We propose a USA/DRC collaborative project to elucidate the relationship between food (cassava, Manihot esculenta Crantz) cyanogenic toxins and the occurrence of a motor system disease --- known as konzo --- in sub-Saharan Africa. The causes of konzo have largely remained unclear, and other forms of cassava-related neurodevelopmental/cognitive impairment may exist during childhood and adult life. We will bring together country-specific research capabilities and needs to reach the following goals: (a) illuminate the impact of cassava neurotoxicity on human motor and cognition abilities, (b) increase understanding of lifespan interactions between environmental stressors (toxicants), diet (nutritional status), and genetics in relation to motor system degeneration, (c) and enhance the clinical/neurotoxicolgy research capacity of the Democratic Republic of Congo (DRC). Our central hypothesis is that risk for cassava-associated motor/cognition deficits (MCD) is determined by chronic sulfur amino acid-deficiency and/or genetic variations that impair the metabolism of cassava cyanogens with subsequent increase in cyanate (neurotoxin) production and risk for neurodegeneration. To test our hypothesis and achieve our goals, we will address the following specific aims: (1) elucidate the epidemiological pattern of motor cognition deficits (MCD) associated with chronic dietary reliance on cassava, (2) determine the risk for MCD in relation to sulfur amino acid deficiency and genetic polymorphisms in the cyanogen-detoxifying enzyme rhodanese (thiosulfate sulfurtransferase), and (3) increase the manpower for clinical/neurotoxicology research in DRC. MCD will be ascertained by neuropsychological testing in a cross-sectional study (baseline characterization) followed by a case-cohort design to capture neurodevelopmental delays in school-age children. TST polymorphisms will be studied using PCR-based sequencing techniques. Serum carbamoylation will be analyzed and quantified using state-of-the-art proteomic methodologies i.e. liquid chromatography tandem mass spectrometry (LC/MS-MS). Young DRC investigators will be trained through active participation in supervised field work and mentoring for career development. Relevance. At the completion of the proposed studies, our findings will help develop a scientific rationale to address and develop strategies to reduce the burden of neurotoxicity associated with cassava, a staple food for more than 500 million people around the globe. The overall goal of this proposal meshes well with the global health mission of the NIH while integrating the institute-specific missions of FIC, NIEHS, NINDS, and NICHD.

Public Health Relevance

We propose research activities of global health significance to elucidate risk factors for konzo (irreversible paralysis) or cognition deficits that occur among populations that rely on cyanogenic cassava (aka manioc, or tapioca, or yucca) as staple food. Because konzo mostly affects children and women, and cassava is a staple for more than 500 million people around the globe, understanding its neurotoxicity potential is pertinent to global health, economy, and security. Our results will also help regulating agencies set safety standards in relation to international trade and consumption of other cyanogenic foods (e.g. lima beans) or cyanogenic exposure in occupational settings (e.g. painting industries, or gold mining, or theatres of wars).

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ICP2-N (50))
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Kirshner, Annette G
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Oregon Health and Science University
Schools of Medicine
United States
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Kambale, K J; Ali, E R; Sadiki, N H et al. (2016) Lower sulfurtransferase detoxification rates of cyanide in konzo-A tropical spastic paralysis linked to cassava cyanogenic poisoning. Neurotoxicology :
Tshala-Katumbay, Desire D; Ngombe, Nadege N; Okitundu, Daniel et al. (2016) Cyanide and the human brain: perspectives from a model of food (cassava) poisoning. Ann N Y Acad Sci 1378:50-57
Bumoko, G M-M; Sadiki, N H; Rwatambuga, A et al. (2015) Lower serum levels of selenium, copper, and zinc are related to neuromotor impairments in children with konzo. J Neurol Sci 349:149-53
Tshala-Katumbay, Desire; Mwanza, Jean-Claude; Rohlman, Diane S et al. (2015) A global perspective on the influence of environmental exposures on the nervous system. Nature 527:S187-92
Kimani, S; Sinei, K; Bukachi, F et al. (2014) Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents. Metab Brain Dis 29:105-12
Makila-Mabe, Bumoko G; Kikandau, Kambale J; Sombo, Thérèse M et al. (2014) Serum 8,12-iso-iPF2α-VI isoprostane marker of oxidative damage and cognition deficits in children with konzo. PLoS One 9:e107191
Banea, Jean Pierre; Bradbury, J Howard; Mandombi, Chretienne et al. (2014) Effectiveness of wetting method for control of konzo and reduction of cyanide poisoning by removal of cyanogens from cassava flour. Food Nutr Bull 35:28-32
Kimani, S; Moterroso, V; Morales, P et al. (2014) Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet. Food Chem Toxicol 66:203-9
Bumoko, G M; Sombo, M T; Okitundu, L D et al. (2014) Determinants of cognitive performance in children relying on cyanogenic cassava as staple food. Metab Brain Dis 29:359-66
Okitundu Luwa E-Andjafono, Daniel; Bumoko Makila-Mabe, Guy; Ayanne, Marie-Thérèse Sombo Safi et al. (2014) [Persistence of konzo epidemics in Kahemba, Democratic Republic of Congo: phenomenological and socio-economic aspects]. Pan Afr Med J 18:213

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