Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid–Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4–12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.

Vanadium concentrations in lung tissue were determined by atomic absorption spectrometry from autopsy specimens taken from residents of Mexico City during the 1960s and 1990s (20 males and 19 females, and 30 males and 18 females, respectively). Samples from the 1990s had significantly increased mean vanadium concentrations (mean ± standard deviation: 1.36 ± 0.08), compared with those from the 1960s (1.04 ± 0.05). Concentrations were not correlated with gender, smoking habit, age, cause of death, or occupation. These findings suggest that vanadium in ambient air is increasing and it represents a potential health hazard for Mexico City residents. Air pollution monitoring efforts should include vanadium concentrations in suspended particles to follow-up the findings reported herein. Researchers need to acquire a better knowledge of the levels of airborne vanadium exposure at which risk to human health occurs.