Classical amyotrophic lateral sclerosis, akinetic–rigid parkinsonism, and dementia are the hallmarks of Guam disease [1]. Affected individuals may suffer from all three neurodegenerative diseases, but some patients present an incomplete phenotype [2]. Indeed, amyotrophic lateral sclerosis usually precedes parkinsonism and dementia is generally not observed until years later [3].

According to early reports, symptom onset typically occurs in middle life, when patients start to suffer from progressive mental illness and movement disorders. Flexor rigidity, most prominent in trunk and neck, and tremor increasingly interfere with fine movements and constitute a major obstacle for managing everyday life [4]. Later on, it has been stated that tremor is rarely severe in Guam disease, but that patients present with an expressionless face and akinesia, generalized slowness and poor coordination [5]. Spontaneous movements diminish progressively and patients struggle more and more with gait and speech disorders and dysphagia [1]. Disorientation and memory deficits, both for recent and past events, have often been described [5], and may be accompanied by mood disorders and depression [2].

The disease follows a progressive course and eventually causes patients to fall immobile, mute and apathetic, and die.

• Pain

  But follow-up experiments in mice suggested unrealistic amounts of cycad flour would need to be consumed to cause disease, especially since Chamorros take pains to wash out most of the toxins. [alzforum.org]

  (noun) : a painful and debilitating infestation contracted by drinking stagnant water contaminated with Guinea worm larvae that can mature inside a human's abdomen until the worm emerges through a painful blister in the person's skin What are the meanings [meaningin.com]

  and tenderness over several weeks Some patients develop fever, weight loss, and loss of appetite Fulminant or necrotising colitis can develop Amoebic liver abscess Most commonly presents as fever, pain in the right upper quadrant of the abdomen, and [dermnetnz.org]

  Call your doctor if anyone in your family has signs or symptoms of amebiasis, such as: diarrhea with blood or mucus diarrhea that lasts longer than 2 weeks belly pain a fever a swollen belly pain or tenderness in the area of the liver (below the ribs [kidshealth.org]

  When symptoms occur they can result in: Amoebic dysentery: Watery or bloody diarrhoea with abdominal pain, tenderness and weight loss. [fitfortravel.nhs.uk]

• Unable to Stand

  The immobility attacked with frightening speed, and within a year, he was unable to stand alone and could not control his posture (2006). [en.wikipedia.org]

• Pallor

  Until 1989, no such distinctive lesion was associated with MSA, and the histopathologic diagnosis was based on nonspecific and variable neuronal-system atrophy, cell loss, myelin pallor, and astrocytosis. [emedicine.medscape.com]

• Hyposmia

  Table 1 Clinical features n M : F Mean onset age (years) Mean survival in years (range) Median survival (years) Pathology confirmed GRPE (of 19 tested) Hyposmia (of 13 tested) EPS Dem FH ALS alone FH ALS PDC FH PDC alone M male; F female; GRPE Guam retinal [academic.oup.com]

• Choking

  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. [en.wikipedia.org]

  […] progression more rapid Titin expression, Reduced COL19A1 expression in muscle: Increased 79 Death Cause of death: Respiratory failure most common Respiratory failure with reduced consciousness: 2 to hypercapnea Death: Usually peaceful & occurs in sleep Choking [neuromuscular.wustl.edu]

• Colorblindness

  —Oliver Sacks, The Island of the Colorblind, Vintage Books, 1996 Progressive dementia is also characteristic of bodig. [en.wikipedia.org]

• Muscular Atrophy

  In addition, we have identified patients with a progressive muscular atrophy phenotype. [academic.oup.com]

  Hyperreflexia and spinal muscular atrophy, developing mainly in the distal extremities, are frequently observed. [link.springer.com]

  MND is a general term for a whole group of diseases, encompassing, apart from the most common form of amyotrophic lateral sclerosis (ALS), rarer conditions such as primary lateral sclerosis (PLS) as well as progressive muscular atrophies (PMA). [annalsofian.org]

  atrophy (PMA) : Lower motor neuron signs only Primary lateral sclerosis (PLS): Upper motor neuron signs only ALS-FTD Possible differential diagnoses Spondylitic myelopathy or radiculopathy Motor neuron disease variant with only lower or upper motor neuron [neuromuscular.wustl.edu]

• Muscle Weakness

  Rigidity, muscle weakness, and loss of control, generalized slowness and poor coordination, gait and speech disorders, and dysphagia make it increasingly difficult to cope with everyday life. [symptoma.com]

  All patients with ALS will experience progressive muscle weakness and paralysis, but not all people will share the same symptoms or the same patterns of progression. [memory.ucsf.edu]

  ALS usually surfaces as muscle weakness, cramping, fatigue, and stiffness of the limbs. [disability-benefits-help.org]

  He had fasciculation in the tongue and respiratory muscle weakness with a low oxygen saturation level (SpO 2 86%). [bmjopen.bmj.com]

• Long Arm

  This gene is located on the long arm of chromosome 15. TRPM7 is an ion channel with serine/threonine protein kinase activity that is abundantly expressed in neurons. [symptoma.com]

• Loss of Initiative

  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. [en.wikipedia.org]

• Tremor

  Flexor rigidity, most prominent in trunk and neck, and tremor increasingly interfere with fine movements and constitute a major obstacle for managing everyday life. [symptoma.com]

  The advanced progression presents as profound motionlessness, or catatonia, accompanied with tremors or rigidity. [en.wikipedia.org]

  This type of damage results in bradykinesia (abnormal slowness of physical movement), rigidity, tremor, forgetfulness, and dementia. [secure.ssa.gov]

  Case ALS-P 2 A 76-year-old (in 2011) man of the Auyu tribe, a resident of Ogorito, had a 5-year history of tremor in both hands in 2010. [bmjopen.bmj.com]

  The tremor tends to be postural, irregular, and jerky, unlike the typical pill-rolling tremor of idiopathic parkinsonism. The dysarthria observed in patients with MSA tends to be hypokinetic. [emedicine.medscape.com]

• Dysarthria

  Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. [profiles.umassmed.edu]

  The dysarthria observed in patients with MSA tends to be hypokinetic. Those with cerebellar features present with gait and limb ataxia, ataxic dysarthria, and sustained gaze-evoked nystagmus. They also tend to develop saccadic pursuit movements. [emedicine.medscape.com]

  The following year, she gradually developed dysarthria. [bmcneurol.biomedcentral.com]

  Younger ALS disease onset Shorter ALS survival A9D mutation Mutation effect: Haploinsufficiency due to loss of GRN secretion Clinical Onset age: 48 to 67 years Amyotrophic lateral sclerosis, atypical: Some patients Extrapyramidal disorder, atypical: Dysarthria [neuromuscular.wustl.edu]

  The symptoms of lower motor neuron disease are muscular weakness, atrophy, fasciculation, cramps, slurred speech (dysarthria), difficulties in swallowing (dysphagia) and difficulties in mastication. [alzheimer-europe.org]

• Hyperreflexia

  Clinical manifestations include progressive weakness, atrophy, FASCICULATION, hyperreflexia, DYSARTHRIA, dysphagia, and eventual paralysis of respiratory function. [profiles.umassmed.edu]

  Hyperreflexia and spinal muscular atrophy, developing mainly in the distal extremities, are frequently observed. [link.springer.com]

  Neurological examination revealed cogwheel rigidity in his upper and lower limbs, bradykinesia, and UMN signs with hyperreflexia in bilateral upper and lower limbs. We diagnosed him as having parkinsonism (Hoehn and Yahr II) in 2010. [bmjopen.bmj.com]

  Extensor plantar responses and hyperreflexia are present in patients with corticospinal dysfunction. Respiratory stridor is observed in 33% of patients; however, they rarely require a tracheostomy. [emedicine.medscape.com]

  […] age: 4th to 8th decade Fronto-Temporal Dementia (FTD) Dementia Language disorders Personality changes Behavioral disorders Amyotrophic lateral sclerosis syndrome (ALS) Bulbar dysfunction: Dysphagia Limb denervation Upper motor neuron signs in limbs Hyperreflexia [neuromuscular.wustl.edu]

• Cogwheel Rigidity

  He had cogwheel rigidity in the wrist and elbow, bradykinesia throughout, a positive Myerson sign, and impairment of coordination and postural reflexes. [bmjopen.bmj.com]

  Three of these patients had tremor, cogwheel rigidity and bradykinesia, and in one of these patients the extrapyramidal signs were asymmetrical. [academic.oup.com]

• Paresis

  Neuron Disease with Ophthalmoplegia & Extrapyramidal disorders 4 Onset 4th to 7th decade Often bulbar dysfunction: Dysarthria Motor Weakness: Bulbar, Arms & Legs Upper motor neuron signs Variably present Tendon reflexes: Brisk or Normal Ocular Gaze paresis [neuromuscular.wustl.edu]

There is no single diagnostic tool that allowed for a definite diagnosis of Guam disease. In this context, the significance of anamnestic data, both personal and familial, cannot be overstated. It is important to inquire whether a patient suffering from multiple neurodegenerative disorders as described above is of Chamorro ancestry or has been living for prolonged periods of time on Guam. Furthermore, it should be evaluated whether family members have suffered from similar illnesses. The association of amyotrophic lateral sclerosis, parkinsonism, and dementia is an epidemiological key feature of Guam disease. If at all possible, the topic of calcium and magnesium intake throughout life should be addressed [1] [4].

Beyond that, the diagnosis of amyotrophic lateral sclerosis, parkinsonism, and dementia is based on the same criteria that are applied in the general population:

• The diagnosis of amyotrophic lateral sclerosis is based on clinical findings that are to be complemented with electromyographic results. The interested reader is referred to the respective guidelines [6].
• Parkinsonism is diagnosed clinically as well. It is important to consider differential diagnoses such as Parkinson's disease, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy.
• To assess a patient's cognitive status and recognize dementia, neuropsychological tests are conducted.

It may be helpful to realize additional examinations. Laboratory analyses of blood samples may point out an electrolyte imbalance, endocrine disorders or other pathological conditions that may account for some of those symptoms described above. Diagnostic brain imaging may reveal anatomical anomalies that interfere with brain function, but the latter may also be evaluated by means of an electroencephalogram. Finally, liquor samples may be analyzed to rule out infectious diseases, neoplasms, and other disorders.

There is no treatment against Guam disease. Nevertheless, patients should be offered symptomatic therapy and psychological support. Unfortunately, there is next to no literature available describing the efficacy of distinct therapies in patients suffering from Guam disease. They'd most likely benefit from a multidisciplinary approach, though: physical therapy, speech therapy, orthopedic aids, and medication to alleviate specific complaints experienced by the individual patient. In this context, symptomatic dopaminergic therapy has been recommended to treat overlapping Parkinsonian syndrome and motor neuron disease [7].

The disease is uniformly fatal. Survival times after the onset of neurological symptoms may occasionally be longer than ten years [1], but as of yet, no treatment is available that would slow down disease progression or even cure this neurodegenerative disorder. Patients eventually fall into a vegetative state, and most finally die of infectious diseases.

Guam disease has been related to mutations in the gene encoding for transient receptor potential cation channel subfamily M member 7 (TRPM7) [8] [9]. This gene is located on the long arm of chromosome 15.

TRPM7 is an ion channel with serine/threonine protein kinase activity that is abundantly expressed in neurons [10]. Channel activation requires auto-phosphorylation of the kinase, which may be mediated and potentiated by distinct ligands. Although PIP2 has been identified as a key regulator of TRPM7, little is known about possible endogenous activators and the channel's involvement in intra- and intercellular signaling cascades [11]. Upon ligand binding and auto-phosphorylation, the ion channel opens and facilitates the passage of divalent cations. Even though magnitude and direction of cation flow depend on ion concentrations on either side of the membrane, TRPM7 is most often discussed as a key player in calcium and magnesium homeostasis [10] [12].

In this context, it should be considered that neuronal function largely depends on the cells' intracellular calcium and magnesium concentrations. Thus, it may be speculated that dysfunctional regulation of intracellular cation levels due to anomalies of TRPM7 contribute to neurodegeneration in Guam disease [9]. However, epidemiological studies suggested disease susceptibility to rather depend on environmental factors: Most cases of Guam disease have been reported in the mid-20th century, but its incidence decreased dramatically after 1965. It has been proposed that alterations of levels of calcium and magnesium in drinking water account for this development [13].

Finally, long-term exposure to low levels of calcium and magnesium may alter TRPM7 function in genetically predisposed people and trigger Guam disease. Although this is the most widely accepted hypothesis regarding the etiology of Guam disease, further research is necessary to fill remaining knowledge gaps. For instance, it remains an issue of speculation if those people that provided samples to Hermosura and colleagues, but that did not test positive for TRPM7 mutations, were genetically predisposed to develop Guam disease? How does Guam disease relate to cases of amyotrophic lateral sclerosis and parkinsonism-dementia reported in Kii island, Japan?

Besides TRPM7 mutations and electrolyte deficiencies, prolonged exposure to β-N-methylamino-l-alanine, a cyanobacterial toxin present in the traditional Chamorro diet, namely in cycad seeds and flying foxes, has been proposed as possible causes of Guam disease [14]. Meanwhile, these hypotheses have been refuted, but they came up again on repeated occasions [15] [16].

As its name implies, the disease has mainly been observed among the population of Guam. Highest incidence rates have been reported for the Chamorro people, an indigenous group originating from this island. Guam is one of the Mariana Islands and has about 160,000 inhabitants - less than half of them are assumed to be of Chamorro ancestry. Several thousand Chamorro people live on other Mariana Islands and in the United States.

The incidence of Guam disease has been varying over time: While incidence rates are still highest among the Chamorro people of Guam, they barely exceed those reported in the United States. Chamorro people born after 1920 are much less likely to develop this neurodegenerative disorder than those born in the early 20th century. Initially, men were affected two or three times as often as women, but this difference has almost leveled out [17]. This development has often been explained by modernization and improvements in dietary electrolyte supply.

While most patients fall ill in their sixth decade of life, symptom onset may occur at any time in adulthood [2].

There is a general consensus that divalent cations, mainly calcium and magnesium, are key players in the pathogenesis of Guam disease. Little is known about other players, though.

As has been indicated above, TRPM7 mutations have been related to this neurodegenerative disorder [9]. Magnesium is known to modulate this ion channel's activity in such a manner that high intracellular magnesium levels reduce channel activity. Missense mutations of TRPM7, as have been detected in patients suffering from Guam disease, were found to increase the channel's sensitivity to inhibition by intracellular magnesium ions. Thus, mutated ion channels are less likely to be available even if intracellular magnesium concentrations remain quite low. As a consequence, calcium and magnesium homeostasis may be disturbed, and this condition may affect countless cellular processes, e.g., neurotransmitter release, neuronal survival and cell death.

On the other hand, cell biological research has shown TRPM7-deficient cells to become magnesium-deficient, i.e., in the absence of TRPM7 channels that can be activated by their endogenous ligands, an intracellular depletion of magnesium occurs [18]. This condition may be aggravated in the given situation of a prolonged undersupply of dietary magnesium and in fact, TRPM7-deficient cells may be rescued by supplementation of extracellular magnesium [18].

Thus, it seems feasible that those people carrying TRPM7 mutations associated with an increased sensitivity to an intracellular magnesium block are more likely to suffer the consequences of electrolyte deficiencies and to ultimately develop Guam disease.

From what little is known about etiology and pathogenesis of Guam disease, it can be inferred that an adequate dietary supply of calcium, magnesium, and possibly other cations may reduce the likelihood to develop this disorder.

Several names have been used to refer to this disorder, e.g. amyotrophic lateral sclerosis-parkinsonism-dementia complex 1, amyotrophic lateral sclerosis-parkinsonism-dementia complex of Guam or Guam disease. It mainly affects people pertaining to the Chamorro ethnic group living on Guam. Of note, Chamorro people refer to this detrimental neurodegenerative disorder as lytico-bodig disease.

Affected individuals suffer from amyotrophic lateral sclerosis, atypical parkinsonism, and/or dementia, with all of them being progressive and universally fatal diseases. The etiology of Guam disease is yet a matter of dispute: It has been associated with the ingestion of neurotoxic amino acids, prolonged calcium and magnesium deficiencies, and mutations in the TRPM7 gene. Neither of those hypothesis is universally accepted. Today, most authors consider the disease to be a multifactorial disorder mainly affecting genetically predisposed people who have been exposed to certain environmental factors for decades [19].

Amyotrophic lateral sclerosis-parkinsonism-dementia complex 1 or Guam disease is a neurodegenerative disorder almost exclusively seen in Chamorro people living on Guam.

The causes of Guam disease are only incompletely understood. On the one hand, Guam disease occurs in familial clusters, i.e., relatives of affected individuals are more likely to develop the disease than those who are not related with patients suffering from this disorder. This fact argues in favor of a genetic predisposition. Several studies have been conducted to this end, but conclusive results have not yet been presented. On the other hand, Guam disease is not observed outside the Mariana Islands and has become increasingly rare even on Guam in the last decades. It has been speculated that this trend is due to dietary adjustments and a better supply of calcium and magnesium to the island's inhabitants.

Symptom onset occurs in adulthood, most likely in the sixth decade of life, but possibly earlier. Progressive mental illness and movement disorders are the hallmarks of amyotrophic lateral sclerosis, parkinsonism, and dementia, and usually manifest in a delayed manner. Rigidity, muscle weakness, and loss of control, generalized slowness and poor coordination, gait and speech disorders, and dysphagia make it increasingly difficult to cope with everyday life. Some patients additionally suffer from mood disorders and depression. Unfortunately, Guam disease eventually renders affected individuals apathetic and immobile, and leads to death.

There is no cure for Guam disease and it is currently not possible to slow down disease progression. Further research is required to better understand the causes of this rare form of complex neurodegeneration and to eventually provide treatment options. As of today, patients suffering from Guam disease die within a few years of symptom onset.

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