Cariappa-Muren disease

Cariappa-Muren disease (CMD)
Media

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Micrograph of 35kD membrane glycoprotein that has formed amyloid fibers from its prion structure.
Micrograph of 35kD membrane glycoprotein that has formed amyloid fibres from its prion structure.
Type
Acquired
Cause
Dietary consumption of PTAE-infected fish
Infectivity rate
817 per million population
Incubation period
4 to 60 years
Diagnostic method
Medical colloid
Symptoms
Memory and behavioural changes, problems with movement that worsen chronically, and ultimately death
Treatment
Supportive care
Prognosis
80% die within 3 months of becoming symptomatic, 100% within 6 months

Cariappa-Muren disease (CMD), previously known as acquired prionopathic neurodegeneration syndrome (APNS), is a universally fatal neurodegenerative disorder resulting from the transmission of piscine transmissible amyloidotic encephalopathy (PTAE) to humans. It is estimated that over three million people were infected with CMD after a popular line of farmed Atlantic bluefin tuna inadvertently contaminated with PTAE was introduced to the food chain in 2034 and went undiscovered until 2039.

Due to the causative role played by an abnormal isoform of the prion protein, CMD is classified as a transmissible spongiform encephalopathy (TSE), though it is considered a subtype because its pathogenesis lacks any apparent spongiosis. The misfolded prion proteins exponentially convert adjacent proteins into the same abnormal conformation, resulting in the disruption of neuronal cell function.

Symptoms of CMD are behavioural and psychiatric impairments with progressive decline in cognitive and motor functions. There are some available treatments that offer relatively small symptomatic benefit as the search for a cure continues. The number of confirmed infections stands at 1,620,450 (with a current death toll of 39,705) as more cases continue to be appreciated because of CMD's long incubation period.

The World Health Organisation (WHO) has determined that the feeding practices of Lassgard Bioteknik, the company that developed the contaminated tuna, were the likely origin of the PTAE epizootic that led to the outbreak of CMD, though this remains a controversial matter of debate amongst a minority of researchers.

CMD's unchecked spread and psychological toll, which has been described separately as CMD phobia, had a profound sociopolitical impact. It is widely seen as the primary motivation for the United Nations to revisit its biosurveillance initiatives, which led to the installation of G6 and the concurrent rise of China to the status of superpower. This also caused a drastic drop in worldwide military budgets in favour of information technology spending while accelerating the overlap between the two.

Pathology

Etiology

CMD is one of a small number of diseases known as transmissible spongiform encephalopathies (TSEs), which are caused by prions. Unlike viruses, which essentially are tightly coiled packages of DNA or RNA, prions can affect hosts in different ways without using DNA to pass along different sets of instructions to living cells. The normal prion protein (designated as PrPc) plays a role in the long-term upkeep of multiple cellular functions, including cell adhesion, ion channel activity, and neuronal excitability. When this protein misfolds, it creates an infectious form (designated as PrPSc) which is able to convert normal PrPc proteins into the abnormal isoform by changing their conformation.

Pathogenesis

When misfolded PTAE prions are ingested, they are absorbed from the small intestine into the bloodstream. From there, they travel to the brain and spinal cord, where they begin to convert normal prions into abnormal ones. This creates polymers composed of PrPSc that act as seeds to propagate the conversion of more prions. When they aggregate extracellularly within the central nervous system, they form amyloid plaques that disrupt the normal tissue structure. In other TSEs, this accumulation process tends to be characterised by holes in the tissue with resultant spongy architecture (hence "spongiform"), but due to the PTAE cross-species transmission, CMD causes no spongiosis in the neurons.

Symptoms

CMD has a relatively long incubation period during which there are no apparent symptoms, even though the conversion of PrPc into PrPSc has started. As with most prion diseases, the incubation period varies depending on, among others, the exponential growth rate of PrPc concentration, brain weight, and genetic quantitative trait loci.[1] Determining the mean and range of CMD's incubation period is further complicated by species-barrier effects delaying the clinical period. The shortest documented time elapsed between exposure and onset of symptoms is a little over four years, and it is estimated that CMD can incubate for up to 60 years based on available data from the second wave of variant Creutzfeldt-Jakob disease (vCJD) cases recorded in the former United Kingdom.[2]

Once symptoms do appear, CMD progresses rapidly, leading to brain damage and death within three to six months. Initial psychiatric and behavioural symptoms may include aggression, anxiety, apathy, ataxia, depression, emotional lability, insomnia, loss of memory, poor concentration, paranoid delusion, recklessness, and withdrawal. Some patients may also show signs of sensory disturbance such as pain, paresthesia, and dysesthesia.

Neurologic symptoms occur at least two months after the onset of psychiatric symptoms and include cognitive impairment, difficulty speaking, involuntary spasms (which may be dystonic), and unsteadiness. Urinary incontinence and akinetic mutism are the late onset signs. Most people eventually lapse into a coma. Heart failure, respiratory failure, pneumonia or other intercurrent infections are generally the cause of death.

Transmission

The major transmission route of PTAE to humans, causing CMD, is widely considered to be dietary consumption of PTAE-infected fish. The World Health Organisation (WHO) eliminated this primary infection vector with the ban of Lassgard tuna, but secondary transmissions remain a pressing concern. Prions have been identified in bodily fluids such as blood, saliva, milk, urine, and feces as early as nine months after infection, and successful transmission has been demonstrated via the nose, mouth, eyes, open wounds, and cuts and abrasions.[3] Prions are also unusually resistant to conventional chemical and physical decontamination methods, and can be transmitted via reused neurosurgical equipment. Consequently, there is continued awareness of the potential that some individuals may be asymptomatic "silent carriers" who can transmit and perpetuate CMD in susceptible hosts.[4]

Susceptibility

CMD susceptibility has been observed with similar results across all genders, age groups, and geographic areas sampled. The most significant and well-defined factor which influences susceptibility to developing CMD relates to a common variation in the gene encoding PrPc itself. A polymorphism at codon 129 of this gene specifies the body to encode two different amino acids: methionine and valine. Methionine is known to be the preferred substrate for the conversion of PrPc into PrPSc, and genetic testing of CMD-positive samples has revealed the methionine homozygous (MM) genotype in nearly all confirmed cases.

A minor proportion of CMD-positive samples has displayed the methionine/valine heterozygous (MV) genotype. Based on established research into vCJD, which is similarly influenced by the codon 129 genotype variation, it is believed that MV individuals are susceptible to developing CMD over longer incubation periods, making them asymptomatic carriers who remain at risk of secondary transmission. No CMD-positive samples to date have displayed the valine homozygous (VV) genotype, though it is yet unclear whether this genotype confers a resistance against the development of CMD.

As soon as genetic data accumulated through G6 was deemed comprehensive enough for a representative sample, a survey commissioned by the International CMD Society (ICS) determined that the distribution of the codon 129 genotypes varies geographically between 33-54% for MM, 37-58% for MV, and 7-19% for VV.[5] G6 has automatically screened for the MM and MV genotypes since 2042.

Diagnosis

When the discovery of CMD and the implications of its spread prompted the need for a rapid screening test, it was quickly found that the most efficient diagnosis method for vCJD was equally effective for CMD. This diagnosis tool, which was devised by a research team at the University of Düsseldorf after a second wave of vCJD cases began in 2014, involves fitting colloid electrodes with chemical sensors that can detect PrPSc in brain tissue, even when initially present at only one part in a hundred billion (10−11). Medical colloids with CMD-specific sensors are now used worldwide to screen for latent CMD infections.

Treatment

The ICS and the WHO are working at all levels to find a treatment for CMD, which has to date resulted only in several therapeutic strategies that extend life and provide relief in patients. Supportive care generally includes administering vCJD-effective drugs such as daunocycline to prolong the preclinical period, and neurostimulation via colloids to mitigate psychiatric and behavioural symptoms in the clinical period. These strategies have been known to increase life expectancy by as much as 20%.

Extensive tests with the currently applied treatment for vCJD have had no success against CMD. This treatment involves antibodies specifically coded to a side chain of amino acids exposed by PrPSc but not by PrPc.[6] Such antibodies can stimulate an immune response to the abnormal prions and leave normal proteins intact, but CMD prions have been found to expose no amino acid side chain that can be targeted, likely due to the cross-species transmission between fish and humans.

At present, the most promising CMD-specific avenue of research involves eliminating the total number of PrP molecules in cells, regardless of PrPc or PrPSc isoform, by using targeted effectors. Animal trials have indicated that this therapeutic strategy is successful in reversing the symptomatic stage of CMD, though there is some concern regarding its long-term effects. Early knockout studies have shown that eliminating PrPc alongside its infectious isoform can disrupt multiple cellular functions after an extended period of latency.

History

Nomenclature

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Epidemiologist Sunil Cariappa, pictured in 2048.

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Neuropathologist Connie Muren, pictured in 2039.

CMD is named after epidemiologist Sunil Cariappa and neuropathologist Connie Muren, who described the disease in July 2039 after their individual avenues of research into prion-based encephalopathies led them to its shared discovery.[7] CMD was originally given the medical name acquired prionopathic neurodegeneration syndrome (APNS), but the eponymous name was ultimately chosen to avoid confusion with the simultaneous description of PTAE as a causative agent.

Discovery

The very first victims of the PTAE-infected tuna were domestic cats who became symptomatic much quicker due to their lower body mass and brain weight. After his own cat became infected in November 2038, Sunil Cariappa found a notable uptick in records of similar cases through the Global Public Health Intelligence Network (GPHIN). He requested necropsies on several of the deceased cats, including his own, and found that many exhibited signs of what appeared to be feline spongiform encephalopathy (FSE), though the lack of any apparent spongiosis in the brain tissue prevented him from confirming this diagnosis. When he found the common link between all FSE-affected cats to be their diet, which included Lassgard tuna, he surmised that this line of tuna was infected with a novel prion agent.

Worried that the prion infection was spreading to humans as well, Cariappa contacted Connie Muren, whose team at the University of Düsseldorf had published a paper on YouTuber Yuki Hasegawa, an atypical vCJD patient in Itabashi, Tokyo. Since Hasegawa's young age fell well outside established incubation models and no vCJD-specific treatments had any effect, Muren had proposed that a new sporadic prion mutation was the causative agent.[8]

Cariappa, having been alerted to Muren's paper because it also mentioned a lack of spongiosis, suggested to her that Hasegawa had instead contracted the same prion agent responsible for the epizootic in cats. The connection became more tenable when analysis of Hasegawa's dietary habits revealed a high consumption of Lassgard tuna, which also explained the relatively rapid onset of symptoms in his case. Hasegawa, who died on November 29th 2038, has posthumously become known as the first human victim of CMD.

Further analysis

In December 2038, Cariappa joined Muren's team in Düsseldorf to confirm their find. They analysed brain samples of preprocessed Lassgard tuna sold in East Asia, Europe, Africa, and the United States (US), finding that a significant proportion of the samples displayed characteristics of amyloidosis, such as numerous plaque deposits that resembled PrPSc aggregates. They described this amyloidosis as piscine transmissible amyloidotic encephalopathy (PTAE), though there was some uncertainty regarding its origin. At the time, the most likely candidate was considered to be an inherited prion mutation attributed to Lassgard Bioteknik's practice of genetically modifying its fish stock.

Given that Lassgard tuna accounted for roughly 80% of worldwide tuna consumption by late 2038, the team reported its discovery to the Global Foodborne Infections Network (GFN) in January 2039, but with only a single suspected case in humans at that point, no immediate health hazard to the population was considered. The only concession was a notice issued in the WHO's monthly Bulletin to advise against feeding tuna to pets. Muren believed that the WHO was underestimating the long-term implications of PTAE's discovery and publicly critiqued the organisation's inaction, which prompted GFN officials to convene an Outbreak Control Team (OCT) on February 4th. Muren decided to focus the OCT's efforts on determining PTAE's transmission potential to humans while Cariappa developed several epidemiological models.

Passage of infected brain material collected from Lassgard tuna to transgenic mice revealed that they could develop a clinical disease strikingly consistent with the pathology described in Hasegawa's case. By the time this test was completed in July 2039, five more suspected human cases had been detected in Japan, all showing similar symptoms and dietary habits. When the OCT reported its additional findings to the WHO, the decision was made to formally declare a Public Health Emergency of International Concern (PHEIC) and allocate more resources to the OCT.

WHO investigation

Although public awareness of prion diseases and their years-long incubation periods had increased with the second wave of vCJD cases, the WHO faced difficulty in convincing authorities that the discovery of CMD (then named APNS) represented a public health threat. This has been attributed largely to the perceived lack of immediacy when compared to other foodborne disease outbreaks, in that significant fatality rates would only gradually become apparent in the decades to come. In addition, the WHO was met with pressure from Lassgard Bioteknik, which refused to reveal any details about its closely guarded production process, and the Aquaculture Advisory Council (AAC), which lobbied heavily against any efforts to halt the sale of Lassgard tuna pending the investigation.

These hurdles continued until October 2039, when a leak of internal Lassgard Bioteknik correspondence reflected that the company had been aware as early as March 2037 that its tuna stock was exhibiting erratic behaviour due to the PTAE epizootic. The leaked documents also revealed that the AAC's efforts to discredit the OCT were backed by several undisclosed financial transfers from Lassgard Bioteknik officials, who had been closely monitoring Muren's activities ever since she first reported her team's findings to the WHO.

The leak and the resulting scandal gave the OCT the international scope and recognition required for the WHO to successfully ban the sale of Lassgard tuna. Subsequent to this, CMD (then renamed from APNS) began to receive much greater prominence in international media. The WHO elected to classify the outbreak as a pandemic despite its low contagion level, arguing that CMD had managed to spread to multiple continents in the five years it went undiscovered. In coordination with the Global Outbreak Alert and Response Network (GOARN), the WHO issued a global alert on October 25th 2039.

Global epidemiology

Based on product tracking data of Lassgard tuna and CMD-specific susceptibility rates, the WHO estimated that approximately three million people were infected with CMD during the five years Lassgard tuna was sold for human consumption. A more defined estimate was complicated by lingering issues with enforcing the ban of Lassgard tuna. Not all vendors with surplus stock immediately complied with the ban, leading to contaminated tuna still being sold illegally until full compensation was offered in late 2040. There were also reports of Lassgard tuna being available on the black market until well into 2041.

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Total confirmed number of CMD cases between 2038 and 2049.

After the global alert was issued, the WHO coordinated with local, regional, and national health agencies to distribute information packets and diagnostic colloids with CMD-specific sensors to physicians and hospitals. In order to gather more precise epidemiology data, all positive diagnoses were then logged by a blockchain on loan from GOARN. By January 2040, this had resulted in an official tally of close to one million confirmed infections, though it is assumed that unobserved infections due to death from other causes and the rapid proliferation of unofficial take-at-home CMD tests and vaccines meant that many cases weren't counted.

Continued G6 monitoring over the years has pushed the number of confirmed CMD infections up to a current total of 1,620,450. The yearly incidence rate has steadily tapered off since 2047, but extrapolated epidemiological models from the bovine spongiform encephalopathy (BSE) epidemic of the late 20th century indicate that a second wave of cases in MV-susceptible individuals is likely to be observed in the coming decades.

Legacy

Sociopolitical impact

Main article: CMD phobia

On April 19th 2040, then-WHO Director-General Yang Jinglei officially declared the CMD pandemic contained. This announcement was made at the urging of Sunil Cariappa, who at that point was concerned with the psychological impact of the information glut surrounding CMD's unchecked spread and latency effects. This form of cyberchondria and its potential societal effects had first been described as CMD phobia in February 2040.[9] Further research into its international spread and prevalence has established a causal link between CMD phobia as a mass hysteria and the establishment of G6. Though in differing proportions to one another, CMD and CMD phobia are both seen as directly responsible for the subsequent rise of China to the status of superpower and the demographic shifts that G6 has precipitated.

Economic effects

Due to CMD's origin as a foodborne disease transmitted through Lassgard tuna, consumer confidence in fish products dropped to an all-time low, resulting in the collapse of the aquaculture industry and an economic loss equivalent to about 0.7% of the global GDP. Many businesses in the entertainment and service industries also suffered losses in revenue, while the healthcare industry reported profit gains.

Research into prion diseases

CMD has dramatically intensified the study of prions and their infectious properties. The most significant discovery resulting from this accelerated body of research is a scientific consensus on the protein-only hypothesis, meaning that the conversion of PrPc into PrPSc is now linked solely to conformational isoform changes without any other actors underlying this process (such as a slow virus or spiroplasma, as was previously considered).[10]

A 2048 survey showed that over 70% of ICS funding for research into prion diseases has gone to studies that specify the finding of a cure to CMD as an explicit aim.[11] In that respect, scientists and academics have criticised the ICS for creating unrealistic expectations and needlessly narrowing the research required to arrive at a viable cure for CMD and other prion diseases.

See also

References

  1. Ngai, L; Mishra, S; Verheiden, K et al. (August 2045). "Identification of Multiple Quantitative Trait Loci Linked to Cariappa-Muren Disease Incubation Period." International Journal of CMD Studies↩︎

  2. Muren, C. (February 2023). "Overall incidence of variant Creutzfeldt-Jakob disease (vCJD) expected to double after second wave of cases." News Medical↩︎

  3. Da Costa Dias, B; Weiss, S. (June 2010). "A Kiss of a Prion: New Implications for Oral Transmissibility." The Journal of Infectious Diseases↩︎

  4. Mathiason, C. (December 2015). "Silent Prions and Covert Prion Transmission." PLOS Biology↩︎

  5. Cariappa, S; Ngai, L; Mishra, S et al. (October 2044). "Distribution of Genotypes at Codon 129 in World Population." International Journal of CMD Studies↩︎

  6. Paramithiotis, E; Pinard, M; Lawton, T et al. (July 2003). "A prion protein epitope selective for the pathologically misfolded conformation." Nature Medicine↩︎

  7. Cariappa, S; Muren, C. (July 2039). "Acquired Prionopathic Neurodegeneration Syndrome (APNS): Pathology, Transmission, and Epidemiology." Bulletin of the World Health Organisation↩︎

  8. Muren, C; Kobl-Thissen, G; Matthes, B et al. (November 2038). "A Novel Type 5 Sporadic Prion Mutation in Humans." The Lancet↩︎

  9. Feng-Xiang, L. (February 2040). "CMD phobia: Escalating illness anxiety disorder related to Cariappa-Muren disease." Chinese Journal of Psychiatry↩︎

  10. Laurent, M. (August 1996). "Prion diseases and the 'protein only' hypothesis: a theoretical dynamic study." Biochemical Journal↩︎

  11. Amankwah-Crouse, E. (December 2048). "ICS grants for applied research into CMD too often use cure as unrealistic goal." World Tomorrow↩︎