Dietary consumption of piscine transmissible amyloidotic encephalopathy (PTAE), secondary transmission
- Infectivity rate
817 per million population
- Incubation period
4 to 60 years
- Diagnostic method
Memory and behavioural changes, problems with movement that worsen chronically, and ultimately death
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.
Table of contents
Cariappa-Muren disease (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. 
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.
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.  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 United Kingdom. 
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.
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.  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. 
When the discovery of CMD and the implications of its spread prompted the need for a rapid screening test, it was 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 2009, 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 through G6.
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.  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.
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