| Except where noted otherwise, data are given for|
materials in their standard state
(at 25 °C, 100 kPa)
Infobox disclaimer and references
Tetrodotoxin (anhydrotetrodotoxin 4-epitetrodotoxin, tetrodonic acid, TTX) is a potent neurotoxin with no known antidote, which blocks action potentials in nerves by binding to the pores of the voltage-gated, fast sodium channels in nerve cell membranes. The binding site of this toxin is located at the pore opening of the voltage-gated Na+ channel. Its name derives from Tetraodontiformes, the name of the order that includes the pufferfish, porcupinefish, ocean sunfish or mola, and triggerfish, several species of which carry the toxin. Although tetrodotoxin was discovered in these fish and found in several other animals, it is actually the product of certain bacteria such as Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, as well as some others.
Its mechanism was discovered in the early 1960s by Toshio Narahashi working at Duke University
Tetrodotoxin sources in nature
Tetrodotoxin has also been isolated from widely differing animal species, including western newts of the genus Taricha (where it was termed "tarichatoxin"), parrotfish, toads of the genus Atelopus, several species of blue-ringed octopodes of the genus Hapalochlaena (where it was called "maculotoxin"), several starfish, an angelfish, a polyclad flatworm, several species of Chaetognatha (arrow worms), several nemerteans (ribbonworms) and several species of xanthid crabs. The toxin is variously used as a defensive biotoxin to ward off predation, or as both a defensive and predatory venom (the octopodes, chaetognaths and ribbonworms). Tarichatoxin and maculotoxin were shown to be identical to tetrodotoxin in 1964 and 1978, respectively. Recent evidence has shown the toxin to be produced by bacteria within blue-ringed octopodes , and it is believed that pufferfish acquire the toxin through their diet. Evidence for the source of the toxin in other sources has not yet been determined Template:Fix/category. The most common source of bacteria associated with TTX production are 'Vibrio' bacteria, with Vibrio alginolyticus being the most common species. TTX has been found in nemerteans, Phylum nemertea, (sometimes called Ribbon worms), and both pufferfish and nemerteans have been shown to contain Vibrio alginolyticus and TTX.
Tetrodotoxin binds to what is known as site 1 of the fast voltage-gated sodium channel. Site 1 is located at the extracellular pore opening of the ion channel. The binding of any molecules to this site will temporarily disable the function of the ion channel. Saxitoxin and several of the conotoxins also bind the same site.
The use of this toxin as a biochemical probe has elucidated two distinct types of voltage-gated sodium channels present in humans: the tetrodotoxin-sensitive voltage-gated sodium channel (TTX-s Na+ channel) and the tetrodotoxin-resistant voltage-gated sodium channel (TTX-r Na+ channel). Tetrodotoxin binds to TTX-s Na+ channels with a binding affinity of 5-15 nanomolar, while the TTX-r Na+ channels bind TTX with low micromolar affinity. Nerve cells containing TTX-r Na+ channels are located primarily in cardiac tissue, while nerve cells containing TTX-s Na+ channels dominate the rest of the body. The prevalence of TTX-s Na+ channels in the central nervous system makes tetrodotoxin a valuable agent for the silencing of neural activity within a cell culture.
The toxin blocks the fast Na+ current in human myocytes (the contractile cells of the muscles), thereby inhibiting their contraction. By contrast, the sodium channels in pacemaker cells of the heart are of the slow variety, so action potentials in the cardiac nodes are not inhibited by the compound. The poisoned individual therefore dies not because the electrical activity of the heart is compromised, but because the diaphragm is effectively paralyzed and breathing ceases.
Blocking of fast Na+ channels has medicinal use in treating some cardiac arrhythmias. Tetrodotoxin has also proved useful in the treatment of pain (originally used in Japan in the 1930's) from such diverse problems as terminal cancer, migraines, & heroin withdrawal.
Y. Kishi et al Nagoya University, Nagoya, Japan, (now at Harvard University) reported the first total synthesis of D,L-tetrodotoxin in 1972. M. Isobe et al at Nagoya University, Japan and J. Du Bois et al at Stanford University, USA, reported the asymmetric total synthesis of tetrodotoxin in 2003. The two 2003 syntheses used very different strategies, with Isobe's route based on a Diels-Alder approach and Du Bois's work using C-H bond activation.
Fish poisoning by consumption of members of the order Tetraodontiformes is extremely serious. The skin and organs of the pufferfish can contain levels of tetrodotoxin sufficient to produce paralysis of the diaphragm and death due to respiratory failure. Toxicity varies between species and at different seasons and geographic localities, and the flesh of many pufferfish may not usually be dangerously toxic.
The first recorded cases of tetrodotoxin poisoning were from the logs of Captain James Cook. He recorded his crew eating some local tropic fish (pufferfish), then feeding the remains to the pigs kept on board. The crew experienced numbness and shortness of breath, while the pigs were all found dead the next morning. In hindsight, it is clear that the crew received a mild dose of tetrodotoxin, while the pigs ate the pufferfish body parts that contain most of the toxin, thus killing them.
Symptoms and diagnosis
The diagnosis of pufferfish poisoning is based on the observed symptomology and recent dietary history.
Symptoms typically develop within 30 min of ingestion but may be delayed by up to 4 h. Death has occurred within 17 min of ingestion. Paresthesias of the lips and tongue are followed by sialorrhea, sweating, headache, weakness, lethargy, ataxia, incoordination, tremor, paralysis, cyanosis, aphonia, dysphagia, seizures, dyspnea, bronchorrhea, bronchospasm, respiratory failure, coma, and hypotension. Gastroenteric symptoms are often severe and include nausea, vomiting, diarrhea, and abdominal pain. Cardiac arrhythmias may precede complete respiratory failure and cardiovascular collapse.
|Diseases||History and Physical||Diagnostic tests||Other Findings|
|Motor Deficit||Sensory deficit||Cranial nerve Involvement||Autonomic dysfunction||Proximal/Distal/Generalized||Ascending/Descending/Systemic||Unilateral (UL)
or Bilateral (BL)
No Lateralization (NL)
|Onset||Lab or Imaging Findings||Specific test|
|Adult Botulism||+||-||+||+||Generalized||Descending||BL||Sudden||Toxin test||Blood, Wound, or Stool culture||Diplopia, Hyporeflexia, Hypotonia, possible respiratory paralysis|
|Infant Botulism||+||-||+||+||Generalized||Descending||BL||Sudden||Toxin test||Blood, Wound, or Stool culture||Flaccid paralysis (Floppy baby syndrome), possible respiratory paralysis|
|Guillian-Barre syndrome||+||-||-||-||Generalized||Ascending||BL||Insidious||CSF: ↑Protein
|Clinical & Lumbar Puncture||Progressive ascending paralysis following infection, possible respiratory paralysis|
|Eaton Lambert syndrome||+||-||+||+||Generalized||Systemic||BL||Intermittent||EMG, repetitive nerve stimulation test (RNS)||Voltage gated calcium channel (VGCC) antibody||Diplopia, ptosis, improves with movement (as the day progresses)|
|Myasthenia gravis||+||-||+||+||Generalized||Systemic||BL||Intermittent||EMG, Edrophonium test||Ach receptor antibody||Diplopia, ptosis, worsening with movement (as the day progresses)|
|Electrolyte disturbance||+||+||-||-||Generalized||Systemic||BL||Insidious||Electrolyte panel||↓Ca++, ↓Mg++, ↓K+||Possible arrhythmia|
|Organophosphate toxicity||+||+||-||+||Generalized||Ascending||BL||Sudden||Clinical diagnosis: physical exam & history||Clinical suspicion confirmed with RBC AchE activity||History of exposure to insecticide or living in farming environment. with : Diarrhea, Urination, Miosis, Bradycardia, Lacrimation, Emesis, Salivation, Sweating|
|Tick paralysis (Dermacentor tick)||+||-||-||-||Generalized||Ascending||BL||Insidious||Clinical diagnosis: physical exam & history||-||History of outdoor activity in Northeastern United States. The tick is often still latched to the patient at presentation (often in head and neck area)|
|Tetrodotoxin poisoning||+||-||+||+||Generalized||Systemic||BL||Sudden||Clinical diagnosis: physical exam & dietary history||-||History of consumption of puffer fish species.|
|Stroke||+/-||+/-||+/-||+/-||Generalized||Systemic||UL||Sudden||MRI +ve for ischemia or hemorrhage||MRI||Sudden unilateral motor and sensory deficit in a patient with a history of atherosclerotic risk factors (diabetes, hypertension, smoking) or atrial fibrillation.|
|Poliomyelitis||+||+||+||+/-||Proximal > Distal||Systemic||BL or UL||Sudden||PCR of CSF||Asymmetric paralysis following a flu-like syndrome.|
|Transverse myelitis||+||+||+||+||Proximal > Distal||Systemic||BL or UL||Sudden||MRI & Lumbar puncture||MRI||History of chronic viral or autoimmune disease (e.g. HIV)|
|Neurosyphilis||+||+||-||+/-||Generalized||Systemic||BL||Insidious||MRI & Lumbar puncture||CSF VDRL-specifc||History of unprotected sex or multiple sexual partners.|
|Muscular dystrophy||+||-||-||-||Proximal > Distal||Systemic||BL||Insidious||Genetic testing||Muscle biopsy||Progressive proximal lower limb weakness with calf pseudohypertrophy in early childhood. Gower sign positive.|
|Multiple sclerosis exacerbation||+||+||+||+||Generalized||Systemic||NL||Sudden||↑CSF IgG levels
|Clinical assessment and MRI ||Blurry vision, urinary incontinence, fatigue|
|Amyotrophic lateral sclerosis||+||-||-||-||Generalized||Systemic||BL||Insidious||Normal LP (to rule out DDx)||MRI & LP||Patient initially presents with upper motor neuron deficit (spasticity) followed by lower motor neuron deficit (flaccidity).|
|Inflammatory myopathy||+||-||-||-||Proximal > Distal||Systemic||UL or BL||Insidious||Elevated CK & Aldolase||Muscle biopsy||Progressive proximal muscle weakness in 3rd to 5th decade of life. With or without skin manifestations.|
Therapy is supportive and based on symptoms, with aggressive early airway management. Alpha adrenergic agonists are recommended in addition to intravenous fluids to combat hypotension. Anticholinesterase agents have been used with mixed success. Nothing equivalent to an antivenom has been developed--presumably because the toxin acts quickly and binds with an affinity that is not easily overcome.
Course of tetrodotoxin poisoning and complications
The first symptom of intoxication is a slight numbness of the lips and tongue, appearing between 20 minutes to three hours after eating poisonous pufferfish. The next symptom is increasing paresthesia in the face and extremities, which may be followed by sensations of lightness or floating. Headache, epigastric pain, nausea, diarrhea, and/or vomiting may occur. Occasionally, some reeling or difficulty in walking may occur. The second stage of the intoxication is increasing paralysis. Many victims are unable to move; even sitting may be difficult. There is increasing respiratory distress. Speech is affected, and the victim usually exhibits dyspnea, cyanosis, and hypotension. Paralysis increases and convulsions, mental impairment, and cardiac arrhythmia may occur. The victim, although completely paralyzed, may be conscious and in some cases completely lucid until shortly before death. Death usually occurs within 4 to 6 hours, with a known range of about 20 minutes to 8 hours.
Geographic frequency of tetrodotoxin toxicity
Poisonings from tetrodotoxin have been almost exclusively associated with the consumption of pufferfish from waters of the Indo-Pacific ocean regions. Several reported cases of poisonings, including fatalities, involved pufferfish from the Atlantic Ocean, Gulf of Mexico, and Gulf of California. There have been no confirmed cases of tetrodotoxicity from the Atlantic pufferfish, Sphoeroides maculatus. However, in three studies, extracts from fish of this species were highly toxic in mice. Several recent intoxications from these fishes in Florida were due to saxitoxin, which causes paralytic shellfish poisoning with very similar symptoms and signs. The trumpet shell Charonia sauliae has been implicated in food poisonings, and evidence suggests that it contains a tetrodotoxin derivative. There have been several reported poisonings from mislabelled pufferfish and at least one report of a fatal episode in Oregon when an individual swallowed a Rough-skinned Newt, Taricha granulosa.
Relative frequency of tetrodotoxin ingestive poisonings
From 1974 through 1983 there were 646 reported cases of pufferfish poisoning in Japan, with 179 fatalities. Estimates as high as 200 cases per year with mortality approaching 50% have been reported. Only a few cases have been reported in the United States, and outbreaks in countries outside the Indo-Pacific area are rare, except in Haiti, where Tetrodotoxin plays a key role in the creation of so called zombie poisons.
Genetic background is not a factor in susceptibility to tetrodotoxin poisoning. This toxicosis may be avoided by not consuming animal species known to contain tetrodotoxin, principally pufferfish; other tetrodotoxic species are not usually consumed by humans. Poisoning from tetrodotoxin is of particular public health concern in Japan, where pufferfish, "fugu", is a traditional delicacy. It is prepared and sold in special restaurants where trained and licensed chefs carefully remove the viscera to reduce the danger of poisoning. There is potential for misidentification and mislabelling, particularly of prepared, frozen fish products.
The mouse bioassay developed for paralytic shellfish poisoning (PSP) can be used to monitor tetrodotoxin in pufferfish and is the current method of choice. An HPLC method with post-column reaction with alkali and fluorescence has been developed to determine tetrodotoxin and its associated toxins. The alkali degradation products can be confirmed as their trimethylsilyl derivatives by gas chromatography/mass spectrometry. These chromatographic methods have not yet been validated.
- Clairvius Narcisse, a Haitian alleged to have been buried alive under the effect of the drug
- (a) Hwang, D. F., Arakawa, O., Saito, T., Noguchi, T., Simidu, U., Tsukamoto, K., Shida, Y., Hashimoto, K. Marine Biology 1989, 100, 327-332 (DOI 10.1007/BF00391147). (abstract)
- (a) Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9217-9219. (b) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J. Am. Chem. Soc. 1972, 94, 9219-9221.
- (a) Ohyabu, N.; Nishikawa, T.; Isobe, M. J. Am. Chem. Soc. 2003, 125, 8798-8805 (b) Angew. Chem. Int. Ed. 2004, 43, 4782 (DOI 10.1002/anie.200460293). See a free online review
- Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510 -11511. (DOI 10.1021/ja0368305)
- Talukder RK, Sutradhar SR, Rahman KM, Uddin MJ, Akhter H (2011). "Guillian-Barre syndrome.". Mymensingh Med J. 20 (4): 748–56. PMID 22081202.
- Merino-Ramírez MÁ, Bolton CF (2016). "Review of the Diagnostic Challenges of Lambert-Eaton Syndrome Revealed Through Three Case Reports.". Can J Neurol Sci. 43 (5): 635–47. PMID 27412406. doi:10.1017/cjn.2016.268.
- Gilhus NE (2016). "Myasthenia Gravis.". N Engl J Med. 375 (26): 2570–2581. PMID 28029925. doi:10.1056/NEJMra1602678.
- Ozono K (2016). "[Diagnostic criteria for vitamin D-deficient rickets and hypocalcemia-].". Clin Calcium. 26 (2): 215–22. PMID 26813501. doi:CliCa1602215222 Check
- Kamanyire R, Karalliedde L (2004). "Organophosphate toxicity and occupational exposure.". Occup Med (Lond). 54 (2): 69–75. PMID 15020723.
- Pecina CA (2012). "Tick paralysis.". Semin Neurol. 32 (5): 531–2. PMID 23677663. doi:10.1055/s-0033-1334474.
- Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A (2014). "Tetrodotoxin: chemistry, toxicity, source, distribution and detection.". Toxins (Basel). 6 (2): 693–755. PMC . PMID 24566728. doi:10.3390/toxins6020693.
- Kuntzer T, Hirt L, Bogousslavsky J (1996). "[Neuromuscular involvement and cerebrovascular accidents].". Rev Med Suisse Romande. 116 (8): 605–9. PMID 8848683.
- Laffont I, Julia M, Tiffreau V, Yelnik A, Herisson C, Pelissier J (2010). "Aging and sequelae of poliomyelitis.". Ann Phys Rehabil Med. 53 (1): 24–33. PMID 19944665. doi:10.1016/j.rehab.2009.10.002.
- West TW (2013). "Transverse myelitis--a review of the presentation, diagnosis, and initial management.". Discov Med. 16 (88): 167–77. PMID 24099672.
- Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG; et al. (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients.". J Neurol Sci. 317 (1-2): 35–9. PMID 22482824. doi:10.1016/j.jns.2012.03.003.
- Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–72. PMID 24365430. doi:10.1016/B978-0-7020-4088-7.00098-5.
- Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–9. PMC . PMID 22421697. doi:10.1097/OLQ.0b013e31824ee574.
- Falzarano MS, Scotton C, Passarelli C, Ferlini A (2015). "Duchenne Muscular Dystrophy: From Diagnosis to Therapy.". Molecules. 20 (10): 18168–84. PMID 26457695. doi:10.3390/molecules201018168.
- Filippi M, Preziosa P, Rocca MA (2016). "Multiple sclerosis.". Handb Clin Neurol. 135: 399–423. PMID 27432676. doi:10.1016/B978-0-444-53485-9.00020-9.
- Giang DW, Grow VM, Mooney C, Mushlin AI, Goodman AD, Mattson DH; et al. (1994). "Clinical diagnosis of multiple sclerosis. The impact of magnetic resonance imaging and ancillary testing. Rochester-Toronto Magnetic Resonance Study Group.". Arch Neurol. 51 (1): 61–6. PMID 8274111.
- Riva N, Agosta F, Lunetta C, Filippi M, Quattrini A (2016). "Recent advances in amyotrophic lateral sclerosis.". J Neurol. 263 (6): 1241–54. PMC . PMID 27025851. doi:10.1007/s00415-016-8091-6.
- Michelle EH, Mammen AL (2015). "Myositis Mimics.". Curr Rheumatol Rep. 17 (10): 63. PMID 26290112. doi:10.1007/s11926-015-0541-0.