Lytico-Bodig; An obscure malady of Guamanian Chamorros.

History of Guam and the Mariana Islands

In 1521, the explorer Ferdinand Magellan discovered the island of Guam during his circumnavigation of the world. It was a very small speck of land in the vast Western Pacific Ocean and it was the first contact between the Europeans and Pacific people. The inhabitants called themselves Chamorros, and the Spanish regarded them as uncivilized because they went naked. But, the Chamorros were robust and long-lived. Their society was complex and they were skilled in fishing and had a healthy, subsistence lifestyle. Oppressive Spanish colonization severely reduced the Chamorro population to 10,000 by 1898 when it was ceded to the United States after the Spanish-American War. The new American Naval administration improved living conditions and the Chamorro population rose to be 30,000 in just 40 years at the onset of World War II and Guam’s occupation by the Japanese from 1941 to 1945. After the War,the island changed dramatically and became a main military outpost in the Pacific. It was rapidly westernized and many migrants of other ethnicities arrived. In 2012, Guam is a modern American place with a population of 150,000. Sixty thousand Chamorros live on Guam, and 60,000 others have relocated to the US mainland since the War.

The mysterious neurological disease of Guam

For 150 years, lytico-bodig, a common neurodegenerative disease of Guam, has taken the lives of many Chamorros. It is also known as the amyotrophic lateral sclerosis/parkinson-dementia complex (ALS/PDC). For 60 years, neuroscientists have investigated its cause and expected that understanding it could provide a cure for Alzheimer’s and Parkinson’s disease, and amyotrophic lateral sclerosis (ALS/ Lou Gehrig’s disease) in other parts of the world. Lytico-bodig can begin as young as 15, but others may not have symptoms until their 80s. ALS/PDC is always progressive and patients usually die within four to five years, though its course may be fulminant with death in six months or prolonged with survival for more than 30 years. In the past 50 years, lytico-bodig has declined and its age in onset has increased. By 2011, ALS has ended, parkinsonism is uncommon, and only dementia still occurs in elderly Chamorros.

Symptoms of lytico-bodig

Persons suffering ALS develop weakness, wasting, and then paralysis of the arms and legs. They become bed-bound, cannot speak or swallow, and have difficulty in breathing. They require total care by their family, but their memory and thinking remain very clear. With parkinsonism, patients become slow in their movements. Their posture is stooped and often they have trembling of the hands and legs. Their walking is unsteady and they frequently fall backwards. Many develop trouble in memory, which may precede the onset of these parkinsonian symptoms. Dementia is the third way lytico-bodig shows itself. Patients become forgetful and cannot remember what they have just been told. As dementia advances, patients become confused, they are irritable, suspicious and often, they have hallucinations. The dementia of lytico-bodig is similar to Alzheimer’s disease in other parts of the world and can only be distinguished by postmortem examinations of the brain.

Other places with lytico-bodig

This same disease occurs in two other Pacific regions. It is present in two clusters of five villages each in the mountains of the Kii Peninsula of Honshu Island in Japan. The villages are separated by 100 kilometers and ALS/PDC does not occur in other villages of the peninsula or in other parts of Japan. ALS/PDC also affects 7,000 headhunting tribes’ people who live on the coastal plain of West New Guinea. ALS/PDC there has now disappeared as it is disappearing on Guam.Japanese neurologists report that ALS/PDC continues there.

Searching for the cause of lytico-bodig

Since these three geographic isolates of ALS/PDC were described, neuroscientists have expected that understanding its cause in these separate places would provide understanding about common and related diseases elsewhere. By such understanding of its disease mechanisms, they hoped to develop cures for ALS, Parkinson’s and Alzheimer’s disease, and progressive supranuclear palsy (PSP). The most intense research for its cause has been on Guam and in Japan. Studies in West New Guinea have been difficult because of inaccessibility.

Everyone has agreed it should be very simple to identify the cause of this common disease in these places, but its discovery has evaded research studies by foremost scientists from all parts of the world during the past 50 years. In 2011, the cause of ALS/PDC is still unknown.

Genetic inheritance as the cause of ALS/PDC

Because the disease occurred in successive generations and affected many members of some Chamorro families, scientists first thought ALS/PDC must be due to inheritance and genetic transmission. But studies have not shown a genetic mutation. Furthermore, genetic diseases do not disappear in just one generation,as has happened with ALS/PDC on Guam and New Guinea. Also, migrants of other ethnicity do not contract genetic diseases as has occurred on Guam among Caucasians and Filipinos. For these several reasons, genetic inheritance is unlikely, although molecular biologists continue to investigate genetic predisposition.

Neurotoxins in cycad seeds as the cause of ALS/PDC

Leonard Kurland’s hypothesis of overall cycad seeds toxicity

Early researchers Leonard Kurland and Donald Mulder looked for a unique habit of Guamanian Chamorros to explain the reason for ALS/PDC. One difference between Guam and other Pacific Islands they identified was the Chamorro habit of leeching poisonous seeds of the false sago palm [cycas Micronesica] as flour for baking; a practice they had learned from Mexicans on Spanish galleons who taught them its preparation.Three toxins of the cycad seeds are now known and include BMAA, cycasin, and steryl glucosides. Each toxin is favored by different advocates as the cause of ALS/PDC, but none of them reproduce the disease in experimental animal, and all are doubted by many to be sufficiently toxic to cause this progressive and fatal disease many years after eating small amounts of the prepared flour. During the 1950s and 60s, the National Institutes of Health held six international, multidisciplinary conferences about the neurotoxicity of cycad seeds. By these conferences, they concluded that none of its toxins caused ALS/PDC.

Peter Spencer’s hypothesis of cycad derived BMAA toxicity

In the 1980s, neurotoxicologist Peter Spencer favored BMAA as the cause of ALS/PDC. It is a glutamate excitotoxin related to BOAA, the amino acid of chickling peas [Lathyrus sativus], which causes subacute paralysis and lathyrism when eaten in excess. Spencer observed that prolonged, forced feeding of primates with BMAA caused weight loss and weakness. But the amount of BMAA he fed them was much larger than the amount which could be consumed by humans, and the pathological changes were not characteristic of ALS/PDC. His hypothesis was given up by most in the early 1990s.

Chris Shaw’s hypothesis of cycad derived steryl glucoside toxicity

In early 2000, ophthalmologist Chris Shaw proposed that insoluble steryl glucosides were the cause of ALS/PDC. But his feeding of animals with these compounds has not reproduced the disease.

Paul Cox’s hypothesis of cyanobacteria derived BMAA toxicity

In 2002, botanist Paul Cox revived BMAA as the likely cause of ALS/PDC when he and Oliver Sacks observed a parallel decline between the disease and the flying fox population of Guam. He postulated that the foxes, which fed on cycad seeds, accumulated this toxin and they poisoned people who ate them. Subsequently, he suggested that BMAA was elaborated by cyanobacteria in the cycad roots. He generalized the hypothesis of BMAA neurotoxicity and proposed that ubiquitous cyanobacteria of water sources produced BMAA, which caused ALS and Alzheimer’s disease in humans. Others observe that foxes are eaten in all Pacific islands, that cycad trees grow on these islands for foxes to feed on, and yet ALS/PDC does not occur in these places. Furthermore in two of the three isolates where ALS/PDC does occur, flying foxes are not present and cannot be eaten by their residents. And finally researchers cannot reproduce Cox’s BMAA findings in tissues of ALS/PDC, ALS and AD orin water sources. Many people now doubt his hypothesis and think its origins were an epidemiological coincidence rather than an etiological association.

Peter Spencer’s hypothesis of cycasin and BMAA genotoxicity

In 2011, Dr. Spencer and Glen Kisby proposed that cycasin is the important culprit of ALS/PDC and that with BMAA, it causes genotoxic disruption in those who consume these two toxins and that together they dispose people to develop tauopathy and ALS/PDC.

Minerals and metals of the environment as the cause of ALS/PDC

In the late 1970s, colleagues of Carleton Gajdusek proposed that ALS/PDC was caused by abnormal concentrations of mineral and metalin the three isolates. When others did not confirm their analyses of low calcium and magnesium, and high aluminum in all three areas, their hypothesis of secondary hyperparathyroidism was given up by the mid 1990s.

Infection due to transforming, misfolded proteins akin to prion disease as the cause of ALS/PDC

Kuru is a progressive, neurological degeneration affecting the Fore people of central New Guinea. In the 1950s, Dr. Carleton Gajdusek was awarded a Nobel Prize in medicine when he showed that kuru was a transmitting disease between people and due to an abnormal, misfolded protein [now named a prion] they consumed during ritualistic cannibalism. He proved transmissibility by injecting brain tissue from patients with kuru into monkeys and observed that they too developed the same illness, many months later. Gajdusek then attempted to transmit other neurodegenerative diseases including ALS/PDC, ALS, Parkinson’s and Alzheimer’s disease, but he was not successful by the same techniques that had transmitted kuru. By 1982, he concluded that these other diseases were not transmissible by direct inoculation of infected tissues into primates.

Subsequent observations indicating protein transformation in humans

In 2008, pathologists observed that healthy stems cells injected into patients with Parkinson’s disease accumulated the same abnormal protein that causes this disease.They concluded that the abnormal protein of the diseased cells adjacent to the stem cells had caused normal proteins in the stem cells to transform and to become abnormal and misfolded. Since that seminal observation, othershave attempted to transmit abnormal proteinsof other neurodegenerative diseases. They are beginning to show that these misfolded proteins are capable of changing normal proteins to misfolded ones. They are suggesting that this disease process spreads slowly from cell to cell, in an orderly fashion throughout the nervous system.

What causes proteins to misfold in these diverse diseases is not yet certain. However, we do know they do occur after some acute infections. By example, postencephalitic parkinsonism (PEP), which follows encephalitis lethargica, has similar protein pathology to ALS/PDC and PSP. In subacute sclerosing panencephalitis (SSPE), which occurs after measles infection, the spongiform pathology is similar to kuru, and to Jakob Creutzfeldt disease, which are both caused by misfolded prion proteins.

Future transmission studies

There are many epidemiological similarities between kuru, PEP and SSPE, which suggest a common disease mechanism with ALS/PDC. Their similarities are silent and asymptomatic exposure and onset, long incubation and latency, and slow decline after the infectious event. These new ideas of a progressive transformation of healthy proteins by abnormal, misfolded ones have revitalized our research of ALS/PDC and related neurodegenerative diseases. Professor Michel Goedert of the Medical Research Council in Cambridge, UK is currently trying to transmit ALS/PDC to mice.

Linear Pigment Retinal Epitheliopathy [LPRE]

Twenty-five years ago, neuropthalmologist Terry Cox identified a statistically significant association between a linear retinopathy of Guamanian Chamorros and ALS/PDC. The same association occurs in the Kii Peninsula, but neither of these two unique conditions occurs in any other part of the world. The retinopathy has no symptoms and precedes the onset of the neurological disease. The depigmented tracks do not change and they have the appearance of a transient larva migrans through the RPE. They predict the occurrence of ALS/PDC and we think are a persisting marker of the etiological event of ALS/PDC, which is to follow.

Conclusion

Umatac and Merizo are small villages in southern Guam, which are adjacent to one another. They are by the ocean’s edge, their residents are Chamorro, and they have similar habits and lifestyles. Yet, for more than 100 years, ALS/PDC has been much more common in Umatac families and has affected many of their members in successive generations of all its families. The disease is disappearing now in both villages and all other parts of the island. But at one time, the environmental cause of ALS/PDC was most common in Umatac and it is still most likely to be identified here. Like Rosetta, the small Egyptian town where broken stone tablets gave understanding of hieroglyphics, we remain optimistic that will identify the cause of ALS/PDC in the six square miles of the Umatac district to end this medical mystery, and to understand the disease mechanism of related and universal neurodegenerative diseases.

Pollara B. Cobb, University of Guam

John C. Steele, Neurologist, Guam Memorial Hospital

December 15, 2011.