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ALS/Parkinsonism-Dementia Complex of the Kii peninsula, Japan (Kii ALS/PDC)

The southern　area　in　the　Kii　peninsula　of　Japan (Muro　district)　is　one　of　the　hyperendemic　foci　of　amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC), together with Guam island. High accumulation of phosphorylated tau protein in neurons and glial cells in the central nervous system is the hallmark of ALS/PDC. Epidemiologically, marked decline in ALS incidence and concomitant increase in PDC incidence occurred in 1970s, suggesting changes of some unsolved environmental factors may have induced phenotypic changes of the disease. A research on genetic factors, environmental factors and their interaction is now going on.

Shigeki Kuzuhara, MD,PhD. Professor Emeritus of Neurology, Mie University

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Essay on Muro disease – ALS/PDC –

ALS/PDC and Cycad (1)

Amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) is a rare neurological disorder found exclusively in Guam, the Kii Peninsula, and Papua (the Indonesian province of Papua, not Papua New Guinea; the western half of New Guinea Island). Patients often have a family history of the disease (70-80% of patients have blood relatives with the same condition), and ALS and PDC (Parkinson's symptoms combined with dementia) coexist within the same family lineage. In the Kii Peninsula, there are clusters in the southern coastal regions of Wakayama and Mie Prefectures. This area has historically been referred to as “Muro,” so locally, ALS/PDC is known as “Muro disease.” Guam Island was first “discovered” by Westerners in 1521 during Magellan's circumnavigation of the globe and became a Spanish colony in 1565. Regarding the intriguing question of when ALS/PDC first appeared on Guam Island, the first documented case of a disease resembling ALS/PDC was reported by de la Corte in the 1870s, over 300 years after Guam became a Spanish colony. Did ALS/PDC suddenly emerge at this time, or whether the Spanish had simply not noticed it before, remains unclear. Following the Spanish-American War of 1898, Guam became a U.S. territory. After being occupied by Japan during World War II, it became a U.S. commonwealth after the war. ALS/PDC was rediscovered by American epidemiologists in the 1950s. ALS/PDC in Guam is considered a disease unique to the indigenous Chamorro people, and it was speculated that the cause of the disease may be related to the Chamorro people's lifestyle and/or dietary habits. Dr. M. Whiting (https://manoa.hawaii.edu/library/research/collections/archives/manuscript-collections/other-manuscript-collections/marjorie-grant-whiting-papers/), a cultural anthropologist at the U.S. National Institutes of Health (NIH), lived for six months in a village in Umatac (the port where Magellan first landed in Guam) and discovered that the Chamorro people regularly consumed tortillas made from cycad. This led to the proposal of the cycad theory for ALS/PDC. Dr. M. Whiting also lived for two months in the Muro region of Wakayama Prefecture in the same year, but reported that the local population did not consume cycad. We reject the cycad theory for the cause of ALS/PDC in the Kii Peninsula. The basis for this is: ① Cycad is not consumed in the Muro region, ② ALS/PDC does not exist on Amami Oshima islands, where cycad is a staple food, ③ Shōichi Yokoi, a former Japanese soldier who lived in Guam for 26 years and regularly consumed cycad, developed Parkinson's symptoms in his later years, but autopsy results revealed he had Parkinson's disease, not ALS/PDC, ④ Mass spectrometry analysis of brain tissue from Muro disease patients did not detect BMAA, the neurotoxin attributed to cycad. (2) However, if cycad is the cause of the disease in Guam, which is neuropathologically similar (or even identical) to Muro disease, could a substance similar to cycad be the causative agent in Kii, even if cycad itself is not the direct cause?

1)MJ Whiting. Food practice in ALS foci IN Japan, the Marianas, and New Guinea. Third conference of toxicity of cycads. Federation Proceeding. 1964;23:1343-1345.

2) Y.Kokubo, S.Morimoto, M.Yoshida. Questioning the cycad theory of Kii ALS-PDC causation. Nature Reviews Neurology 2024 https://doi.org/10.1038/s41582-024-00936-0

Publication in the Journal "Acta Neuropathologica" (15 May 2024)

The titled "Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes" by Leventoux N, Morimoto S et al. was published in the Jounal "Acta Neuropathologica (Impact Factor: 16.2)"

Publication in the Journal "Proc Natl Acad Sci U S A" (19 December 2023)

The titled "Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold" by Ci C et al. was published in the Jounal "Proc Natl Acad Sci U S A (Impact Factor: 12.0)"

Kii ALS / PDC - Muro disease -

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