Lower serum levels of selenium, copper, and zinc are related to neuromotor impairments in children with konzo

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Highlights

  • Selenium deficiency is a risk factor for motor impairments in konzo.

  • Dual effects of cyanide and low selenium may mediate oxidative damage in konzo.

  • Selenoproteins with antioxidant and cyanide-scavenging properties may help prevent konzo.

Abstract

We assessed the relationship between key trace elements and neurocognitive and motor impairments observed in konzo, a motor neuron disease associated with cassava cyanogenic exposure in nutritionally challenged African children. Serum concentrations of iron, copper, zinc, selenium, and neurotoxic lead, mercury, manganese, cadmium, and cobalt were measured in 123 konzo children (mean age 8.53 years) and 87 non-konzo children (mean age 9.07 years) using inductively coupled plasma mass spectrometry (ICPMS). Concentrations of trace elements were compared and related to performance scores on the Kaufman Assessment Battery for Children, 2nd edition (KABC-II) for cognition and Bruininks–Oseretsky Test, 2nd edition (BOT-2) for motor proficiency. Children with konzo had low levels of selenium, copper, and zinc relative to controls. Selenium concentration significantly correlated with serum 8,12-iso-iPF-VI isoprostane (Spearman r = 0.75, p < 0.01) and BOT-2 scores (r = 0.31, p = 0.00) in children with konzo. Elemental deficiency was not associated with poor cognition. Mean (SD) urinary level of thiocyanate was 388.03 (221.75) μmol/l in non-konzo compared to 518.59 (354.19) μmol/l in konzo children (p < 0.01). Motor deficits associated with konzo may possibly be driven by the combined effects of cyanide toxicity and Se deficiency on prooxidant mechanisms. Strategies to prevent konzo may include dietary supplementation with trace elements, preferentially, those with antioxidant and cyanide-scavenging properties.

Introduction

Epidemiological studies consistently show an association between poor nutrition, chronic dietary reliance on poorly processed bitter cassava, a staple for millions of people under the tropics, and outbreaks of a distinct motor neuron disease known as konzo [1], [2], [3], [4], [5], [6]. A recent study indicates that children from konzo-affected areas may also present with poor cognition [7]. Whether the motor and cognition deficits associated with the disease share the same mechanisms has yet to be elucidated to better inform policy and strategies for the prevention of the cassava-associated neurological disease. We recently found a significant correlation between serum levels of 8,12-iso-iPF2α isoprostane, a well-established marker of oxidative damage, and poor cognition in children affected by konzo [8]. Our first and plausible explanation was that oxidative damage was induced by cyanide poisoning through the ingestion of poorly processed bitter cassava. Alternative explanations include but not limited to nutritional deficiencies and/or yet to be uncovered exposures to neurodevelopmental toxicants [8]. While permissive limits of potentially neurotoxic elements in blood and levels of essential elements seem to be established, little is known about elemental toxicity threats which may vary under conditions of co-morbid conditions common to most of the developing countries. For example, deficiencies in select essential elements may increase the toxicity of lead. Co-exposures may influence the levels of essential and/or potentially toxic elements in blood and modify their respective kinetic and biological (toxicity) behaviors [9].

A recent study raised concerns over exposures to toxic elements in the Democratic Republic of Congo (DRC) [10]. However, studies on the human health effects resulting from such exposures, within the context of malnutrition, are still lacking. In this study, we sought to determine the relative contribution of essential versus potentially neurotoxic elements to the neurocognitive impairments observed in children with konzo.

Section snippets

Subjects

A detailed description of the study population including children with konzo (N = 123) or without the disease (N = 87; gender and tentatively age-matched to those with konzo) has been provided in a previous publication by our study group [7]. Children with the diagnosis of konzo had to fulfill the WHO criteria for the disease i.e. a visible symmetric spastic abnormality of gait while walking or running; a history of onset of less than 1 week followed by a non-progressive course in a formerly healthy

Overall neurocognitive performances and biochemical profiles

Children with konzo had a mean (SD) BOT-2 motor proficiency score of 24.86 (6.00) relative to 35.32 (7.54) in children with no konzo, and a mean KABC-II score of 58.51 (8.16) relative to 61.40 (9.08) in those with no konzo (p  0.02 for all comparisons). Urinary levels of thiocyanate ranged from 34.40 to 1032.00 or 17.20 to 1720.00 μmol/l in non-konzo or konzo children, respectively; with a mean (SD) of 388.03 (221.75) in non-konzo versus 518.59 (354.19) μmol/l in konzo children (p < 0.01). One

Discussion

We report, for the first time, low serum levels of Se, Cu, and Zn in proportion to motor deficits in children with konzo. Low levels of these trace elements may be explained by low dietary intake in the context of chronic malnutrition. Concomitant changes in serum levels of the aforementioned elements and perhaps several other trace elements explored in our study group may also reflect the interplay between individual elemental metabolic pathways [12]. We also showed stunting is associated with

Conflict of interest

No conflict of interest.

Acknowledgment

We would like to thank M. Duffy in the Elemental Analysis Core at OHSU for sample preparation, measurements, data analysis as well as for contributing to the method in this paper. We also thank the community of Kahemba as well as Dr. Jean-Jacques Kaniki, Dr. Sombo Marie-Therese, and Mr. Kambale Kikandau for their participation in the current research project. This work was funded by the National Institutes of Health (grant number NIEHS/FICR01ES019841) which had no role in study design, data

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