodegenerative disorders characterized by progressively worsening myoclonus, epilepsy, early dementia and death.5 LD, first described by Lafora in 1911, is particularly frequent in Mediterranean countries (Spain, Italy, France), Northern Africa, the Middle East, and in some regions of Southern India where a high rate of consanguinity is present.3,5 LD classically starts in adolescence in otherwise neurologically normal individuals, usually with action and stimulus-sensitive myoclonus as well as tonic-clonic, absence, atonic, and visual seizures. Neuropsychiatric symptoms such as behavioral changes, depression, apathy, are also often present. Initial symptoms are followed by rapidly progressive dementia, refractory status epilepticus, psychosis, cerebellar ataxia, dysarthria, mutism, and respiratory failure which lead to death within about a decade.3, 5

The main differential diagnosis is with four other forms of PMEs: Unverricht-Lundborg disease (EPM1), the neuronal ceroid lipofuscinoses, myoclonic epilepsy with ragged red fibers (MERRF), and sialidosis.3,5 The age of onset, presenting symptoms, occurrence of occipital seizures and the progressive and rapid course, together with the EEG features suggest LD, until the diagnosis is definitively confirmed by skin biopsy or genetic analysis. The pathologic hallmark of LD is the presence of the typical PAS-positive intraneuronal inclusions (Lafora bodies, LBs). LBs are also found in other tissues such as heart, liver, muscle and skin composed of an abnormal form of glycogen.5,6 Importantly, neuronal LB exclusively localize in perikarya and dendrites but not in axons. LB may be conveniently identified in the eccrine ducts or apocrine myoepithelia of sweat glands obtained from skin biopsy1. LD is caused by mutations in the EPM2A4 or the EPM2B (NHLRC1) 2 genes, encoding the laforin dual specificity protein phosphatase and the malin E3 ubiquitin ligase respectively, both involved in a complex poorly understood pathway regulating glycogen metabolism. At present, LD treatment remains palliative.

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 61:1611-4.
  2. 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. Nat Genet 35:125-127.
  3. Ganesh S, Puri R, Singh S, Mittal S, Dubey D (2006) Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet 51:1-8
  4. 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. Nat Genet 20:171-174.
  5. Minassian BA. (2001) Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol 25:21-29.
  6. Van Heycop Ten Ham M.W (1975) Lafora disease, a form of progressive myoclonus epilepsy. In The Epilepsies. Handbook of Clinical Neurology, vol. 15, 382-422 (Eds. Vinken PJ and Bruyn GW), North-Holland, Amsterdam

Contributed by Pasquale Striano, Cameron A. Ackerley, Mariarosaria Cervasio, Jean-Marie Girard, Julie Turnbull, Maria Laura Del Basso-De Caro, Salvatore Striano, Federico Zara, and Berge A. Minassianf

International Society of Neuropathology