In 1960s, epidemiological surveys in both Kozagawa and Hobara foci revealed the characteristics of Kii ALS as follows: younger age at onset. M/F ratio of 1.5-1.8:1, familial clustering and presence of Alzheimer's neurofibrillary tangles (NFTs). The segregation ratio of six families in Hobara was estimated 0.304 +/- 0.096 ( p +/- 95% confidence level), suggesting a multifactorial inheritance. Kii environmental studies showed that extremely low contents of calcium (Ca) and magnesium (Mg) in the birthplace's rivers of ALS patients inversely and significanthy correlated with high mortality rates, aluminum (Al) contents, and densities of hipocampal NFTs. In experimental animals, a low Ca and Mg, and high Al content diet led to a neuronal loss with axonal swellings and chromatolysis, and positive staining of cortical neurons with anti-PHF antibodies. Recently, a significant loss of dopaminergic neurons was identified exclusively in the substantia nigra in 1-year-old rat fed under a low Mg intake over two generations. Kii people may have a predisposition to develop ALS/PDC precipitated by their environmental status, suggesting gene-environmental interactions.
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