Lytico-bodig (also Lytigo-bodig
) disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC)
is a
neurodegenerative disease
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
of uncertain
etiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
endemic to the
Chamorro people
The Chamorro people (; also CHamoru) are the indigenous people of the Mariana Islands, politically divided between the United States territory of Guam and the encompassing Commonwealth of the Northern Mariana Islands in Micronesia. Today, signif ...
of the island of
Guam
Guam (; ch, Guåhan ) is an organized, unincorporated territory of the United States in the Micronesia subregion of the western Pacific Ocean. It is the westernmost point and territory of the United States (reckoned from the geographic cent ...
in Micronesia. ''Lytigo'' and ''bodig'' are
Chamorro language
Chamorro (; ch, Finuʼ Chamorro, links=no (CNMI), (Guam)) is an Austronesian language spoken by about 58,000 people (about 25,800 people on Guam and about 32,200 in the rest of the Mariana Islands and elsewhere). It is the native and spoken ...
words for two different manifestations of the same condition. ''ALS-PDC'', a term coined by
Asao Hirano
was a Japanese physician, academic, medical researcher and neuropathologist. He is credited with having first observed Hirano bodies which are intracellular aggregates of actin and actin-associated proteins in the neurons (nerve cells).
Caree ...
and colleagues in 1961, reflects its resemblance to
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS),
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
.
First reports of the disease surfaced in three
death certificate
A death certificate is either a legal document issued by a medical practitioner which states when a person died, or a document issued by a government civil registration office, that declares the date, location and cause of a person's death, as ...
s on Guam in 1904 which made some mention of
paralysis
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
. The frequency of cases grew amongst the Chamorro until it was the leading cause of adult death between 1945 and 1956.
The incidence rate was 200 per 100,000 per year and it was 100 times more prevalent than in the rest of the world.
Neurologist
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
Oliver Sacks
Oliver Wolf Sacks, (9 July 1933 – 30 August 2015) was a British neurologist, naturalist, historian of science, and writer. Born in Britain, Sacks received his medical degree in 1958 from The Queen's College, Oxford, before moving to the Uni ...
detailed this disease in his book ''
The Island of the Colorblind
''The Island of the Colorblind'' is a 1997 book by neurologist Oliver Sacks about achromatopsia on the Micronesian atoll of Pingelap. It was published in the UK as ''The Island of the Colour-blind''. The second half of the book is devoted to the m ...
''.
Sacks and
Paul Alan Cox
Paul Alan Cox is an American ethnobotanist whose scientific research focuses on discovering new medicines by studying patterns of wellness and illness among indigenous peoples. Cox was born in Salt Lake City in 1953.
Education
After receiving h ...
subsequently wrote that
bat
Bats are mammals of the order Chiroptera.''cheir'', "hand" and πτερόν''pteron'', "wing". With their forelimbs adapted as wings, they are the only mammals capable of true and sustained flight. Bats are more agile in flight than most ...
s had been feeding on Federico nuts (''
Cycas micronesica'') and concentrating
β-methylamino-L-alanine (BMAA), a known neurotoxin, in their body fat.
The hypothesis suggests that consumption of the bats by the Chamorro exposed them to BMAA, contributing to or causing their condition.
Decline in consumption of the bats has been linked to a decline in the incidence of the disease.
[
]
Symptoms and signs
Lytico-bodig disease presents itself in two ways:
* Lytico is a cortical degeneration that resembles
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS) and
frontotemporal degeneration
* Bodig is a subcortical degeneration resembling
parkinsonism
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability. These are the four motor symptoms found in Parkinson's disease (PD), after which it is named, dementia with Lewy bo ...
and
progressive supranuclear palsy
Progressive supranuclear palsy (PSP) is a late-onset degenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty ...
.
Lytico
As with bodig, the symptoms and forms of lytico present themselves differently from patient to patient.
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.
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.
Bodig
No standard form of bodig has been reported and the documented cases of the disease manifested in many different clinical presentations.
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
Aphasia is an inability to comprehend or formulate language because of damage to specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine but aphasia due to stroke is estimated to be 0.1–0.4% in t ...
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.
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.
Cause
Some hypotheses as to the cause of the disease include genetics,
cycad
Cycads are seed plants that typically have a stout and woody (ligneous) trunk (botany), trunk with a crown (botany), crown of large, hard, stiff, evergreen and (usually) pinnate leaves. The species are dioecious, that is, individual plants o ...
seeds, and ingested
beta-Methylamino-L-alanine
β-Methylamino--alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin and its potential role in various neurodegenerative disorders is the subject of scientific research.
Structure and properties ...
(BMAA) from the consumption of fruit bats.
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.
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
AGexpansions, and FUS and ALS2 mutations.
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
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 hydro ...
, was a potent toxin; it was discovered in the 1950s. As toxic as it was, it would not be the cause of the symptoms of lytico-bodig. Not only that, after nearly two decades of NIH-funded research, animal models failed to reproduce the chronic Lytico-Bodig and the hypothesis was rejected for the first time.
In 1967, following studies that linked
lathyrism
Lathyrism is a condition caused by eating certain legumes of the genus ''Lathyrus''. There are three types of lathyrism: ''neurolathyrism'', ''osteolathyrism'', and ''angiolathyrism'', all of which are incurable, differing in their symptoms and ...
to
ODAP, Marjorie Whiting, a nutritional antrophologist asked Arthur Bell, a plant biochemist, to test cycad seeds.
Arthur Bell and his colleagues discovered another toxic substance in the seeds,
BMAA
β-Methylamino--alanine, or BMAA, is a non-proteinogenic amino acid produced by cyanobacteria. BMAA is a neurotoxin and its potential role in various neurodegenerative disorders is the subject of scientific research.
Structure and properti ...
(beta-Methylamino-L-alanine).
Initial laboratory results found low levels of free BMAA in cycad flour.
The cycad hypothesis was abandoned the second time because the acute toxicity showed by Spencer and Nunn was due to BMAA concentrations in orders of magnitude higher.
Further laboratory analysis which included protein-bound BMAA found significant levels in fadang, and found also that the levels were higher in fadang made at settlements with a higher incidence of lytico-bodig.
The theory was resurrected by
Paul Alan Cox
Paul Alan Cox is an American ethnobotanist whose scientific research focuses on discovering new medicines by studying patterns of wellness and illness among indigenous peoples. Cox was born in Salt Lake City in 1953.
Education
After receiving h ...
and
Oliver Sacks
Oliver Wolf Sacks, (9 July 1933 – 30 August 2015) was a British neurologist, naturalist, historian of science, and writer. Born in Britain, Sacks received his medical degree in 1958 from The Queen's College, Oxford, before moving to the Uni ...
after re-examining aspects of the Chamorro diet.
Cox and his colleagues found that BMAA is produced by symbiotic cyanobacteria found in the coralloid roots of cycads.
Other than that, fruit bats or
flying foxes
''Pteropus'' (suborder Yinpterochiroptera) is a genus of megabats which are among the largest bats in the world. They are commonly known as fruit bats or flying foxes, among other colloquial names.
They live in South Asia, Southeast Asia, Austr ...
feed on cycad seeds, and were a common food for the Chamorros. The bats
bioaccumulate
Bioaccumulation is the gradual accumulation of substances, such as pesticides or other chemicals, in an organism. Bioaccumulation occurs when an organism absorbs a substance at a rate faster than that at which the substance is lost or eliminated ...
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.
Cox also observed decline in fruit bat consumption matching the decline in lytico-bodig.
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.
Mechanism
The mechanism is complex and poorly understood. During autopsies,
neurofibrillary tangle
Neurofibrillary tangles (NFTs) are 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 kn ...
s are found in the brain which are congruent to the brain of an
Alzheimer's
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
patient.
The following is an excerpt from ''Island of the Colorblind'', in which samples of
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
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."
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.
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.
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.
No treatment has been found to cure lytico-bodig. In some cases, the drug
L-DOPA
-DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -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.
Diagnosis
See also
*
β-Methylamino-L-alanine (BMAA)
*
Kuru (disease)
Kuru is a rare, incurable, and fatal Neurological disorder, neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea. Kuru is a form of transmissible spongiform encephalopathy (TSE) caused by the transmission ...
References
External links
{{Medical resources
, ICD10 =
, ICD9 =
, ICDO =
, OMIM = 105500
, DiseasesDB =
, MedlinePlus =
, eMedicineSubj =
, eMedicineTopic =
, MeSH =
, GeneReviewsNBK =
, GeneReviewsName =
, Orphanet = 90020
Corticobasal syndrome
Neurological disorders