Konzo risk factors, determinants, and etiopathogenesis: Review and new perspectives

Konzo is an upper motor neuron disease characterized by a sudden onset of symmetrical, non-progressive, and irreversible spastic paraparesis. This crippling disease mostly affects children from 2 years of age and childbearing women, causing permanent gait difficulties. It occurs only in food-deprived communities exposed to dietary cyanide from insufficiently processed toxic cassava (Manihot esculenta Crantz). Although protein malnutrition and dietary cyanide poisoning are undeniably identified as major risk factors of konzo, the relative importance of each of these two risk factors and the underlying mechanisms of konzo remain largely unknown. In this thesis, using a multi-disciplinary approach, we aimed at a better understanding of konzo risk factors, determinants, and etiopathogenesis. The Democratic Republic of the Congo (DRC) holds the highest prevalence of konzo, with over a half of all reported cases documented in two provinces of the DRC: the former Bandundu Province, in the western part of the country, and South-Kivu province, in the eastern DRC. Strikingly, in South-Kivu, all konzo cases were recorded in Burhinyi and its immediate neighborhoods, while cassava constitutes the staple food for all inhabitants of this province, and cassava-derived cyanide poisoning was documented as a contributive factor to a high prevalence of endemic goiter in Idjwi, another rural area of South-Kivu since the 1970s, with no konzo case reported so far. By comparing data on nutritional status and level of cyanide poisoning of subjects from the two areas of South-Kivu (Burhinyi and Idjwi), our findings showed a similar profile of healthy subjects from Burhinyi and those from Idjwi, with a low prevalence of wasting (3.3% and 6.5%, respectively), intermediate prevalence of stunting (26.7% and 23.9%, respectively) and a high prevalence of dietary cassava-derived cyanide poisoning (50.0% and 63.0%, respectively). As well, konzo patients (from Burhinyi) had a high prevalence cyanide poisoning (81.8%) but, unlike healthy subjects from both areas, had also a high prevalence of both wasting (54.5%) and stunting (72.7%). Thus, a compromised nutritional status was the only factor differentiating konzo patients from healthy individuals exposed to cyanide poisoning. This further suggests that, besides the known role of cyanide poisoning in the pathogenesis of konzo, protein malnutrition may be a key factor for the disease occurrence. In addition, our results showed a seasonal variation in the two above-mentioned konzo risk factors, with acute nutritional deterioration in Burhinyi and higher cyanide intoxication both in Burhinyi and in Idjwi during the dry season. Investigations on local cassava varieties showed high cyanide content in fresh cassava roots both of bitter and sweet taste, but the usual processing methods (maintained during the raining season) proved to be effective enough to reduce cyanide content in cassava roots till safe cyanide levels (< 10 ppm) in obtained flour. In the dry season, however, the cyanide content in cassava flour significantly increased, following a shortening of cassava-processing. Skipping heap-fermentation during cassava processing, as well as a preferential consumption of bitter cassava roots, were the two factors independently associated with very high urinary thiocyanate levels (witnessing a high cyanide poisoning) in participants from Idjwi and Burhinyi during the dry season. Thus, restoring the traditional processing methods (in particular a sufficiently long heap-fermentation) should ensure safe consumption of cassava. Finally, in vitro investigations on the neurotoxic effects of the two major cyanide metabolites (namely cyanate and thiocyanate) confirmed the neurotoxicity of cyanate in two neuron-like cell lines (mouse Neuro-2A neuroblastoma cell line and human SH-SY5Y neuroblastoma cell line) as it induced a drastic drop in cell viability from relatively low concentrations (0.3 mM in Neuro-2A and 3 mM in SH-SY5Y), contrary to thiocyanate which required to reach extremely high concentrations (30 mM), well above physiologically encountered magnitudes, to induce a modest cell death in cell lines. Cyanate neurotoxicity would act simultaneously on several mechanisms, including apoptosis related to caspases (3, 8, and 9), oxidative stress, and excitotoxicity (through AMPA and NMDA receptors activation, probably following a presynaptic release of glutamate). In conclusion, the occurrence of konzo is likely a consequence of the interplay between several factors. An acute worsening of the nutritional status appears to be a key risk factor, favoring an impairment of cyanide detoxification process in subject undergoing high cassava-related cyanide poisoning, leading to an unusual excessive production of minor metabolite (especially cyanate) which, in fine, are responsible for an upper motor neuron damage through various mechanisms (including apoptosis, oxidative stress, and excitotoxicity). Geo-environmental, cultural, and behavioral factors, as well as other factors of individual susceptibility (not yet fully identified) seems to also play a role in the appearance of konzo, although their exact contribution still needs to be elucidated.

Jaar van publicatie:2022

Toegankelijkheid:Embargoed