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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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The Difference Between Kozagawa and Hohara

The Kii Peninsula has two clusters: Kozagawa in Wakayama Prefecture and Hohara in Mie Prefecture. Since the Meiji period, the southern Kii Peninsula has been known as a high-incidence area for ALS. In the 1960s, epidemiological surveys by Wakayama Medical University identified two such high-incidence areas.¹⁾ As will be discussed later, since most patients in Kozagawa had ALS, the Wakayama Medical University survey also focused on ALS. Consequently, in later years, the impression took hold that “the Kii Peninsula is an ALS high-incidence area.”

In the 1990s, we reported the first PDC autopsy case in the Hohara district, proving the actual existence of PDC on the Kii Peninsula. ²⁾ Our investigations to date revealed that while the Kozagawa area was a hotspot for ALS, PDC was virtually absent; most cases were sporadic with no family history; tau protein levels in the brain were extremely low; and C9orf72 gene mutations³⁾ or OPTN gene mutations⁴⁾ were identified in some patients. In contrast, in Hohara, both ALS and PDC exist, over 70% of cases are familial, substantial tau protein accumulation is observed in the brain, and no C9orf72 or OPTN gene mutations are detected (Figure 1). These findings closely resemble the Guam ALS/PDC pattern.

In Guam, ALS/PDC had nearly disappeared by the 2000s, whereas new cases continue to be observed in the Hohara district. (Figure 2) Environmental factors play a major role in the onset of ALS/PDC. Identifying the environmental factors that disappeared in Guam but remain in Hohara is key to solving the mystery of this disease.

1) Shiraki H, Yase H. Amyotrophic lateral sclerosis in Japan. Handbook of Clinical Neurology, Systemic dysorders and atrophies (Vinken PJ, Bruyn GW), Amsterdam: Elsevier;1975.vol.22. PartⅡ. p. 353-419. 2) Kuzuhara S, Kokubo Y, Sasaki R, Narita Y, Yabana T, Hasegawa M, Iwatsubo T. Familial amyotrophic lateral sclerosis and parkinsonism - dementia complex of the Kii peninsula of Japan: clinical and neuropathological study and tau analysis. Ann Neurol 49：501－511, 2001 3)Hiroyuki Ishiura, Yuji Takahashi, Jun Mitsui, Sohei Yoshida, Tameko Kihira, Yasumasa Kokubo, Shigeki Kuzuhara, Laura P. W. Ranum, Tomoko Tamaoki, Yaeko Ichikawa, Hidetoshi Date, Jun Goto, Shoji Tsuji. C9ORF72 Repeat Expansion in Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan. Archives of neurology 69:1154-1158, 2012 4)HIROYA NARUSE, YUJI TAKAHASHI, TAMEKO KIHIRA,SOHEI YOSHIDA, YASUMASA KOKUBO , SHIGEKI KUZUHARA , HIROYUKI ISHIURA , MASAHARU AMAGASA , SHIGEO MURAYAMA, SHOJI TSUJI & JUN GOTO. Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population. Amyotrophic lateral sclerosis 13:562-566, 2012

Figure 1 Differences in Disease Patterns Between Kozagawa and Hohara

Figure 2 Changes in Prevalence in the Kii Peninsula High-Incidence Area

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)"

Kii ALS / PDC - Muro disease -

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