Etiology of Konzo, epidemic spastic paraparesis associated with cyanogenic glycosides in cassava: Role of thiamine deficiency?

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Abstract

Konzo is a syndrome of symmetrical, non-progressive, non-remitting spastic paraparesis occurring in epidemic and endemic forms in several countries in Africa, invariably associated with monotonous consumption of inadequately processed bitter cassava roots (Manihot esculenta) with very minimal protein supplementation.

Despite numerous epidemiological, clinical and biochemical studies by authors in several countries aimed at elucidating the etiological mechanisms of Konzo, the etiology remains unknown. High cyanide consumption with low dietary sulfur intake due to almost exclusive consumption of insufficiently processed bitter cassava roots was proposed as the cause of Konzo, but there has been no evidence of a causal association between cyanide consumption and Konzo.

In this paper a new etiological mechanism of thiamine deficiency is presented, based on detailed review of the epidemiological, clinical and biochemical features of Konzo. It is postulated that in Konzo patients, a severe exacerbation of thiamine deficiency results from the inactivation of thiamine that occurs when, in the absence of dietary sulfur-containing amino acids; the sulfur in thiamine is utilized for the detoxification of cyanide consumed in improperly processed bitter cassava. Thiamine is known to be rendered inactive when the sulfur in its thiazole moiety is combined with hydrogen cyanide.

This hypothesis may stimulate studies examining the role of thiamine in the etiology of Konzo, and may lead to the formulation of strategies for the prevention and treatment of this debilitating disease.

Introduction

Konzo is an upper motor neuron disease, characterized by abrupt onset of symmetrical, non-progressive, non-remitting spastic paraparesis [1] occurring in epidemic and endemic forms in several countries in eastern, central and southern Africa. Epidemics of Konzo have been reported from Tanzania [2], from the Central African Republic [3] and from Mozambique [4], [5]; where it was referred to as Mantakassa [6]. Epidemic outbreaks and sporadic, endemic cases have also been reported from Zaire [7]. By 1994, almost 4000 cases of Konzo had been confirmed in studies and reports from Africa [8], with more than 1000 cases in one epidemic in Mozambique [6]. Several hundreds of cases have been reported since [9], [10], and the disease still continues to be prevalent in endemic areas [11].

The diet in patients who succumb to Konzo in all countries from where it has been described is uniformly similar. There are several weeks of almost exclusive, monotonous consumption of improperly processed bitter cassava roots, with very minimal protein supplementation; often associated with famine or war. Eighty percent of Konzo patients in Zaire denied eating animal protein prior to succumbing to the disease [7]. The frequency of food intake during the epidemics may approach starvation levels, with some families eating only once a day [12].

Despite several studies aimed at elucidating the etiological mechanisms of Konzo, the etiology remains unknown. High cyanide and low sulfur dietary intake due to exclusive consumption of insufficiently processed bitter cassava roots have been proposed as the cause of Konzo, [2], [8], [13] but as discussed below; there has been no clear evidence of a causal association.

Cyanide may be metabolized to cyanate [14]. Tor-Agbidye et al. demonstrated a significant increase in the plasma cyanate concentrations of sulfur amino acid-deficient rats treated with potassium cyanide [15]. Prolonged cyanate treatment is known to induce neuropathologic abnormalities in primates and humans [16], [17]. It therefore appeared plausible that the metabolism of cyanide to cyanate may lead to the development of neurological disease in cassava-dependent populations. It has however been suggested that the predominantly myelinotoxic effects of cyanate toxicity [16] are more closely related to cassava-associated ataxic myelopathy than to Konzo [15].

An etiological role for retroviral infection in Konzo was suggested [18], with one report suggesting that cyanide exposure may trigger the myelopathic effects of HTLV 1 infection [19]. However, HTLV-1 associated myelopathy is characterized by paraparesis of gradual onset and progressive course, while the paraparesis in Konzo is clinically different with a sudden onset and a non-progressive course. Human retroviruses have been conclusively shown to be uninvolved in the causation of Konzo [20].

A nutritional deficiency was considered, given that cassava was a poor source of vitamin B. This consideration was however dismissed because there were no muco-cutaneous abnormalities suggestive of riboflavin deficiency detected on physical examination in Konzo patients [18]. Vitamins B12 and B6 were tested as part of an extensive battery of hematological and biochemical tests in patients with Konzo and found to be unremarkable [1].

There is no known prevention or treatment for Konzo, since the etiology is unknown. The need for therapy and prevention is of particular importance and urgency, given the fact that Konzo is a severe disease with very significant disability, preferentially affecting children between 4 and 12 years and women of reproductive age [6], [18]. It is the most common cause of gait disability in these age groups in the affected areas.

Evidence from the literature against a causal role for cyanide intoxication in the etiology of Konzo is discussed in this paper. A new etiological hypothesis of thiamine deficiency is presented, and evidence supporting a role for thiamine deficiency in the etiology of Konzo is discussed.

Section snippets

Cassava diet and cyanide consumption in patients with Konzo

Cassava produces linamarin, a cyanogenic glycoside which is located in the plant vacuole. The parenchyma of cassava roots contains different amounts of linamarin, depending on the plant variety. Bitter cassava species have high linamarin content in the root parenchyma and have to be processed properly prior to eating. The enzyme linamarase, located in the cell wall; catalyzes the hydrolysis of linamarin to form acetone cyanohydrin, which is then hydrolyzed to hydrogen cyanide and acetone.

Evidences against the etiological hypothesis of cyanide intoxication

The cyanide hypothesis suggested that Konzo is caused by cyanide intoxication from insufficiently processed bitter cassava in combination with a sulfur amino acid-deficient diet [8], [13], [22], with the high cyanide intake indicated by high serum and urinary thiocyanate levels. Several arguments can be advanced against the cyanide hypothesis:

  • i.

    Thiocyanate levels are similar in cases and controls

High serum and urinary thiocyanate levels, while supporting the fact that the consumption of

A new hypothesis of thiamine deficiency

It is postulated in this paper that Konzo is a thiamine-deficiency state resulting from the inactivation of thiamine that occurs when, in the absence of dietary sulfur-containing amino acids; the sulfur in thiamine is utilized for the detoxification of cyanide consumed in improperly processed bitter cassava.

There is widespread thiamine deficiency in susceptible population

The cassava-induced inactivation of thiamine is more likely to lead to clinical thiamine-deficiency syndromes in populations with marginal thiamine intake and low baseline thiamine levels. This appears to be the case in Zaire, where there is evidence of low thiamine intake below 60% of dietary reference intake [31] and low baseline thiamine levels assessed by determination of the activation coefficient of erythrocyte transketolase, which showed that 51% of apparently healthy residents in Zaire

Discussion

In the last 7 decades, numerous epidemiological, clinical and biochemical studies by authors in several countries have been conducted in an effort to unravel the etiological mechanisms of Konzo. Despite these efforts, the etiology had remained elusive.

In this paper a new etiological mechanism of thiamine deficiency is presented, based on detailed review of the epidemiological, clinical and biochemical features of Konzo. It is postulated that Konzo is a thiamine-deficiency state occurring in

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