Impaired Thiamine Metabolism in Amyotrophic Lateral Sclerosis and Its Potential Treatment With Benfotiamine: A Case Report and a Review of the Literature

Abstract

Homogenates of brain tissue from the frontal cortex at autopsy in patients with amyotrophic lateral sclerosis (ALS) showed dramatically reduced levels of the enzyme thiamine pyrophosphatase (TPPase), the enzyme responsible for the conversion of thiamine pyrophosphate (TPP) to thiamine monophosphate (TMP). Additionally, free thiamine (vitamin B1) and TMP levels have been shown to be significantly reduced in the plasma and cerebral spinal fluid (CSF) of patients with ALS. These findings suggest that there is impaired thiamine metabolism in patients with ALS. Impaired thiamine metabolism decreases adenosine triphosphate (ATP) production and is a well-established cause of neurodegeneration. Decreased levels of TPPase, resulting in decreased levels of TMP in the cells of the frontal cortex, might account for the focal neurodegenerative changes observed in motor neurons in ALS. Benfotiamine, a safe, lipid-soluble, highly absorbable thiamine analogue, significantly raises free thiamine, TMP, and TPP levels in the blood. A case in which benfotiamine may have positively impacted the symptoms of a patient with ALS is presented. The use of benfotiamine in patients with ALS appears to be a promising therapeutic option. Considering the severity and the lack of satisfactory treatment options associated with this disease, more research on the effects of benfotiamine on the course of ALS is urgently needed.

Keywords: amyotrophic lateral sclerosis; benfotiamine; motor neuron disease; neurodegeneration; neurodegenerative disease; thiamin; thiamine; thiamine deficiency; vitamin b1; vitamin b1 deficiency.

Figure 1. Thiamine metabolism.

In healthy thiamine metabolism, free thiamine is converted to thiamine pyrophosphate (TPP) through the actions of thiamine pyrophosphokinase (TPK). TPP is converted to thiamine monophosphate (TMP) via the actions of thiamine pyrophosphatase (TPPase). TMP is converted to free thiamine via the actions of thiamine monophosphatase (TMPase). TPP is essential for adenosine triphosphate (ATP) production and normal cellular functioning. It acts as a coenzyme for enzymes of the Krebs cycle and other metabolic pathways. TPP may also be converted to thiamine triphosphate and adenosine thiamine triphosphate. The biological significance of these thiamine triphosphate forms does not appear to be related to ATP production and their functions are not well understood.

Figure 2. The potential effect of benfotiamine on impaired thiamine metabolism in ALS.

Benfotiamine increases levels of free thiamine, TMP, and TPP thereby improving thiamine metabolism with the likely effect of countering the impaired thiamine metabolism that occurs in ALS due to decreased activity of thiamin pyrophosphatase.