Cariappa-Muren disease

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 1,620,702 (with a current death toll of 39,718) 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.

NomenclaturePermalink

Cariappa-Muren disease (CMD) is named after Sunil Cariappa and 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. ^[1] 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 piscine transmissible amyloidotic encephalopathy (PTAE) as a causative agent.

PathologyPermalink

EtiologyPermalink

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 PrP^c) 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 PrP^Sc) which is able to convert normal PrP^c proteins into the abnormal isoform by changing their conformation. ^[2]

PathogenesisPermalink

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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 PrP^Sc 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.

SymptomsPermalink

CMD has a relatively long incubation period during which there are no apparent symptoms, even though the conversion of PrP^c into PrP^Sc has started. As with most prion diseases, the incubation period varies depending on, among others, the exponential growth rate of PrP^c concentration, brain weight, and genetic quantitative trait loci. ^[3] 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 and Europe. ^[4]

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.

TransmissionPermalink

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. ^[5] 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. ^[6]

SusceptibilityPermalink

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 PRNP, the gene encoding PrP^c itself. A polymorphism at codon 129 of PRNP specifies the body to encode two different amino acids: methionine (M) and valine (V). Methionine is known to be the preferred substrate for the conversion of PrP^c into PrP^Sc, 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 PRNP codon 129 genotypes varies geographically between 33-54% for MM, 37-58% for MV, and 7-19% for VV. ^[7] G6 has automatically screened for the MM and MV genotypes since 2042. Extrapolated epidemiological models from the bovine spongiform encephalopathy (BSE) epidemics indicate that a second wave of cases in MV-susceptible individuals is likely to be observed in the coming decades.

DiagnosisPermalink

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 PrP^Sc in brain tissue, even when initially present at only one part in a hundred billion (10⁻¹¹). ^[8] Medical colloids with CMD-specific sensors are now used worldwide to screen for latent CMD infections through G6.

TreatmentPermalink

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 PrP^Sc but not by PrP^c. ^[9] 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.

Research into this cross-species transmission has been hampered by the scarcity of Lassgard tuna samples after Lassgard Bioteknik‘s entire stock was destroyed due to concerns over residual prion contaminations. CMD’s uncharacteristically high transmission rate, rapid clinical progression, and lack of spongiosis as a symptom have also been difficult to explain because of this scarcity.

At present, the most promising CMD-specific avenue of research involves eliminating the total number of PrP molecules in cells, regardless of PrP^c or PrP^Sc isoform, by using targeted effectors. Animal trials have indicated that this therapeutic strategy is successful in reversing the symptomatic stage of CMD.

See alsoPermalink

• CMD pandemic
• Piscine transmissible amyloidotic encephalopathy
• CMD phobia
• Lassgard Bioteknik

ReferencesPermalink