Desire Tshala-Katumbay

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.

Analysis of motor pathway involvement in Konzo using transcranial electrical and magnetic stimulation

To elucidate the involvement of motor pathways in konzo, 21 konzo subjects (mean age 22 years) underwent transcranial electrical stimulation (TES) in 1998. Fourteen konzo subjects (mean age 21 years) underwent transcranial magnetic stimulation (TMS) in 2000. Three subjects underwent both TES and TMS. Motor evoked potentials (MEPs) were recorded in the abductor pollicis brevis (APB) muscle with TES, and in the abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with TMS. APB‐MEPs were normal in 2 of 21 subjects and absent in 9; central conduction time (CCT) was prolonged in 10. Resting ADM‐MEPs were absent in 9 of 14 subjects with clinically preserved upper limbs. Among these nine, seven subjects responded after facilitation. Most subjects (13 of 14) failed to show TA‐MEPs. Of the subjects who underwent both types of stimulation, one had normal TES‐MEP but abnormal ADM‐MEP with TMS. These findings suggest involvement of both corticomotoneurons and motor descending pathways in konzo.

Probing Mechanisms of Axonopathy. Part II: Protein Targets of 2,5-Hexanedione, the Neurotoxic Metabolite of the Aliphatic Solvent n-Hexane

Neuroprotein changes in the spinal cord of rodents with aliphatic gamma-diketone axonopathy induced by 2,5-hexanedione (2,5-HD) are compared with those reported previously in aromatic gamma-diketone-like axonopathy induced by 1,2-diacetylbenzene (1,2-DAB). Sprague-Dawley rats were treated intraperitoneally with 500 mg/kg/day 2,5-HD, equimolar doses of 2,3-hexanedione (negative control), or an equivalent amount of saline containing 50% dimethyl sulfoxide (vehicle), 5 days a week, for 3 weeks. Analysis of the lumbosacral proteome by 2-dimensional differential in-gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight/tandem mass spectrometry revealed 34 proteins markedly modified by 2,5-HD of which neurofilament triplet L, gelsolin, protein disulfide isomerase, glutathione S-transferase, nicotinamide adenine dinucleotide (reduced) dehydrogenase 1 alpha, pyruvate kinase, and fatty acid synthase were also modified by 1,2-DAB. The expression of proteins involved in maintaining the physical integrity of the cytoskeleton or controlling the redox and protein-folding mechanisms was reduced, whereas that of proteins supporting energy metabolism was mainly increased. The similarity of the neuroproteomic patterns of 2,5-HD and 1,2-DAB axonopathy suggests common biomarkers and/or mechanisms of neurotoxicity associated with exposure to their parent chemicals, namely the industrial solvents n-hexane and 1,2-diethylbenzene, respectively.

Cassava food toxins, konzo disease, and neurodegeneration in sub-Sahara Africans

Endemoepidemic neurodegenerative diseases putatively caused by food toxins have been reported around the globe with no clear understanding of their pathogenetic mechanisms. These diseases include the amyotrophic lateral sclerosis/parkinsonism dementia complex among the Guamanians; neurolathyrism among Europeans, Indians, and populations of the Horn of Africa; and tropical ataxic neuropathy or konzo among sub-Sahara Africans.1,2 We focus on the molecular determinants of susceptibility to konzo, a poorly known self-limited and irreversible upper motor neuron disease (spastic paraparesis) highly prevalent in Congo-Kinshasa, Mozambique, Tanzania, Central African Republic, Angola, and Cameroon. The main clinical picture consists of a symmetrical, permanent, and irreversible spastic paraparesis with no signs of sensory or genitourinary impairments.2,3 Severely affected individuals may present with a tetraparesis and pseudobulbar signs. The disease konzo was named after a fetish used by the “Yaka” population of Congo-Kinshasa. The World Health Organization has adopted the following epidemiologic criteria for the disease: 1) an abrupt onset (<1 week) of weakness in legs and a nonprogressive course of the disease in a formerly healthy person, 2) a symmetrical spastic abnormality when walking and/or running, and 3) bilaterally exaggerated knee and/or ankle jerks without signs of disease of the spine.

On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure.

Konzo is a self-limiting central motor-system disease associated with food dependency on cassava and low dietary intake of sulfur amino acids (SAA). Under conditions of SAA-deficiency, ingested cassava cyanogens yield metabolites that include thiocyanate and cyanate, a protein-carbamoylating agent. We studied the physical and biochemical modifications of rat serum and spinal cord proteins arising from intoxication of young adult rats with 50-200mg/kg linamarin, or 200mg/kg sodium cyanate (NaOCN), or vehicle (saline) and fed either a normal amino acid- or SAA-deficient diet for up to 2 weeks. Animals under SAA-deficient diet and treatment with linamarin or NaOCN developed hind limb tremors or motor weakness, respectively. LC/MS-MS analysis revealed differential albumin carbamoylation in animals treated with NaOCN, vs. linamarin/SAA-deficient diet, or vehicle. 2D-DIGE and MALDI-TOF/MS-MS analysis of the spinal cord proteome showed differential expression of proteins involved in oxidative mechanisms (e.g. peroxiredoxin 6), endocytic vesicular trafficking (e.g. dynamin 1), protein folding (e.g. protein disulfide isomerase), and maintenance of the cytoskeleton integrity (e.g. α-spectrin). Studies are needed to elucidate the role of the aformentioned modifications in the pathogenesis of cassava-associated motor-system disease.

Neuro-ophthalmologic findings in konzo, an upper motor neuron disorder in Africa.

Purpose To investigate the neuro-ophthalmological manifestations in konzo, a non-progressive symmetric spastic para/tetraparesis of acute onset associated with consumption of insufficiently processed bitter cassava roots combined with a low protein intake. Methods Twenty-one Congolese konzo patients underwent neuro-ophthalmological investigations including visual acuity testing, assessment of light pupillary reflexes, evaluation of ocular motility and deviation, direct ophthalmoscopy, and visual field perimetry. Objective refraction including retinoscopy and keratometry, and slit-lamp biomicroscopy were also done. Results Five patients had visual impairment, and 14 had temporal pallor of the optic disc. Fourteen presented visual field defects, the most frequent being concentric constriction and peripheral defects. Overall, 11 subjects had symptoms qualifying for the diagnosis of optic neuropathy. Two had spontaneous pendular nystagmus in primary position of gaze. Visual field defects and pallor of the optic discs were found in mild, moderate and severe forms of konzo. No correlation was found between the severity of the motor disability of konzo and the extent of visual field loss. Conclusions Konzo was associated with optic neuropathy and a few patients had nystagmus. Although the etiopathogenesis of this optic neuropathy remains to be elucidated, the symmetry of the involvement suggests a toxic origin. We suggest that cyanide causes the neuro-ophthalmological damage in konzo. However, the optic neuropathy in konzo patients does not resemble the features of the epidemic optic neuropathy in Tanzania, Cuba or Nigeria, Lebers hereditary optic neuropathy, tobacco amblyopia or vitamin B deficiency.

EEG findings in konzo: A spastic para/tetraparesis of acute onset

EEGs were recorded on 21 konzo subjects (median age 17 years) and 13 of their close healthy relatives (median age 41 years). Konzo subjects were clinically selected and classified according to the WHO criteria. Standard waking EEG recordings were performed according to the International 10-20 System. Slowing of the background activity with theta activity was the most common abnormality (57%). The more clinically severely affected the konzo subject, the more often generalized EEG abnormalities were seen. None of these abnormalities were considered specific for konzo nor related to the duration of the disorder; however, the findings indicate involvement of the cerebral cortex.

Probing Mechanisms of Axonopathy. Part I: Protein Targets of 1,2-Diacetylbenzene, the Neurotoxic Metabolite of Aromatic Solvent 1,2-Diethylbenzene

Motor neuron axonopathy in diseases such as amyotrophic lateral sclerosis can be modeled and probed with neurotoxic chemicals that induce similar patterns of pathology, such as axonal spheroids that represent focal accumulation of anterogradely transported neurofilaments (NFs). The aromatic gamma-diketone-like 1,2-diacetylbenzene (1,2-DAB), but not its 1,3-DAB isomer, reacts with epsilon-amino- or sulfyhydryl groups of (neuro)proteins, forms adducts, and causes NFs to accumulate at proximal sites of elongate motor axons. We exploit the protein-reactive properties of neurotoxic 1,2-DAB versus the nonprotein-reactive properties of non-neurotoxic 1,3-DAB to unveil proteomic changes associated with this type of pathology. We used two-dimensional differential in-gel electrophoresis (2D-DIGE), matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry to analyze the lumbosacral spinal cord proteome of adult Sprague-Dawley rats treated systemically with 20 mg/kg/day 1,2-DAB, equimolar dose of 1,3-DAB, or equivalent volume of vehicle (saline containing 2% acetone), 5 days a week, for 2 weeks. 1,2-DAB significantly altered the expression of protein disulfide isomerase, an enzyme involved in protein folding, and gelsolin, an actin-capping and -severing protein. Modifications of these two proteins have been incriminated in the pathogenesis of nerve fiber degeneration. Protein-reactive and neurotoxic 1,2-DAB appears to be excellent tool to dissect mechanisms of nerve fiber (axon) degeneration.

Visual Evoked Potentials in Konzo, a Spastic Paraparesis of Acute Onset in Africa

Aim: To assess whether or not visual evoked potentials (VEPs) are abnormal in konzo, a para/tetraparesis of sudden onset, and to correlate the findings to the clinical picture of the disorder. Methods: VEPs were recorded in 23 patients (9 men and 14 women, mean age: 23 ± 10 years) suffering from konzo, and 38 healthy subjects (20 men and 18 women, mean age: 27 ± 15 years). The mean P100 latencies and peak-to-peak N75-P100 amplitudes of each eye were measured and compared in the two groups. The mean interocular P100 latency and amplitude differences were calculated and also compared. Results: VEPs were abnormal in 11/23 patients (48%) consisting of P100 prolongation (7 subjects), absence of P100 wave (2 subjects) or an atypical waveform (2 subjects). The mean P100 latency value of the konzo group was significantly increased as compared with the mean (+ 2.5 SD) of the reference values from healthy subjects (p < 0.05). There was a statistically significant decrease of amplitude in konzo patients compared to normal subjects (p < 0.05) with, however, only 2 patients outside the 95% confidence limits. Six patients (27%) had abnormal VEPs despite normal visual acuity. These abnormalities were symmetric and a relation could be found between neither the duration nor the severity of the disease and the VEP perturbation. Conclusion: The main features of these abnormalities are delayed P100 latency and decreased amplitude. These findings indicate involvement of visual pathways and seem to suggest the presence of axonal loss in the prechiasmal visual pathways in konzo. This study provides evidence that the neurodamage in konzo extends to the visual pathways.

A global perspective on the influence of environmental exposures on the nervous system

Economic transitions in the era of globalization warrant a fresh look at the neurological risks associated with environmental change. These are driven by industrial expansion, transfer and mobility of goods, climate change and population growth. In these contexts, risk of infectious and non-infectious diseases are shared across geographical boundaries. In low- and middle-income countries, the risk of environmentally mediated brain disease is augmented several fold by lack of infrastructure, poor health and safety regulations, and limited measures for environmental protection. Neurological disorders may occur as a result of direct exposure to chemical and/or non-chemical stressors, including but not limited to, ultrafine particulate matters. Individual susceptibilities to exposure-related diseases are modified by genetic, epigenetic and metagenomic factors. The existence of several uniquely exposed populations, including those in the areas surrounding the Niger Delta or north western Amazon oil operations; those working in poorly regulated environments, such as artisanal mining industries; or those, mostly in sub-Saharan Africa, relying on cassava as a staple food, offers invaluable opportunities to advance the current understanding of brain responses to environmental challenges. Increased awareness of the brain disorders that are prevalent in low- and middle-income countries and investments in capacity for further environmental health-related research are positive steps towards improving human health.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.