Working together to eliminate cyanide poisoning, konzo, tropical ataxic neuropathy (TAN) and neurolathyrism Cassava Cyanide Diseases & Neurolathyrism Network (ISSN 1838-8817 (Print): ISSN 1838-8825 (Online) Issue Number 24, December 2014 Contents Editorial Editorial ......................................................................... 1 Articles ........................................................................... 2 Fifty year ago, a paper in Biochemistry by Professor 50 years of ODAP and Lathyrus research: Some S.L.N. Rao described the chemical structure of a random thoughts ....................................................... 2 new amino acid occurring abundantly in the seeds Eating raw peeled cassava roots is dangerous of Lathyrus sativus and believed to be the cause of because they contain poisonous cyanide ............... 3 the human crippling disease neurolathyrism. Since then this non-protein amino acid β-N-oxalyl-l-α, β- Three decades of toxic cyanide management in diaminopropionic acid or β-ODAP, has been the Uganda. Doing and communicating more with minimal strategies. Has it been possible? ............... 4 focus of numerous studies in a great variety of disciplines including toxicology, neurology, Consumption of cassava leaves among farmers biochemistry, agronomy and plant biotechnology. from three geographical regions of Ghana ............ 10 On page 2, the author of that memorable paper KONZO: The IBRO Africa Regional Committee explains his present views on this compound. Efforts (ARC) organizes its first Global Advocacy by the research community to prevent Workshop for Neuroscience in Kinshasa .............. 12 neurolathyrism and cassava cyanide diseases have helped in the understanding and prevention of these CCDNN Coordination: crippling diseases of the poor, but as yet there is Prof Fernand LAMBEIN, Coordinator more reason to increase the efforts than to retire. Ghent University, Institute for plant Biotechnology In Kinshasa, D.R. Congo, a “Global Advocacy Outreach (IPBO) Technologiepark 3, B-9052 Gent -Zwijnaarde, Belgium Workshop” on brain development, neurology and Phone: +32 484 417 5005 child development was organized by IBRO – ARC E-mail: [email protected] or on 4-5 September. The workshop included a [email protected] symposium on konzo where the present situation in D.R. Congo and elsewhere was highlighted. A report Dr. Delphin DIASOLUA NGUDI on this workshop is included in this issue. On the neurolathyrism front, a Danish church sponsored Ghent University, Institute for plant Biotechnology Outreach (IPBO) workshop was organized in Bahir Dar, Ethiopia on Technologiepark 3, B-9052 Gent -Zwijnaarde, Belgium 4-6 October. Phone: +32 92 64 52 82 A detailed report on this event can be found online: Email: [email protected] http://reliefweb.int/report/ethiopia/ethiopia-grass- Editorial Board : pea-blessing-and-curse. In this report a preliminary J.P. Banea, Julie Cliff, Arnaldo Cumbana, Ian Denton, D. survey is mentioned that identified some 800 Diasolua Ngudi, F. Lambein. J. Howard Bradbury, affected individuals. N.L.V.Mlingi, Humberto Muquingue, Bala Nambisan, Dulce Five year after the Ghent workshop ‘Konzo and Nhassico, S.L.N. Rao, D. Tshala-Katumbay neurolathyrism: similarities and dissimilarities Country Contacts: between those crippling neurodegenerative Cameroon: E.E. Agbor; diseases of the poor’, an evaluation of progress and D.R. Congo: D. Diasolua Ngudi and J; Nsimire developments and a confrontation of ideas would be Chabwine; opportune. Attempts for obtaining financing for a Indonesia: A. Hidayat; September 2015 workshop in Ghent are being Mozambique: Anabela Zacarias; made and suggestions are welcome. Progress and Nigeria: M.N. Adindu and P.N. Okafor planning will be communicated when available. Website: Wishing you all a peaceful and successful year http://www.ugent.be/we/genetics/ipbo/en/networking/ccd 2015. nn/overview.htm Fernand Lambein 1 Articles be the reason why white mice become susceptible to ODAP following pretreatment with tyrosine due to activation of the melanin pathway 50 years of ODAP and Lathyrus research: Some as a consequence of inhibition of TAT. Several random thoughts intermediates in the Tyrosine- melanin pathway (neuromelanins) have infact been implicated in The saga of Lathyrus research over the last 50 6 years was marked by two very significant certain neurological manifestations . Since the developments, firstly the discovery of ODAP and melanin pathway is activated by exposure to its toxicity to certain animals and the realization sunlight there is a strong possibility that that it is only the excessive consumption of exposure to sunlight such as during hard Lathyrus as a staple over a period of time physical labor in field conditions, inhibition of especially during drought and famine that is TAT by ODAP may result in activation of minor responsible for Neurolathyrism. In India in catecholamine pathways due to increased levels particular the disease has almost disappeared of tyrosine. This could well be the reason why and in the recent past only Ethiopia and women are less prone to Lathyrus toxicity. Bangladesh had some episodes. Recent Another puzzling feature of ODAP toxicity to surveys from India suggest that wherever animals and humans relates to the inVivo Lathyrus has been consumed as part of a metabolism of ODAP. Administered or ingested normal diet there are no cases of ODAP is excreted mostly unchanged (not neurolathyrism1. As a yesteryears Lathyrus metabolized) in all laboratory animals, but in humans however, it is nearly quantitatively researcher I consider it relevant to highlight 7 through this dedicated newsletter some of my degraded . The steps involved in this process random thoughts on new directives that could in need to be identified and this raises a spectre of the near future remove the unfortunate stigma doubt whether such a mechanism could be that is attached to Lathyrus sativus and establish absent or deficient in susceptible individuals. its deserved status as a food legume. One of the hypotheses concerning toxicity of ODAP toxicity: A clear cut toxicity of ODAP ODAP relates to its non NMDA receptor following either oral or intraperitoneal interactions (AMPA receptors) unlike BMAA administration is seen only in two laboratory (beta-methylaminoalanine), the cycad animals, the day old chick and the C57BL/6 neurotoxin. However, some studies suggest that 2 ODAP interactions at glutamate receptors may black mice . A primate model developed quite 8 early in the sixties employed (after failure with be mostly nonspecific . A recent report shows oral feeding regimens) a rather unorthodox that BMAA fed Drosophila develop severe intrathecal administration of ODAP to locomotor disability and eventual death while demonstrate toxicity3. Other studies with ODAP feeding had no effect on locomotor capabilities although both compounds behaved primates, goats, horses have been reported 9 claiming toxicity but these have generally as NMDA agonists . employed very complex feeding and/or During the last few years ODAP has also taken treatment regimens and might be difficult to a new avatar under the name Dencichine which reproduce. A rat model of neurolathyrism has has been discovered in the traditional Chinese also been produced by repeated injection of medicinal herb Panax notoginseng and other ODAP to neonatal rats4. While the C57BL black species of Panax10. Many of the medicinal mice are susceptible to ODAP toxicity the properties of Ginseng are now attributed to BALB/C (Albino) mice are not susceptible but Dencichine (= ODAP) and few patents utlising its become susceptible if pretreated with tyrosine. hemostatic properties have already appeared. This led to the discovery of inhibition of TAT Band aid strips and toothpastes containing activity (Tyrosine amino transferase) by ODAP are now commercially available in ODAP2.This observation may hold the real key China11,12 Other properties of ODAP in areas like to several unanswered questions relating to wound healing, neurogenesis, angiogenesis and human neurolathyrism. Over the years, the hypoxia are in the patents pipeline. ODAP effect of ODAP has been examined on a variety though born as a neurotoxin is gradually making of biochemical parameters but the only effect headways into human health. that is significant and that can be reproduced in any laboratory is the stereospecific inhibition of Homoarginine, the first unusual amino acid to be TAT activity by L-ODAP but not by D-ODAP. Any discovered in Lathyrus had almost been ignored mechanism of toxicity proposed for ODAP since it was nontoxic. Homoarginine is now should in fact take this into consideration. The recognized as a normal metabolite in humans glutamate receptor interactions by ODAP for and its importance in the cardiovasculature is 13, 14 instance is a very basic biochemical mechanism growing . This should make Lathyrus a and cannot be different between two strains of prized legume as a functional food and creates a mice and the same argument also holds good totally new avenue into Lathyrus research as it for reports on the inhibition of NADH could become the only known dietary source dehydrogenase by ODAP5. The one primary (nutraceutical !) of this amino acid. biochemical difference between the two mice strains is that black mice have a predominant melanin (catecholamines) pathway. This could 2 References Eating raw peeled cassava roots is dangerous 1Arjun L. Khandare, J.J Babu,, M. Ankulu, N. Aparna, Amol because