Working together to eliminate cyanide poisoning, konzo, tropical ataxic neuropathy (TAN) and neurolathyrism.
Cassava Cyanide Diseases & Neurolathyrism Network ______Issue Number 15, June 2010 Contents Brain glutathione as a target first proposed by Rudra and for aetiological factors in Chowdhury 1 and in konzo by Cliff et 2 Brain glutathione as a target for neurolathyrism and konzo al. aetiological factors in It is pertinent to revisit, in the neurolathyrism and konzo …..1 Both neurolathyrism and konzo are diamond jubilee year of its publication, the concept advanced Predicting cyanogen levels in associated with the nutritional 1 dependence of human populations by Rudra and Chowdhury. These cassava under future emission authors thought that methionine scenarios ………………………2 on a single plant food. These diseases express themselves as deficiency formed the backdrop to Correct and incorrect ways to chronic disorders of upper motor neurolathyrism and that another process cassava leaves – a neurones, leading to signs and factor then precipitated warning………………………... 2 symptoms that are characteristic of neurodegeneration. If sulphur amino acid deficiency predisposes subjects Can we meet the first Millenium motor neurone disease. The plant food associated with neurolathyrism to the neuropathology observed in Development Goal in konzo and is grass pea, which contains the both neurolathyrism and konzo, lathyrism settings by 2015? 3 neurotoxic-N-oxalyl-α,β mechanistic research on the toxins The burden of cassava cyanide- diaminopropionic acid ( β-ODAP). contained in grass pea and cassava continues to be justified to induced disease:Estimates for The plant food associated with determine the major features that konzo is cassava, which may the World Health Organization 4 constitiute the ‘second attack’ on contain significant concentrations of Konzo count…………………… 4 human upper motor neurones in cyanogenic glycosides and their these disorders. -ODAP interacts degradation products. A β with many cellular processes; e.g., it monotonous diet of grass pea is likely to generate nutritional is an excitotoxin; it affects deficiencies; it is proposed that one mitochondrial function and CCDN Coordinator: of these, plasma methionine generates free radicals, which inhibit Dr. J. Howard Bradbury cystathionine lyase. β-ODAP deficiency, may predispose - EEG, Research School of Biology, inhibits the cystine/glutamate x c Australian National University neurones to the neurotoxic effects of β-ODAP. Subjects suffering from transporter and is itself transported Canberra ACT 0200, Australia by the same system; it perturbs Phone: +61-2-6125 0775 konzo also have low concentrations 2+ E-mail: [email protected] of plasma methionine as a result of intracellular Ca homeostasis. a dietary deficiency of this amino Examples of the biological activities Coordinating Group: acid. However, the plasma cystine of cyanide, include its long J.P.Banea, Julie Cliff, Arnaldo concentration is also compromised established role in inhibiting Cumbana, Ian Denton, Fernand because cyanide released from mitochondrial electron transport, its Lambein, N.L.V.Mlingi, Humberto cyanogenic glycosides in cassava reaction with cystine to yield 2- Muquingue, Bala Nambisan, Dulce imino-4-thiazolidine carboxylic acid, Nhassico, S.L.N. Rao. probably reacts with plasma cystine non-enzymatically. The product of and its role in increasing cytosolic free Ca 2+ concentrations. In sulphur Country Contacts: this reaction is the neurotoxin 2- amino acid deficiency cyanide is Cameroon : E.E. Agbor; imino-4-thiazolidine carboxylic acid. D.R. Congo : D.D. Ngudi; Since both plasma methionine and metabolised to neurotoxic cyanate, Indonesia : A. Hidayat; cystine are used for glutathione which inhibits glutathione reductase Mozambique : Anabela Zacarias; synthesis it seems likely that one and depletes intracellular reduced Nigeria : M.N. Adindu and P.N. Okafor; common feature that leads to motor glutathione. Tanzania : N.L.V. Mlingi neurone death in neurolathyrism With these and other mechanisms affected by β-ODAP and cyanide we Website: and konzo is the depletion of brain glutathione. That deficiencies in still have no clear idea of the likely www.anu.edu.au/BoZo/CCDN sequence of events that precipitates dietary sulphur amino acids are significant in neurolathyrism was the death of motor neurones in neurolathyrism and konzo. It has 1 been proposed that the mechanism If there is more CO 2 in the atmospheric conditions they were by which plasma methionine atmosphere (or less O 2) the grown under. The danger to humans concentrations are depressed in production of carbohydrates may come from the decrease in human populations stems from the becomes more efficient and less protein from other foods such as normal physiological response to energy is lost in photorespiration. grains, increasing the overall feeding protein which is deficient in When an established plant is cyanogen: protein ratio in the diet an essential amino acid. If this transferred to an atmosphere that is overall. One serious unexpected mechanism is correct, the high in CO 2, the production of finding in our experiment was that prevention of neurolathyrism and carbohydrates and the growth rate the size and number of tubers was konzo lies in nutritional increases. This is sometimes called much less in the plants grown at supplementation with methionine. the “CO 2 – fertilisation” effect. elevated CO 2. Those grown at 720 Rudra and Chowdhury’s own data However, when plants are ppm had an 80% reduction in yield suggest that, where available, rice established and grown in an overall. Unpublished data for other 3 supplements would be ideal. atmosphere with enhanced CO 2, cultivars supports these results. We Unfortunately, it is unlikely that they acclimatise to it so that the do not have a good explanation for subjects already chronically affected fertilisation effect is significantly less this and further experiments are would benefit from this intervention. than was predicted by the short term underway. We also do not know experiments. The main reason for what effects temperature and References this seems to be that plants grown drought will have. 1 Rudra MN, Chowdhury LM, (1950) at high CO 2 make less Rubisco, What our research does show is that Methionine content of cereals and legumes. reducing the demand for nitrogen higher levels of CO 2 in the Nat. 166, 568. 2 fertiliser and allowing the plants atmosphere are not necessarily Cliff J. Lundquist P. Martennson J. Rosling H, Sorbo B. (1985) Association of high cyanide resources to be reallocated to other good for plants, and that there may and low sulphur intake in cassava-induced processes. be unexpected consequences for spastic paraparesis. Lancet ii, 1211-1213. The immediate consequence for major staple crops. Certainly 3 Nunn PB, Lyddiard JRA, Perera KPWC, (2010) Brain glutathione as a target for human nutrition from CO 2- cassava is not behaving in a way aetiological factors in neurolathyrism and acclimation is that leaves and grains that was predicted by the models konzo. Food Chem. Toxicol., in press of plants using the normal C3 developed for other crop plants. It is Peter B. Nunn photosynthetic system have 15-20% important that plant breeders School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth U.K. less protein when grown at about continue to monitor the cyanogen [email protected] 720 ppm, about twice the amount of levels of their cultivars as well as the CO 2 in today’s air. Plants such as yield. as the composition of the Predicting cyanogen levels in maize and sorghum use a different atmosphere changes. Equally cassava under future photosynthetic system (C4) and the important is that end users continue emission scenarios reduction in protein is about half to process cassava products that. Another less appreciated thoroughly to reduce the amount of The concentration of carbon dioxide consequence of the lower protein cyanogens in the overall diet. concentrations is the flow on effect (CO 2) is increasing in the atmosphere as a result of burning to other herbivore defence References compounds such as cyanogenic 1 Gleadow RM (2010) Food security in a fossil fuels and land clearing. In the warming world. Australasian Science Jan/Feb past 50 years the concentration has glycosides. 2010, 33-35. increased from about 340 ppm to We grew cassava (MCol 1468) in air 2 Gleadow RM, Evans JR, McCaffrey S, and 380 ppm, and given the current high with today’s concentration of CO 2 (360 ppm), and air containing one Cavagnaro TR, (2009). Growth and nutritive levels of CO 2 emissions, is expected value of cassava ( Manihot esculenta Cranz.) to reach 700 ppm by the middle of and a half times and twice the are reduced when grown at elevated CO 2. concentration of CO 2 (550 ppm and Plant Biology 11, (Suppl. 1) 76–82. this century. Because CO 2 is a 710 ppm). 2 Surprisingly, total leaf greenhouse gas, rising CO 2 is Ros Gleadow usually discussed as one of the nitrogen, used here as a proxy for School of Biological Sciences, Monash University, Victoria., Australia forcing agents of climate change. leaf protein, was actually higher in plants grown in the elevated CO [email protected] Another important consequence is 2 treatments. Leaves of cassava the direct effect of CO 2 on plants Correct and incorrect ways to through the process of grown at 1.5 times the CO 2 showed only a small, significant increase in process cassava leaves – A photosynthesis which in turn affects Warning the nutritional value of plants. 1 cyanogens, but those grown at
Photosynthesis is the process twice-ambient CO 2 contained two to Processed cassava leaves are used whereby plants convert CO to three times the concentrations of 2 widely in Africa 1,2 as a good source carbohydrates using sunlight and cyanogens, compared with control of proteins,vitamins and minerals. water. The enzyme that drives this plants (depending on the type of However the leaf protein is of poor conversion, Rubisco (Ru), combines fertiliser). This means that in the quality, being short of essential S- the substrate RuBP (a sugar) with future cassava leaves will be more containing amino acids. 3 Cassava either CO (to make carbohydrates), toxic as the cyanogen: protein ratio 2 leaves contain 500-2000 ppm 4 of or oxygen (O ) in an energy almost doubled. The peel also had 2 cyanogenic glucosides (linamarin consuming process called similar levels of cyanogens and total and a small amount of lotautralin) photorespiration. Rubisco is the nitrogen, in plants grown in the which are very poisonous to most abundant protein on the planet future emission scenarios. humans. The enzyme linamarase and makes up to 50% of the protein The good news is that the tubers catalyses the breakdown of and 25% of the nitrogen in the leaf. had the same concentration of cyanogens, no matter what linamarin to glucose and acetone 2 cyanohydrin and hydroxynitrile lyase References rely almost exclusively on products (HNL) catalyses its further 1 Achidt AU, Ajayi OA, Bokanga M, Maziya- derived from those two resistant decomposition to hydrogen cyanide Dixon B (2005) The use of cassava leaves as crops and the consequences of this food in Africa, Ecol. Food Nutr. 44, 423-435. (HCN) and acetone. 2 are outbreaks of those two 2 Bokanga, M. (1994) Processing of cassava 2 Bokanga found that pounding leaves for human consumption. Acta Hort. 375, diseases. Both konzo and lathyrism cassava leaves containing 900-1200 203-207. occur almost exclusively among 3 Ngudi, D.D., Kuo, Y.H. and Lambein, F. ppm of total cyanide for 15 min (2003) Amino acid profiles and protein quality subsistence farmers who consume reduced the cyanide by 62-72% and of cooked cassava leaves or ‘saka-saka’. J Sci virtually only the produce of their their subsequent boiling in water for Food Agric 83, 529-534. often marginal land. 4 15 minutes reduced the cyanide Cardoso, A.P., Mirione, E., Ernesto, M., These diseases do not travel easily. Massaza, F. Cliff, J. Haque, M.R. and content to < 1%. We found that Bradbury, J.H.(2005) Processing of cassava They are mostly concentrated in pounding for 15 min of young leaves roots to remove cyanogens, J Food Comp settings of extreme poverty and in from four varieties of sweet cassava Anal. 18, 451-460. remote rural areas with a high 5 Ngudi, D.D., Kuo, Y.H. and Lambein, F. containing about 500 ppm total (2003) Cassava cyanogens and free amino proportion of people whose income cyanide, reduced the cyanide to acids in raw and cooked leaves. Food Chem is less than 1 US $ a day at 10% and subsequent boiling for 15 Toxicol. 41, 1193-1197. purchasing power parities (PPP) 6 min reduced the cyanide content to FAO/WHO (1991) Joint FAO/WHO Food values. The 1 US $ a day at PPP Standards Programme, Codex Alimentarias 0.4%. These results confirm earlier prices is an international poverty line 2,5 Commission XII, Supplement 4, FAO, Rome. work that pounding of cassava extensively used and computed by leaves followed by boiling is a very J. Howard Bradbury and Ian C. Denton the World Bank. This poverty line is good method of removing cyanide [email protected] supposed to define the inability to 3 from them. Can we meet the first pay for food needs. The low Like virtually all enzymes, Millenium Development Goal commercial value of the products of linamarase and HNL are inactivated these subsistence famers has on boiling in water. Thus, if the intact in konzo and lathyrism contributed to this phenomenon. leaves are placed in boiling water settings by 2015? The affected households are poor these enzymes are inactivated and and often illiterate and have little or hence are unable to catalyse the Tens of thousands of people are no political voice. The proportion of break down of linamarin to HCN. We affected by konzo and lathyrism, two illiterate people is high and these found that using the same sample of toxico-nutritional neuro-degenerative diseases thrive in places with unsafe young leaves as above, 25-30% of diseases which persist exclusively water, poor sanitation, and limited total cyanide (125-150 ppm) among the poorest and most access to basic health care. These remained after boiling leaves in marginalized communities. factors also contribute to the water for 15 min. Loss of linamarin Konzo and (neuro-) lathyrism are underreporting of konzo and was due to its solubility in water. clinically similar with spastic lathyrism. There was no further loss of cyanide paraparesis of the legs as a In September 2000, the world’s on subsequently pounding the common picture. As of now, there is leaders agreed on the Millennium leaves for 15 min. Clearly, boiling no geographical overlap in the Development Goals (MDGs), cassava leaves is a very poor cultivation and consumption of committing their countries to exert method of processing, because cassava ( Manihot esculenta , the stronger efforts to reduce poverty, dangerous amounts of cyanide causative agent of konzo) and grass improve education and health levels, (>100 ppm) remain in the leaves. pea ( Lathyrus sativus , the causative achieve gender equality, and (The World Health Organization safe agent of lathyrism) and in the environmental sustainability. The level for total cyanide in cassava occurrence of those two diseases, first general MDG is to “eradicate flour is 10 ppm. 6) This dangerous caused by their prolonged extreme poverty and hunger”. In method of processing cassava overconsumption. Konzo is only particular, target 1 states the goal of leaves is used in the Democratic reported in sub-Saharan Africa halving poverty between 1990 and Republic of Congo and whereas lathyrism occurs in Ethiopia 2015, the proportion of people recommended on the internet in and the Indian Subcontinent. whose income is less than 1 US $ a many sites. Lathyrism is now eradicated from day at purchasing power parities Based on these studies we issue the Europe where several countries (PPP) values. 4 following warnings: (Spain, Greece, Poland, Ukraine) Improving conditions to prevent 1,2 1. Under no circumstances should were affected in the past century. konzo and lathyrism is possible but fresh young cassava leaves be Epidemics of konzo and lathyrism many countries remain far from eaten without processing, because usually appear when environmental reaching the first (UN) millennium they contain highly dangerous levels conditions result in heavy dietary development goal (MDG) by 2015, of cyanide (500-2000 ppm). reliance on cassava or on grass and much of the progress is being 2. Processing of cassava leaves pea, respectively. These two crops eroded by the recent global food should be carried out by pounding are high-yielding with relative price and economic crises. 5 for 15 min followed by boiling in resistance to abiotic stress such as Increasing the commercial value of water for 15 min. 2 Never boil the drought or low fertility of the soil, or products from those subsistence intact leaves in water first, because to entomological and farmers could help them to better boiling inactivates the enzymes and phytopathological attacks. However, access more varied and thus dangerous amounts of cyanide are adverse environmental conditions healthier diets, and would certainly retained in the leaves, which can such as drought, demographic contribute to the achievement of the cause cyanide poisoning and pressure, climate change or war UN Millennium Development Goals. possible death. forced the poorest populations to live on subsistence farming and to 3
References of reported cases in published 2 Diasolua Ngudi D (2004). Konzo and cassava 1 Tshala-Katumbay D. and Spencer P.S. articles, doctoral theses, the grey toxicity: a study of associated nutritional factors (2007). Toxic disorders of the upper motor in the Popokabaka District, Democratic neuron system. In: Eisen A. & Shaw P. (Eds), literature and in the proceedings of Republic of Congo. Faculty of Bioscience the workshop on Toxico-nutritional Engineering . Ghent, 2004-5 pp. 162. Handbook of Clinical Neurology, Motor Neuron 3 and Related Diseases. Elsevier, Edinburgh, pp Degenerations Konzo and Medecins du Monde, Lutte contre la malnutrition. 353-74. Lathyrism, Ghent, 2009, see CCDN 2 Lambein, F., Diasolua Ngudi, D. and Kuo, www.medecinsdumonde.be/Urgence- News 14. For Mozambique, I used a nutritionnelle-a-Mwetshi.html Y.H. (2010). Progress in prevention of toxico - 4 nutritional neuro-degenerations. ATDF J. 6, database of reported cases. Lantum, H.(1998) Spastic paraparesis. konzo 60-65. Table 1 shows that the total number - in the Garoua Boulai Health District, East
Konzo count * Corrected with currently available data ** Two reported deaths added The total number of reported konzo cases was first estimated by 1 CCDN News is the Newsletter of th e Cassava Cyanide Diseases and Neurolathyrism Network (CCDNN). The CCDNN is a Tylleskar in his doctoral thesis. He free, worldwide network commenced in June 2001, which is working towards the elimination of konzo, TAN and other gave a total of 3711 cases up to cassava cyanide diseases. CCDN News will consider for publication short articles and letters (1-3 pages A 4 double spaced) written in English 1993. In this article, I update the Because CCDN News is a newsletter, full-size original papers or reviews cannot be considered for publication. Material count with more recent data (see published in CCDN News may be freely reproduced, but please always indicate that it comes from CCDN News. Please send all correspondence to the CCDNN Coordinator, Dr J Howard Bradbury, Evolution, Ecology and Genetics, Research School of References).I searched for numbers Biology, Australian National University, Canberra, ACT 0200, Australia. 4