Amyotrophic Lateral Sclerosis on Guam: A Clinical Study and Review of the Literature

Koerner, Donald R.

doi:10.7326/0003-4819-37-6-1204

Cited by 90 publications

(6 citation statements)

References 32 publications

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“…A rare form of the disease called Guam ALS– Parkinsonism Dementia Complex (ALS/PDC) comprises ALS, often with associated symptoms of Parkinsonism and Alzheimer’s like dementia, occurred in native Chamorro populations with an incidence >50 times that of ALS in most of the world (Arnold et al, 1953; Koerner, 1952; Mulder et al, 1954). Intensive epidemiological studies implicated environmental exposures (Garruto and Yase, 1986; Spencer, 1987), with early attention focusing on highly toxic cycad seeds, which were used for food after repetitive washing and cooking (Kurland, 1972; Whiting, 1963), and a neurotoxic non-protein amino acid, beta-N-methylamino-L-alanine (BMAA, also known as alpha-amino-beta-methylaminopropanoic acid) which they contained (Vega and Bell, 1967).…”

Section: Introductionmentioning

confidence: 99%

Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

Yin

Hsu

et al. 2014

Experimental Neurology

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The neurotoxin beta-N-methylamino-L-alanine (BMAA) was first identified as a “toxin of interest” in regard to the amyotrophic lateral sclerosis–Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30 day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2 days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resembles those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease.

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Section: Introductionmentioning

confidence: 99%

Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

Yin

Hsu

et al. 2014

Experimental Neurology

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“…Koerner (1952) considered the ALS cases examined in Guam as being typical sporadic ALS, although the existence of a familial incidence of the disease was noted. Kurland and Mulder (1954a, 1954b) studied the familial nature of the ALS and found that although most of the 46 patients observed had a typical form of ALS, some showed symptoms of Parkinsonism.…”

Section: Inconsistencies and Questions Regarding The Bmaa Hypothesismentioning

confidence: 99%

“…The brains of 5/29 people considered to be controls exhibited evidence of pathologic changes associated with PDC, and NFTs were observed in various areas of the brain including the hippocampus, cerebral cortex, thalamus, and substantia nigra. Differences between ALS/PDC and ALS, Parkinsonism, and AD include the familial occurrence in Guam (Koerner 1952; Kurland and Mulder 1954a, 1954b; Hirano et al 1966; Morris et al 2001; Zhang et al 1996) and the common mixed disease syndrome in Guam (Malamud, Hirano, and Kurland 1961; Murakami 1999), both being extremely rare elsewhere. Additional factors, indicating that ALS/PDC is distinct from sporadic ALS, Parkinsonism, and AD, include the occurrence of cerebral NFTs in younger population in Guam than elsewhere, the absence of betaamyloid plaques that are characteristic of AD; the absence of ubiquinated Lewy bodies characteristic of Parkinsonism (Hirano et al (1961b); and the observation that the typical “pill rolling” movements in Parkinsonism were rare in ALS/PDC (Brody et al 1971).…”

Section: Inconsistencies and Questions Regarding The Bmaa Hypothesismentioning

confidence: 99%

“…The disease rendered patients incapable of normal movement, produced cognitive deficits, and almost always led to premature death. Initial investigations in Guam centered on clinical aspects of approximately 90 patients, and it was postulated that classic (sporadic) ALS was being observed (Arnold, Edgren, and Palladino 1953; Koerner 1952). Koerner (1952) did note “a spasm or rigidity occurred in seemingly more cases than have been described,” a 20% incidence of “psychosis,” and an unusually high familial incidence of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Initial investigations in Guam centered on clinical aspects of approximately 90 patients, and it was postulated that classic (sporadic) ALS was being observed (Arnold, Edgren, and Palladino 1953; Koerner 1952). Koerner (1952) did note “a spasm or rigidity occurred in seemingly more cases than have been described,” a 20% incidence of “psychosis,” and an unusually high familial incidence of the disease. Kurland and Mulder (1954a, 1954b) studied the epidemiology and symptoms of the disease, and the incidence of ALS in the Chamorros was found to be significantly higher at that time (150/100,000) than in any Caucasian population (1–2/100,000).…”

Section: Introductionmentioning

confidence: 99%

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A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans

Chernoff

Hill

Diggs

et al. 2017

Journal of Toxicology and Environmental Health, Part B

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The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer's disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

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Pathoanatomic Changes in Amyotrophic Lateral Sclerosis on Guam

Malamud

Hirano²,

Kurland

1961

Arch Neurol

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Amyotrophic Lateral Sclerosis on Guam: A Clinical Study and Review of the Literature

Cited by 90 publications

References 32 publications

Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord

A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans

Pathoanatomic Changes in Amyotrophic Lateral Sclerosis on Guam

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