Amyotrophic lateral sclerosis–parkinsonism–dementia complex in the Kii Peninsula of Japan (Muro disease): a review on recent research and new concept

Abstract

More than a century ago, Kin-no-suke Miura, Professor of Internal Medicine of the University of Tokyo discovered a high prevalence of amyotrophic lateral sclerosis (ALS) in the Muro district, the mountainous areas of the southern Kii Peninsula (including the southern parts of the Mie and Wakayama prefectures) (Figure 3.1). In the early 1960s, Kimura, Yase and their colleagues performed a door-to-door survey on patients with ALS in the whole of the Muro district, and discovered two foci of extremely high ALS incidence (i.e. Hohara in the Mie prefecture and Kozagawa in the Wakayama prefecture; see Figure 3.1). ALS in these foci showed clinical signs and symptoms produced by selective anatomical involvement of the upper and lower motor neurones in the same manner as Charcot had described in sporadic ALS, unique neuropathological features were characterized by the presence of many neurofibrillary tangles (NFTs) throughout the central nervous system as in ALS of the Chamorro people in Guam, another high-incidence ALS focus. In the 1960s, Gajdusek discovered a new ALS focus among the Auyu and Jakai people of southeastern West New Guinea. Foci of high-incidence ALS in the Kii Peninsula was thus segregated from classical ALS and classified as ‘Kii ALS’ or ‘Muro disease’, a member of the hyperendemic western Pacific ALS family.In Guam, another peculiar neurodegenerative disease or ‘parkinsonism–dementia complex’ (PDC) was discovered. PDC was characterized clinically by a combination of progressive dementia and atypical progressive parkinsonism poorly responsive to drugs, and neuropathologically by frontotemporal brain atrophy with presence of many NFTs in the whole central nervous system. Mixed ALS and PDC in which both features were clinically and neuropathologically overlapped were also identified, and ALS and PDC in these high-incidence foci were thus regarded as a spectrum of one disease entity or ALS/PDC. Extensive studies failed to solve the cause and pathogenesis of high-incidence ALS/PDC. Meanwhile, high-incidence rates of ALS markedly declined in the 1960s and 1970s, and spontaneously disappeared by the early 1980s in Guam. A similar decline of high-incidence rates of ALS during the 1980s was also reported in foci of the Kii Peninsula and West New Guinea.In early 1990s, Kuzuhara paid attention to the reoccurrence of ALS among residents in the Hohara focus. After several years’ investigations, we confirmed not only the high-incidence rates of ALS but also the coexistence of a high incidence of progressive parkinsonism and dementia associated with many NFTs in the central nervous system neuropathologically, reminiscent of PDC of Chamorro in Guam. The focus of this chapter is to review findings of recent research with respect to the Kii ALS/PDC from the Hohara focus, particularly regarding clinical features, neuroimaging studies, immunohistochemical findings of the brain and spinal cord, genetic studies, and recent epidemiological trends. We will also discuss new disease concepts derived from these findings.