Lytico-bodig disease

Last updated
Lytico-bodig disease
Other namesGuam disease, amyotrophic lateral sclerosis-parkinsonism-dementia, ALS-PDC

Lytico-bodig (also Lytigo-bodig [1] ) disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) [2] is a neurodegenerative disease of uncertain etiology endemic to the Chamorro people of the island of Guam in Micronesia. Lytigo and bodig are Chamorro language words for two different manifestations of the same condition. ALS-PDC, a term coined by Asao Hirano and colleagues in 1961, reflects its resemblance to amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease. [3]

Contents

First reports of the disease surfaced in three death certificates on Guam in 1904 which made some mention of paralysis. The frequency of cases grew amongst the Chamorro until it was the leading cause of adult death between 1945 and 1956. [4] The incidence rate was 200 per 100,000 per year and it was 100 times more prevalent than in the rest of the world. [2] [5] Neurologist Oliver Sacks detailed this disease in his book The Island of the Colorblind . [6] Sacks and Paul Alan Cox subsequently wrote that bats had been feeding on Federico nuts ( Cycas micronesica ) and concentrating β-methylamino-L-alanine (BMAA), a known neurotoxin, in their body fat. [7] The hypothesis suggests that consumption of the bats by the Chamorro exposed them to BMAA, contributing to or causing their condition. [8] [9] Decline in consumption of the bats has been linked to a decline in the incidence of the disease. [10]

Symptoms and signs

Lytico-bodig disease presents itself in two ways:[ citation needed ]

Lytico

As with bodig, the symptoms and forms of lytico present themselves differently from patient to patient.[ citation needed ] Patient presentations include muscle atrophy, maxillofacial paralysis, inability to speak or swallow and subsequent choking. Some patients retain mental lucidity throughout the illness until death, much like ALS patients.[ citation needed ]

Diaphragm and respiratory accessory muscles can become paralyzed, necessitating mechanical ventilation to facilitate breathing. Saliva must be suctioned from the mouth to prevent aspiration. This form of lytico-bodig is fatal in all cases.[ citation needed ]

Bodig

No standard form of bodig has been reported and the documented cases of the disease manifested in many different clinical presentations.[ citation needed ]

The doctor visited a patient who had just suddenly come down with a virulent form. His symptoms had begun 18 months before, starting with a strange immobility and a loss of initiative and spontaneity; he found he had to make a huge effort to walk, to stand, and to make the least movement—his body was disobedient. The immobility attacked with frightening speed, and within a year, he was unable to stand alone and could not control his posture (2006).

—Oliver Sacks, The Island of the Colorblind, Vintage Books, 1996

Progressive dementia is also characteristic of bodig. Those who experience dementia are often aphasic and restless, and demonstrate irrational behavior, such as violence, and deep emotions at odd intervals. Patients experience manic highs and lows, giggling one minute and screaming the next.

Patients in the most virulent stage present with mouths hanging open, with excessive salivation; their tongues hang motionless, rendering speech and swallowing impossible. The patient's arms and legs become severely spastic and bent in immovable tension.[ citation needed ]

The advanced progression presents as profound motionlessness, or catatonia, accompanied with tremors or rigidity. Except in cases with concurrent dementia, most patients are capable of lucid thought and speech throughout the disease's physical progression.[ citation needed ]

Cause

Some hypotheses as to the cause of the disease include genetics, cycad seeds, and ingested beta-Methylamino-L-alanine (BMAA) from the consumption of fruit bats.[ citation needed ]

Genetic hypothesis

Genetics was first hypothesized due to the situation on Guam. Lytico-bodig was found in great numbers among members of the Chamorro community, so genetic factors were possible. The disease was shown to be familial but not genetic. Chamorro who grew up outside of Guam had not developed the disease, and some non-Chamorro who moved to the island and followed the culture did develop it. [11] Targeted high-throughput sequencing in a relatively small sample demonstrates that disease in many patients can be explained by pathogenic mutations in known genes for neurodegeneration. This includes parkinsonism-dementia due to PINK1 homozygous mutations, a DCTN1 mutation that may be causal for Perry syndrome, Huntington's disease due to HTT [CAG] expansions, and FUS and ALS2 mutations. [12]

Cycad hypothesis

The starch from indigenous Cycas micronesica seeds is consumed in the traditional Chamorro diet. The seeds are ground to make a flour called fadang, and the flour is then used to make flatbread and dumplings. The flour is soaked and washed several times, as the seed in its natural form is extremely toxic. Ample research on the cycad hypothesis found a component of the seeds, cycasin, was a potent toxin; it was discovered in the 1950s. As toxic as it was, it was incapable of causing of the symptoms of lytico-bodig. Not only that, after nearly two decades of NIH-funded research, animal models failed to reproduce chronic Lytico-Bodig, and the hypothesis was rejected for the first time. [5]

In 1967, following studies that linked lathyrism to ODAP, Marjorie Whiting, a nutritional anthropologist, asked Arthur Bell, a plant biochemist, to test cycad seeds for their chemical constituents. [8] Bell and his colleagues discovered another toxic substance in the seeds, BMAA (beta-Methylamino-L-alanine). [13] Initial laboratory results found low levels of free BMAA in cycad flour. [14] [15] The cycad hypothesis was abandoned a second time, because the acute toxicity shown by Spencer[ who? ] and Nunn[ who? ] was due to BMAA concentrations orders of magnitude higher. [5] Further laboratory analysis, which included protein-bound BMAA, found significant levels in fadang; the levels were higher in fadang made at settlements with a higher incidence of lytico-bodig. [16]

The cycad hypothesis was resurrected by Paul Alan Cox and Oliver Sacks, after re-examining aspects of the Chamorro diet. [7] Cox and his colleagues found that BMAA is produced by symbiotic cyanobacteria found in the coralloid roots of cycads. [5] Other than that, fruit bats or flying foxes feed on cycad seeds, and were a common food for the Chamorros. The bats bioaccumulate BMAA in their fat, and eating even a few bats would cause a dose of BMAA similar to levels that produced disease symptoms in the earlier animal models. The content of free BMAA in fruit bats was up to 3 mg/g (approximately 30 mM), while that in the broth in which the fruit bats had been cooked was up to 3 mg/250 ml. [17] Cox also observed decline in fruit bat consumption matching the decline in lytico-bodig. [10] [18] Support for the BMAA theory of the Guam disease came from the finding reported in 2016 that chronic dietary exposure of vervet monkeys homozygous for the APOE4 gene (which in humans increases risk of Alzheimer's disease) to the cyanobacterial toxin BMAA produces dense neurofibrillary tangles and sparse amyloid plaques similar to that found in the brains of Chamorro villagers in Guam who died from lytico-bodig. [19]

Mechanism

The mechanism is complex and poorly understood. During autopsies, neurofibrillary tangles are found in the brain which are congruent to the brain of an Alzheimer's patient.[ citation needed ]

The following is an excerpt from Island of the Colorblind, in which samples of substantia nigra are viewed under microscope. "Many of the cells are pale and depigmented. There's a lot of glial reaction, and bits of loose pigment. Shifting to a higher power, he saw a huge number of neurofibrillary tangles, densely staining, convoluted masses, harshly evident within the destroyed nerve cells." [6] Looking at other samples of hypothalamus, spinal cord, and cortex, all were full of neurofibrillary tangles. Neurofibrillary degeneration was everywhere. These slides were similar in appearance to those taken from postencephalitic parkinsonism.[ citation needed ]

While neurofibrillary degeneration is a potential cause of lytico-bodig, much is still undiscovered as to what causes the symptoms, what governs the severity, and how the onset of symptoms progresses. Similar symptoms of Postencephalitic Parkinsonism patients and Alzheimer's patients could account for the similarities in symptoms of lytico and bodig. Lytico-bodig, postencephalitis, and Alzheimer's could possibly be the same disease taking three different forms.[ citation needed ]

Age of onset seems to be increasing with no more teenage cases and almost no patients in their twenties. Presentation also varies between years. One form of the disease will present itself chiefly in one decade and then another form predominates in the next.[ citation needed ]

No treatment has been found to cure lytico-bodig. In some cases, the drug L-DOPA was given to patients to alleviate some of the symptoms of bodig, but this only gave the patients one or two hours of freedom from the complete paralysis and rigidity of limbs. It seems in the case of the Chamorros, family members are the primary caregivers, and they have accepted those who are ill and provide home care for all those inflicted with lytico-bodig.[ citation needed ]

Diagnosis

See also

Related Research Articles

<span class="mw-page-title-main">Frontotemporal dementia</span> Types of dementia involving the frontal or temporal lobes

Frontotemporal dementia (FTD), also called frontotemporal degeneration disease or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of the brain's frontal and temporal lobes. Men and women appear to be equally affected. FTD generally presents as a behavioral or language disorder with gradual onset. Signs and symptoms tend to appear in late adulthood, typically between the ages of 45 and 65, although it can affect people younger or older than this. Currently, no cure or approved symptomatic treatment for FTD exists, although some off-label drugs and behavioral methods are prescribed.

<span class="mw-page-title-main">Excitotoxicity</span> Process that kills nerve cells

In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.

<span class="mw-page-title-main">Cyanotoxin</span> Toxin produced by cyanobacteria

Cyanotoxins are toxins produced by cyanobacteria. Cyanobacteria are found almost everywhere, but particularly in lakes and in the ocean where, under high concentration of phosphorus conditions, they reproduce exponentially to form blooms. Blooming cyanobacteria can produce cyanotoxins in such concentrations that they can poison and even kill animals and humans. Cyanotoxins can also accumulate in other animals such as fish and shellfish, and cause poisonings such as shellfish poisoning.

<span class="mw-page-title-main">Fat choy</span> Species of edible, terrestrial cyanobacterium

Fat choy is a terrestrial cyanobacterium that is used as a vegetable in Chinese cuisine. When dried, the product has the appearance of black hair. For that reason, its name in Chinese means "hair vegetable". When soaked, fat choy has a soft texture which is like very fine vermicelli.

<span class="mw-page-title-main">Neurofibrillary tangle</span> Aggregates of tau protein known as a biomarker of Alzheimers disease

Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary biomarker of Alzheimer's disease. Their presence is also found in numerous other diseases known as tauopathies. Little is known about their exact relationship to the different pathologies.

<span class="mw-page-title-main">Shark cartilage</span> Pseudoscientific diet supplement

Shark cartilage is a dietary supplement made from the dried and powdered cartilage of a shark; that is, from the tough material that composes a shark's skeleton. Shark cartilage is marketed under a variety of brand names, including Carticin, Cartilade, or BeneFin, and is marketed explicitly or implicitly as a treatment or preventive for various illnesses, including cancer.

<span class="mw-page-title-main">Tauopathy</span> Medical condition

Tauopathies are a class of neurodegenerative diseases characterized by the aggregation of abnormal tau protein. Hyperphosphorylation of tau proteins causes them to dissociate from microtubules and form insoluble aggregates called neurofibrillary tangles. Various neuropathologic phenotypes have been described based on the anatomical regions and cell types involved as well as the unique tau isoforms making up these deposits. The designation 'primary tauopathy' is assigned to disorders where the predominant feature is the deposition of tau protein. Alternatively, diseases exhibiting tau pathologies attributed to different and varied underlying causes are termed 'secondary tauopathies'. Some neuropathologic phenotypes involving tau protein are Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

β-Methylamino-<small>L</small>-alanine Chemical compound

β-Methylamino-L-alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin. Its potential role in various neurodegenerative disorders is the subject of scientific research.

<i>Cycas micronesica</i> Species of cycad

Cycas micronesica is a species of cycad found on the island of Yap in Micronesia, the Marianaislands of Guam and Rota, and The Republic of Palau. It is commonly known as federico nut or fadang in Chamorro. The species, previously lumped with Cycas rumphii and Cycas circinalis, was described as a unique species in 1994 by Ken Hill. Paleoecological studies have determined that Cycas micronesica has been present on the island of Guam for about 9,000 years. It has been implicated as a factor in Lytico-Bodig disease, a condition similar to amyotrophic lateral sclerosis (ALS), due to the presence of the neurotoxin BMAA found in its seeds. Seeds were a traditional food source on Guam until the 1960s. The neurotoxin is present due to a symbiosis with cyanobacteria.

<span class="mw-page-title-main">SOD1</span> Protein-coding gene in the species Homo sapiens

Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, familial amyotrophic lateral sclerosis and Parkinson's disease.

<span class="mw-page-title-main">ALS</span> Rare neurodegenerative disease

Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) or Lou Gehrig's disease in the United States, is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and lower motor neurons that normally control voluntary muscle contraction. ALS is the most common form of the motor neuron diseases. ALS often presents in its early stages with gradual muscle stiffness, twitches, weakness, and wasting. Motor neuron loss typically continues until the abilities to eat, speak, move, and, lastly, breathe are all lost. While only 15% of people with ALS also fully develop frontotemporal dementia, an estimated 50% face at least some minor difficulties with thinking and behavior. Depending on which of the aforementioned symptoms develops first, ALS is classified as limb-onset or bulbar-onset.

Hirano bodies are intracellular aggregates of actin and actin-associated proteins first observed in neurons by Asao Hirano in 1965. The eponym ‘Hirano bodies’ was not introduced until 1968, by Schochet et al., three years after Hirano first observed the proteins.

<span class="mw-page-title-main">Cycasin</span> Chemical compound

Cycasin is a carcinogenic and neurotoxic glucoside found in cycads such as Cycas revoluta and Zamia pumila. Symptoms of poisoning include vomiting, diarrhea, weakness, seizures, and hepatotoxicity. In metabolic conditions, cycasin is hydrolyzed into glucose and methylazoxymethanol (MAM), the latter of which dissociates into formaldehyde and diazomethane.

Project MinE is an independent large scale whole genome research project that was initiated by 2 patients with amyotrophic lateral sclerosis and started on World ALS Day, June 21, 2013.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier may occur.

<span class="mw-page-title-main">Benjamin Wolozin</span> American pharmacologist and neurologist

Benjamin Wolozin is an American pharmacologist and neurologist currently at Boston University School of Medicine. He is also an Elected Fellow of the American Association for the Advancement of Science.

There are more than 25 genes known to be associated with amyotrophic lateral sclerosis (ALS) as of June 2018, which collectively account for about 70% of cases of familial ALS (fALS) and 10% of cases of sporadic ALS (sALS). About 5–10% of cases of ALS are directly inherited. Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS. ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.

Research on amyotrophic lateral sclerosis (ALS) has focused on animal models of the disease, its mechanisms, ways to diagnose and track it, and treatments.

A neurological syndrome of unknown cause was identified as a potential novel degenerative disease in a cluster of individuals with similar clinical signs and symptoms in the Canadian province of New Brunswick beginning in 2019. Symptoms listed on the New Brunswick Public Health (NBPH) website include memory problems, muscle spasms, balance problems, difficulty walking or falls, blurred vision or visual hallucinations, unexplained or significant weight loss, behaviour changes, and pain in the upper or lower limbs.

References

  1. ↑ Golbe LI (September 2000). "Progressive supranuclear palsy in the molecular age". Lancet. 356 (9233): 870–1. doi:10.1016/S0140-6736(00)02672-6. PMID   11036887. S2CID   44344682.
  2. 1 2 Steele JC (August 2005). "Parkinsonism-dementia complex of Guam". Mov. Disord. 20 Suppl 12: S99–S107. doi:10.1002/mds.20547. PMID   16092098. S2CID   28721189.
  3. ↑ Moisse, Katie (2013-09-24). ""A Batty Hypothesis on the Origins of Neurodegenerative Disease Resurfaces," Scientific American". Scientificamerican.com. Retrieved 2013-09-28.
  4. ↑ Brody JA, Chen K (1969). "Changing epidemiologic patterns of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia on Guam". Motor Neuron Diseases Research on ALS and Related Disorders: 61–79.
  5. 1 2 3 4 Bradley WG, Mash DC (2009). "Beyond Guam: the cyanobacteria/BMAA hypothesis of the cause of ALS and other neurodegenerative diseases". Amyotroph Lateral Scler. 10 Suppl 2: 7–20. doi:10.3109/17482960903286009. PMID   19929726. S2CID   41622254.
  6. 1 2 Sacks, Oliver (2006). The Island of the Colorblind. New York: Random House. ISBN   0-679-77545-5.
  7. 1 2 Cox PA, Banack SA, Murch SJ (November 2003). "Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam". Proc. Natl. Acad. Sci. U.S.A. 100 (23): 13380–3. Bibcode:2003PNAS..10013380C. doi: 10.1073/pnas.2235808100 . PMC   263822 . PMID   14612559.
  8. 1 2 Holtcamp W (March 2012). "The emerging science of BMAA: do cyanobacteria contribute to neurodegenerative disease?". Environ. Health Perspect. 120 (3): A110–6. doi:10.1289/ehp.120-a110. PMC   3295368 . PMID   22382274.
  9. ↑ Miller G (July 2006). "Neurodegenerative disease. Guam's deadly stalker: on the loose worldwide?". Science. 313 (5786): 428–31. doi:10.1126/science.313.5786.428. PMID   16873621. S2CID   34147464.
  10. 1 2 Monson CS, Banack SA, Cox PA (2003). "Conservation implications of Chamorro consumption of flying foxes as a possible cause of amyotrophic lateral sclerosis-parkinsonism dementia complex in Guam". Conservation Biology. 17 (3): 678–686. Bibcode:2003ConBi..17..678M. doi:10.1046/j.1523-1739.2003.02049.x. S2CID   84948326.
  11. ↑ Morris HR, Al-Sarraj S, Schwab C, Gwinn-Hardy K, Perez-Tur J, Wood NW, Hardy J, Lees AJ, McGeer PL, Daniel SE, Steele JC (November 2001). "A clinical and pathological study of motor neurone disease on Guam". Brain. 124 (Pt 11): 2215–22. doi:10.1093/brain/124.11.2215. PMID   11673323.
  12. ↑ Steele JC, Guella I, Szu-Tu C, Lin MK, Thompson C, Evans DM, Sherman HE, Vilariño-Güell C, Gwinn K, Morris H, Dickson DW, Farrer MJ (2015). "Defining neurodegeneration on Guam by targeted genomic sequencing". Annals of Neurology. 77 (3): 458–68. doi:10.1002/ana.24346. PMID   25558820. S2CID   20492783.
  13. ↑ Vega A, Bell EA (1967). "Alpha-amino-beta-methylaminopropionic acid, a new amino acid from seeds of cycas circinalis". Phytochemistry. 16 (5): 759–762. Bibcode:1967PChem...6..759V. doi:10.1016/s0031-9422(00)86018-5.
  14. ↑ Duncan MW, Steele JC, Kopin IJ, Markey SP (May 1990). "2-Amino-3-(methylamino)-propanoic acid (BMAA) in cycad flour: an unlikely cause of amyotrophic lateral sclerosis and parkinsonism-dementia of Guam". Neurology. 40 (5): 767–72. doi:10.1212/wnl.40.5.767. PMID   2330104. S2CID   25006038.
  15. ↑ Kisby GE, Ellison M, Spencer PS (July 1992). "Content of the neurotoxins cycasin (methylazoxymethanol beta-D-glucoside) and BMAA (beta-N-methylamino-L-alanine) in cycad flour prepared by Guam Chamorros". Neurology. 42 (7): 1336–40. doi:10.1212/wnl.42.7.1336. PMID   1620343. S2CID   71620280.
  16. ↑ Cheng R, Banack SA (2009). "Previous studies underestimate BMAA concentrations in cycad flour". Amyotroph Lateral Scler. 10 Suppl 2: 41–3. doi:10.3109/17482960903273528. PMID   19929730. S2CID   40589338.
  17. ↑ Banack SA, Murch SJ, Cox PA (June 2006). "Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands". J Ethnopharmacol. 106 (1): 97–104. doi:10.1016/j.jep.2005.12.032. PMID   16457975.
  18. ↑ Banack SA, Cox PA (2003). "Biomagnification of cycad neurotoxins in flying foxes". Neurology. 61 (3): 387–389. doi:10.1212/01.wnl.0000078320.18564.9f. PMID   12913204. S2CID   38943437.
  19. ↑ Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA (January 2016). "Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain". Proc. Biol. Sci. 283 (1823). doi:10.1098/rspb.2015.2397. PMC   4795023 . PMID   26791617.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.