Piscine transmissible amyloidotic encephalopathy (PTAE), more commonly known as mad fish disease, is a neurodegenerative disorder that affects the central nervous system of fish. It has to date been described only in farmed Atlantic bluefin tuna developed by Lassgard Bioteknik, though a 2009 study has previously established PTAE infections in gilt-head sea bream.
The transmission of PTAE to humans, primarily via ingestion of infected fish, can result in Cariappa-Muren disease (CMD). Although PTAE entered the food chain in 2034 when Lassgard tuna were put to market, it wasn’t discovered until after the first cases of CMD were reported in 2039. Since PTAE-affected tuna are considered to be the primary infection vector for the CMD pandemic, it precipitated a dramatic overhaul of food safety regulations and the collapse of the aquaculture industry.
Table of contents
Piscine transmissible amyloidotic encephalopathy (PTAE) is classified as a transmissible spongiform encephalopathy (TSE) because its causative agent is considered to be a misfolded protein known as a prion. In the brain, these prions cause native cellular prion protein (designated as PrPc) to misfold into the same infectious state (designated as PrPSc), which goes on to convert further PrPc in an exponential cascade. This results in dense protein aggregates in the form of plaque fibres that disrupt the normal tissue structure. After a long incubation period during which no symptoms are apparent, PTAE leads to degeneration of physical and mental abilities, and ultimately death. 
Though there is as yet no consensus on the exact etiology of PTAE, a majority of researchers believes that it is most likely a variant of bovine spongiform encephalopathy (BSE) with an altered pathogenesis due to the cross-species transmission in fish. This finding is largely based on a 2009 research study, which had demonstrated that orally exposing gilt-head sea bream to homogenates with BSE could result in the fish developing a neurodegenerative amyloidosis.  The study has since been replicated and found to be broadly consistent with PTAE histopathology.
Opponents of this finding cite the 2009 study mentioning a lack of BSE-specific spongiosis as evidence for the hypothesis that PTAE resembles a novel fish amyloidosis more than a classical TSE transmitted to fish, an alternate explanation that the study’s authors also allowed for. In May 2044, researcher Lars Berenger and their colleagues published an article proposing that PTAE may not be a prion disease, but a parasitic encephalitis caused by Miamiensis avidus.  This article has been widely criticised for disregarding the established link between PTAE and Cariappa-Muren disease (CMD) in order to reach its conclusion.
Other disputed theories for the etiology of PTAE include, among others, mercury poisoning, advanced scombroid, and a variant of primary amoebic meningoencephalitis (PAM).
Signs and symptoms
Fish infected with PTAE will not show any immediate symptoms due to the disease’s long incubation period. The clinical period is further delayed due to the significant potential for neurogenesis in fish.  It is thought that the conversion of PrPc into PrPSc is countered, though not outpaced, by the fish brain’s capacity for regenerating a variety of tissues and complete neuronal diversity.
Once the clinical period does begin, erratic swimming and behavioural abnormalities will become apparent and grow progressively worse. Death usually follows the onset of hypokinesia, which prevents fish from maintaining the swimming behaviour required to keep pumping water through their gills. Caged fish, as with aquaculture farming sites, have also been known to kill themselves by swimming into walls and nets as a result of ataxia.  Given the challenging nature of accurately determining anomalous behaviour in individual fish, neuropathological and immunohistochemical examinations of post-mortem brain tissue remain the most reliable diagnosis method.
PTAE was first described in January 2039 by Sunil Cariappa and Connie Muren. It had been discovered by Cariappa in November 2038 when he linked an increased mortality rate in domestic cats to feeding diets that included Lassgard tuna. When this line of farmed tuna was found to be contaminated with a novel prion agent, the focus quickly shifted to its transmission potential to humans and the subsequent discovery of CMD.  As a result, research into the origin and pathology of PTAE did not begin in earnest until the World Health Organisation (WHO) was able to conclusively establish a transmission link between PTAE and CMD after internal documentation on Lassgard Bioteknik’s closely guarded production process was leaked to the public in October 2039.
On April 19th 2040, the WHO published its official findings on PTAE. Based on the collaborative work of sixteen laboratories from eleven countries and an official investigation with full access to Lassgard Bioteknik facilities, the WHO announced that the most likely origin of PTAE was the company’s practice of using in-house developed processed animal protein (PAP) pellets as a feed stock for its farmed tuna.  These pellets, which are less expensive than fish meal and allowed Lassgard Bioteknik’s to fatten up its tuna stock, were rendered from processed waste material of bovine origin, indicating that PTAE is technically a variant of BSE with additional passages in interspecies infection. When prions are passed between species, they take on the characteristics of the recipient species, which had led to the initial description of PTAE instead of a modified strain of BSE.
Immunoassays of the proprietary PAP materials did detect the presence of prion determinants, though molecular data has shown that these determinants do not wholly correspond with bovine recombinant prions. Based on this anomaly, a minority of researchers maintains that PTAE bears more properties of a novel fish amyloidosis than a classical TSE. They cite the absence of prion traces in the abattoirs and factory farms that sold remnant bovine material to Lassgard Bioteknik as further evidence for this hypothesis.
Various spatial epidemiology studies have determined that PTAE’s infectivity rate was closely linked to Lassgard Bioteknik’s handling of its tuna as a product:
- Lassgard Bioteknik maintained relatively high product prices through price fixing, which led to restaurants and retail outlets processing entire Lassgard tuna, including the heads, in order to cut costs. As a result, processed Lassgard tuna were regularly contaminated with central nervous system tissues, which are more likely to contain a high titre of PTAE prions and therefore represent a greater transmission risk to humans. 
- The same risk also applied to the line of canned tuna which Lassgard Bioteknik began marketing and selling in early 2038. These cans generally contained processed fish meat rendered from the less prized parts of Lassgard tuna, such as the heads. Additionally, prions are not destroyed even if the fish or material containing them is canned, cooked, or refrigerated.
- Studies into PTAE’s transmission potential to other tuna and fish species have at present not been able to explain its uncharacteristically high transmission rate to CMD. This is thought to be a unique characteristic of Lassgard tuna as a host for the misfolded proteins, most likely due to Lassgard Bioteknik’s practice of genetically modifying its fish stock. This link has been challenging to explore due to the scarcity of Lassgard tuna samples available for testing, with Lassgard Bioteknik’s entire stock destroyed due to concerns over residual prion contaminations. 
After the WHO ban on the sale of Lassgard tuna and the liquidation of Lassgard Bioteknik in 2039, and the ordered destruction of the company’s entire fish and feed stock in 2040, the PTAE epizootic was declared contained on April 19th 2040.  There have been no further incidences of PTAE recorded since, and it is generally believed that the epizootic recorded at Lassgard Bioteknik was an isolated event. Food safety regulations prohibiting the use of PAP in feed stocks have remained in place and are strictly enforced by the WHO.
- Redway, L; Camargo, C. (August 2039). “Molecular biology of prion diseases.” New Scientist. ↩
- Salta, E; Panagiotidis, C; Konstantinos, E et al. (July 2009). “Evaluation of the Possible Transmission of BSE and Scrapie to Gilthead Sea Bream (Sparus aurata).” PLOS Biology. ↩
- Berenger, L; Cheung, B; Sze, H et al. (May 2044). “Parasitic Infection from the Scuticociliate Miamiensis Avidus Proposed as a Causative Agent for Piscine Transmissible Amyloidotic Encephalopathy.” Molecular and Cellular Biochemistry. ↩
- Zupanc, G. (June 2006). “Neurogenesis and neuronal regeneration in the adult fish brain.” Journal of Comparative Physiology. ↩
- Daems, A. (October 2039). “Lassgard Bioteknik used AI-powered wildlife cameras to diagnose individual tuna.” World News Wire. ↩
- Cariappa, S; Muren, C. (July 2039). “Acquired Prionopathic Neurodegeneration Syndrome: Pathology, Transmission, and Epidemiology.” Bulletin of the World Health Organisation. ↩
- Van Dinther, W. (April 2040). “WHO announces CMD pandemic as contained, confirms origin of disease as foodborne.” ↩ ↩
- Desai, H. (April 2040). “Zero waste policies in restaurants may have contributed to rapid spread of Cariappa-Muren disease.” World News Wire. ↩
- Clough, P. (February 2041). “Scientists say research into CMD hampered by 2040 destruction of all Lassgard tuna.” The Guardian. ↩