The gut microbiome in konzo.

Konzo, a distinct upper motor neuron disease associated with a cyanogenic diet and chronic malnutrition, predominately affects children and women of childbearing age in sub-Saharan Africa. While the exact biological mechanisms that cause this disease have largely remained elusive, host-genetics and environmental components such as the gut microbiome have been implicated. Using a large study population of 180 individuals from the Democratic Republic of the Congo, where konzo is most frequent, we investigate how the structure of the gut microbiome varied across geographical contexts, as well as provide the first insight into the gut flora of children affected with this debilitating disease using shotgun metagenomic sequencing. Our findings indicate that the gut microbiome structure is highly variable depending on region of sampling, but most interestingly, we identify unique enrichments of bacterial species and functional pathways that potentially modulate the susceptibility of konzo in prone regions of the Congo.

Konzo risk factors, determinants and etiopathogenesis: What is new? A systematic review.

Konzo is a toxico-nutritional upper motor neuron disease causing a spastic paraparesis in schoolchildren and childbearing women in some African countries. Almost a century since the first description of konzo, its underlying etiopathogenic mechanisms and causative agent remain unknown. This paper aims at refreshing the current knowledge of konzo determinants and pathogenesis in order to enlighten potential new research and management perspectives. Literature research was performed in PubMed and Web of Science databases according to the PRISMA methodology. Available data show that cassava-derived cyanide poisoning and protein malnutrition constitute two well-documented risk factors of konzo. However, observational studies have failed to demonstrate the causal relationship between konzo and cyanide poisoning. Thiocyanate, the current marker of choice of cyanide exposure, may underestimate the actual level of cyanide poisoning in konzo patients as a larger amount of cyanide is detoxified via other unusual pathways in the context of protein malnutrition characterizing these patients. Furthermore, the appearance of konzo may be the consequence of the interplay of several factors including cyanide metabolites, nutritional deficiencies, psycho-emotional and geo-environmental factors, resulting in pathophysiologic phenomena such as excitotoxicity or oxidative stress, responsible for neuronal damage that takes place at sparse cellular and/or subcellular levels.

Plants with neurotoxic potential in undernourished subjects.

The consumption by humans of plants with potential to induce neurological disorders is widespread, but overt disease surfaces only when the subject's toxic threshold is exceeded. Excessive intake arising from food dependency in the setting of hunger, chronic undernutrition, vitamin deficiency, inadequate detoxication, or other individual susceptibility, can trigger acute encephalopathy (lychee, ackee fruits), sub-acute spastic paraparesis (grasspea, cassava root/leaves) or ataxic neuropathy (cassava root flour). While these disorders are very rarely encountered in high-income countries, they are not only common among impoverished populations but also often occur as outbreaks that impact a significant proportion of an affected community. Unfamiliarity with the adverse effects of plant toxins has sometimes led to the mistaken attribution of nutritional neurotoxic disease to a neurotropic viral or synthetic pesticidal etiology. The combination of human population growth, food and water insecurity, poverty and, with climate change, increased dependency on environmentally tolerant plants with neurotoxic potential, predictably may result in an increased prevalence of nutritional neurotoxic disorders, especially in certain parts of Africa and Asia.

Qualidade físico-química e sensorial da carne de frangos alimentados com mandioca (Manihot esculenta) / Chemical and sensorial quality of the meat of broiler fed with cassava meal (Manihot esculenta)

Objetivou-se avaliar as características químicas e sensoriais da carne de frango alimentados com raspa integral da mandioca (Manihot esculenta) em substituição parcial ao milho. Foram utilizadas 100 aves da linhagem pescoço pelado, alojadas em boxes, criadas de 1 a 90 dias, sendo utilizado cinco tratamentos representados pela raspa de mandioca (0, 10, 20, 30, 40%) em substituição ao milho nas rações experimentais. 10%, das aves foram abatidas para avaliação físico-química e sensorial, os resultados obtidos foram submetidos à análise de variância e regressão. Não houve efeito significativo (p>0,05) para as variáveis analisadas. Portanto a substituição parcial do milho pela raspa de mandioca em até 40% não alterou as características química e sensoriais da carne de frangos.

Konzo: a distinct neurological disease associated with food (cassava) cyanogenic poisoning.

Epidemics of neurodegenerative diseases putatively caused by food toxins have been reported in the tropics with no clear understanding of their pathogenetic mechanisms. These diseases include the disease named Konzo that has been well documented in sub-Sahara Africa, mostly among children and women of childbearing age. Outbreaks of Konzo have occurred in the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroun, and most recently in Zambia. The main clinical picture consists of a symmetrical, permanent and irreversible spastic paraparesis (motor neuron disease) with no signs of sensory or genitourinary impairments. Recently, cognitive impairments and neurodevelopmental delays have been reported among school-aged and very young children. The exact pathogenetic mechanisms of the disease remain unknown. Epidemiological studies consistently show an association between outbreaks of the disease and chronic dietary reliance on insufficiently processed cyanogenic cassava (manioc or tapioca). Biochemical and toxicological studies suggest that the metabolites of linamarin (α-Hydroxyisobutyronitrile ß-D-glucopyranoside, the main cassava cyanogen), notably cyanide (mitochondrial toxin), thiocyanate (AMPA chaotropic agent), and cyanate (protein carbamoylating agent) may play an important role in the pathogenesis of Konzo. Experimental data suggest that thiol-redox and protein- folding mechanisms may also be perturbed. Factors of susceptibility including genetics, poor nutrition, poverty and dietary cyanogen exposure, or their interactions have been suggested. Serological studies have ruled out the role of retroviruses such as the human lymphotropic viruses HIV-I/II or HTLV-I/II. Because there is no cure for Konzo, prevention of the disease remains of paramount importance. Prospects for cognitive rehabilitation still need to be explored and tested.

[A rare cause of optic neuropathy: Cassava]. / Une cause rare de neuropathie optique : le manioc.

INTRODUCTION: Cassava root is a staple food for almost 500 million people worldwide. Excessive consumption of it is a rare cause of optic neuropathy. METHOD: Ten patients diagnosed with cassava root related optic neuropathy were included in this retrospective study. Diagnostic criteria were a bilateral optic neuropathy preceded by significant cassava root consumption. Differential diagnoses were excluded through a neuro-ophthalmic examination, blood tests and a brain MRI. All patients had visual field examination and OCT retinal nerve fiber layer (RNFL) analysis as well as an evaluation of their cassava consumption. RESULTS: All patients had a bilateral optic nerve head atrophy or pallor predominantly located into the temporal sector. Visual field defects consisted of a central or cecocentral scotoma for all patients. RNFL showed lower values only in the temporal sector. Mean duration of cassava consumption prior to the appearance of visual symptoms was 22.7±11.2 years with a mean of 2.57±0.53 cassava-based meals per week. Cassava related optic neuropathy is possibly due to its high cyanide content and enabled by a specific amino-acid deficiency. CONCLUSION: Cassava root chronic consumption is a rare, underappreciated cause of optic neuropathy and its exact mechanism is still uncertain.

Reduced foodborne toxin exposure is a benefit of improving dietary diversity.

Naturally occurring foodborne toxins are common in subsistence diets of low-income human populations worldwide. Often, these populations rely on one or two staple foods for the bulk of their calories, making them more susceptible to chronic intake of certain toxins. Exposure to common foodborne toxins is associated with diverse conditions such as cancer, immunotoxicity, growth impairment, and neurological deficits. Interventions focused solely on reducing toxin levels have proven difficult to sustain. Using case studies of two foodborne toxins, aflatoxin and cassava cyanide, this article addresses the heightened risk of particular diseases from eating monotonous diets based in maize, groundnuts, and cassava: common in sub-Saharan Africa and parts of Asia. We also discuss the potential role of increased dietary diversity in counteracting these diseases. Increased dietary diversity can reduce consumption of toxins and increase intake of nutrients that could counteract the toxicity of such chemicals. In Qidong, China, a population that previously consumed a monotonous maize-based diet and increased dietary diversity since the 1980s has experienced a dramatic reduction in liver cancer mortalities. That liver cancer decreased as dietary diversity increased is the catalyst for the hypothesis that dietary diversity could have a direct impact on reducing health effects of foodborne toxins. Future research, agricultural development, and food policy reforms should take into consideration the multifaceted benefits associated with improved dietary diversity. Collaborations between toxicologists, nutritionists, and policymakers are important to development of sustainable interventions to reduce foodborne toxin exposure and promote health through increased dietary diversity.

Determinants of cognitive performance in children relying on cyanogenic cassava as staple food.

While risk factors for konzo are known, determinants of cognitive impairment in konzo-affected children remain unknown. We anchored cognitive performance (KABC-II scores) to serum levels of free-thyroxine (free-T4), thyroid-stimulating hormone (TSH), albumin, and motor proficiency (BOT-2 scores) in 40 children including 21 with konzo (median age: 9 years) and 19 without konzo (median age: 8 years). A multiple regression model was used to determine variables associated with changes in KABC-II scores. Age (ß: -0.818, 95% CI: -1.48, -0.152) (p = 0.018), gender (ß: -5.72; 95% CI: -9.87, -1.57 for females) (p = 0.009), BOT-2 score (ß: 0.390; 95% CI: 0.113, 0.667) (p = 0.008), and free-T4 (ß: 1.88; 95% CI: 0.009, 3.74) (p = 0.049) explained 61.1 % of variation in KABC-II scores. Subclinical hypothyroidism was not associated with poor cognition. A crude association was found between serum albumin and KABC-II scores (ß: 1.26; 95 % CI: 0.136, 2.39) (p = 0.029). On spot urinary thiocyanate reached 688 µmol/l in children without konzo and 1,032 µmol/L in those with konzo. Female gender and low serum albumin are risk factors common to cognitive and proportionally associated motor deficits in children exposed to cassava cyanogens. The two types of deficits may share common mechanisms.

Memory deficits associated with sublethal cyanide poisoning relative to cyanate toxicity in rodents.

Food (cassava) linamarin is metabolized into neurotoxicants cyanide and cyanate, metabolites of which we sought to elucidate the differential toxicity effects on memory. Young 6-8 weeks old male rats were treated intraperitoneally with either 2.5 mg/kg body weight (bw) cyanide (NaCN), or 50 mg/kg bw cyanate (NaOCN), or 1 µl/g bw saline, daily for 6 weeks. Short-term and long-term memories were assessed using a radial arm maze (RAM) testing paradigm. Toxic exposures had an influence on short-term working memory with fewer correct arm entries (F(2, 19) = 4.57 p < 0.05), higher working memory errors (WME) (F(2, 19) = 5.09, p < 0.05) and longer RAM navigation time (F(2, 19) = 3.91, p < 0.05) for NaOCN relative to NaCN and saline treatments. The long-term working memory was significantly impaired by cyanide with fewer correct arm entries (F(2, 19) = 7.45, p < 0.01) and increased working memory errors (F(2, 19) = 9.35 p < 0.05) in NaCN relative to NaOCN or vehicle treated animals. Reference memory was not affected by either cyanide or cyanate. Our study findings provide an experimental evidence for the biological plausibility that cassava cyanogens may induce cognition deficits. Differential patterns of memory deficits may reflect the differences in toxicity mechanisms of NaOCN relative to NaCN. Cognition deficits associated with cassava cyanogenesis may reflect a dual toxicity effect of cyanide and cyanate.

Neurotoxic effect of linamarin in rats associated with cassava (Manihot esculenta Crantz) consumption.

Cassava (Manihot esculenta Crantz) is a plant widely used for food consumption in different processed products in rural areas of Africa, Asia, and Latin America. Cassava is a good source of carbohydrates and micronutrients. However, if it is not adequately processed or the consumer has nutritional deficiencies, then its cyanogenic glycoside (i.e., linamarin and lotaustralin) content makes it potentially neurotoxic. In the present study, the neurotoxic effects of different concentrations of linamarin (0.075, 0.15, 0.22, and 0.30 mg/kg) contained in cassava juice were evaluated in the open field and swim tests to identify locomotor alterations in adult male Wistar rats. The linamarin concentration in cassava juice was determined by high-performance liquid chromatography, and the juice was administered intraesophageally for 28 days. The results suggested that the consumption of linamarin in cassava juice increased the number of crossings and rearings in the open field test and caused behavioral deficiency, reflected by lateral swimming, in the swim test on days 21 and 28 of treatment. These alterations are possibly related to neuronal damage caused by linamarin in cassava juice in structures of the central nervous system involved in motor processing.

Neuropsychological effects of konzo: a neuromotor disease associated with poorly processed cassava.

BACKGROUND: Konzo is an irreversible upper-motor neuron disorder affecting children dependent on bitter cassava for food. Although the neuroepidemiology of konzo is well characterized, we report the first neuropsychological findings. METHOD: Children with konzo in the Democratic Republic of Congo (mean age 8.7 years) were compared with children without konzo (mean age 9.1 years) on the Kaufman Assessment Battery for Children, second edition (KABC-II), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2). Both groups were also compared with normative KABC measures from earlier studies in a nearby nonkonzo region. RESULTS: Using a Kruskal-Wallis test, children with konzo did worse on the KABC-II simultaneous processing (visual-spatial analysis) (K [1] = 8.78, P = .003) and mental processing index (MPI) (K [1] = 4.56, P = .03) than children without konzo. Both konzo and nonkonzo groups had poorer KABC sequential processing (memory) and MPI relative to the normative group from a nonkonzo region (K [2] = 75.55, P < .001). Children with konzo were lower on BOT-2 total (K [1] = 83.26, P < .001). KABC-II MPI and BOT-2 total were predictive of konzo status in a binary logistic regression model: odds ratio = 1.41, P < .013; 95% confidence interval 1.13-1.69. CONCLUSIONS: Motor proficiency is dramatically affected, and both children with and without konzo have impaired neurocognition compared with control children from a nonoutbreak area. This may evidence a subclinical neurocognitive form of the disease, extending the human burden of konzo with dramatic public health implications.

Manioc flour consumption as a risk factor for lead poisoning in the Brazilian Amazon.

Recent studies reported elevated blood lead (Pb) levels in riparian populations of the Amazon. For this reason, the aim of the present study was to assess the risk to riparians in the Brazilian Amazon to Pb exposure due to the intake of contaminated manioc flour. Lead levels were determined in whole blood (n = 74) and in manioc flour samples (n = 30) in three different communities. Mean blood Pb levels were 16.8 µg/dl, with individuals living in Açaituba presenting the highest mean blood Pb level (22.4 µg/dl), followed by Nova Canaã (17.3 µg/dl) and Santa Cruz (9.8 µg/dl). The minimum blood Pb level found was 0.83 µg/dl and the maximum was 44.3 µg/dl. The estimated daily intake (EDI) was calculated and compared to the benchmark dose lower confidence limit (BMDL) for neurotoxicity. Mean Pb in manioc flour was 0.34 µg/g while EDI was 79 µg/d, corresponding to 260% of the BMDL (varying from 168 to 308%). This finding is of great importance since this high EDI may exert adverse effects on the nervous system of this population. Manioc flour intake may thus present considerable risk of Pb exposure in this region. Risk management strategies and further studies on adverse effects in this population are needed.

Moisture-pressure combination treatments for cyanide reduction in grated cassava.

Several cyanide-associated health disorders have been linked with frequent consumption of mildly toxic cassava (Manihot esculenta crantz) products in individuals on a low-protein diet. Production of bread from cassava often involves application of prolonged physical pressure (pressing) to the freshly grated root for several hours. This study aimed to determine effects of pressure and wetting on grated cassava. Six treatments were applied: confining pressure for 12 h, wetting for 4 h at 25 °C, 2 h at 25 °C, 2 h at 40 °C, and 2 h at 50 °C, or each of the above followed by pressure for 12 h. Treatments released cyanide from samples in the order: 2-h wet at 50 °C + pressing >4-h wet at 25 °C + pressing = 2-h wet at 40 °C + pressing >2-h wet at 25 °C + pressing = 4-h wet at 25 °C >12-h pressing. Wetting for 2 h at 50 °C followed by pressure for 12 h reduced cyanide levels by at least 20% more than that of any other treatment. The combination of moisture and pressure enhanced the contact time between linamarin and linamarase to increase the release of hydrogen cyanide.