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Rich Van Konynenburg, Ph.D.
Independent Researcher and Consultant

[LYMEINFO NOTE: Dr. Van Konynenburg is a proponent of the Glutathione Depletion--Methylation Cycle Block hypothesis for the pathogenesis of CFS. To read more about this theory and treatment, see the links to the left of this page.]

Review of the Glutathione Depletion-Methylation Cycle Block (GD-MCB) Hypothesis for CFS [1]

1. The person inherits a genetic predisposition (polymorphisms in several of certain genes) toward developing CFS. (This genetic factor is more important for the sporadic cases than for the cluster cases of CFS.)
2. The person then experiences some combination of a variety of possible stressors (physical, chemical, biological, psychological/emotional) that place demands on glutathione.
3. Glutathione levels drop, producing oxidative stress, removing protection from B12, allowing toxins to accumulate, and shifting the immune response to Th2.
4. Toxins react with B12, lowering the rate of formation of methylcobalamin. Lack of sufficient methylcobalamin inhibits methionine synthase, placing a partial block in the methylation cycle.
5. Sulfur metabolites drain through the transsulfuration pathway excessively, pass through sulfoxidation, and are excreted.
6. A vicious circle is established between the methylation cycle block and glutathione depletion, and the disorder becomes chronic.
Depletion of glutathione by Borrelia burgdorferi

1. Bb requires cysteine for its metabolism [2].
2. Cysteine diffuses passively into Bb from its host, i.e. there is no active transporter protein [2].
3. Bb uses cysteine in the synthesis of several of its essential enzymes: Osp A, Osp B, CoASH, a hemolysin, and others [2,3].
4. Bb does not use glutathione for its redox control. Instead, it uses reduced Coenzyme A (CoASH) [4].
5. Cysteine is the rate-limiting amino acid for the synthesis of glutathione in humans, so that depletion of cysteine will produce depletion of glutathione [5].
6. Bb lowers the cysteine and glutathione levels in its human host, and inhibits the activity of glutathione peroxidase [6].
7. Low glutathione and low activity of glutathione peroxidase allow a rise in hydrogen peroxide concentration and oxidative stress [7].
8. Elevation of hydrogen peroxide causes Bb to assume its cyst form [8], in which it is less vulnerable to antibiotics [9].
New hypothesis for a link between Lyme disease and chronic fatigue syndrome

1. Borrelia burgdorferi (Bb) deplete glutathione in the host.
2. For a person who is genetically susceptible to developing CFS, this provides a link to the GD-MCB hypothesis for CFS and is one of the possible routes into this disorder.
3. If Bb and its biotoxin were not eliminated, Lyme disease and CFS would coexist in the host, and this would constitute "chronic Lyme disease."
4. If Bb and its biotoxin [10] were eliminated, but the methylation cycle block continued, the person would continue to be ill with CFS. This would constitute "post-Lyme disease syndrome," which would be analogous to the other post-infective fatigue syndromes [11].
5. If Bb and its biotoxin were eliminated, and the methylation cycle block was lifted, I believe it is likely that the person would become well.
In addition,

6. Perhaps the Borrelia burgdorferi toxin is one of the toxins that will react with vitamin B12. Mold toxins have been implicated in such reactions, but no data were cited [12,13].

1. Van Konynenburg, R.A., "Glutathione Depletion.Methylation Cycle Block, A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome," poster paper, 8th Intl. IACFS Conf. on CFS, Fibromyalgia, and Other Related Illnesses, Fort Lauderdale, FL, January 10-14, 2007 LINK.
2. Sambri, V., and Cevenini, R., Incorporation of cysteine by Borrelia burgdorferi and Borrelia hersii, Can. J. Microbiol. 38: 1016-1021 (1992).
3. Williams, L.R., and Austin, F.E., Hemolytic activity of Borrelia burgdorferi, Infection and Immunity 60(8): 3224-3230 (1992).
4. Boylan, J.A., Hummel, C.S., Benoit, S., Garcia-Lara, J., Treglown-Downey, J., Crane, E.J., III, and Gherardini, F.C., Borrelia burgdorferia bb0728 encodes a coenzyme A disulphide reductase whose function suggests a role in intracellular redox and the oxidative stress response, Molecular Microbiol. 59(2), 475-486 (2006).
5. Griffith, O.W., Biologic and pharmacologic regulation of mammalian glutathione synthesis, Free Radic Biol Med. 1999 Nov;27(9-10):922-35.
6. Pancewicz, S.A., Skrzydleweska, E., Hermanowska-Szpakowicz, T., Zajkowska, J., and Kondrusik, M., Role of reactive oxygen species (ROS) in patients with erythema migrans, an early manifestation of Lyme borreliosis, Med. Sci. Monit. 7(6), 1230-1235
7. Levine, S.A., and Kidd, P.M., Antioxidant Adaptation, Its Role in Free Radical Pathology, Allergy Research Group, San Leandro, CA (1985).
8. Murgia, R., and Cinco, M., Induction of cystic forms by different stress conditions in Borrelia burgdorferi, APMIS 112, 57-62 (2004).
9. Kersten, A., Poitschek, C., Rauch, S., and Aberer, E., Effects of penicillin, ceftriaxone and doxycycline on morphology of Borrelia burgdorferi, Antimicrob. Agents Chemother. 39(5), 1127-1133 (1995).
10. Shoemaker, R., Schaller, J., and Schmidt, P., Mold Warriors, Gateway Press, Baltimore (2005).
11. Hickie, I. Davenport, T., Wakefield, D, Vollmer-Conna, U., Cameron, B., Vernon, S.D., Reeves, W.C., Lloyd, A., Dubbo Infection Outcomes Study Group, Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study, BMJ. 2006 Sep 16;333(7568):575. Epub 2006 Sep 1.
12. Anyanwu, E.C., Morad, M., and Campbell, A.W., Metabolism of mycotoxins, intracellular functions of vitamin B12, and neurological manifestations in patients with chronic toxigenic mold exposures. A review, ScientificWorldJournal 4, 736-745 (2004).
13. Anyanwu, E.C., and Kanu, I., Biochemical impedance on intracellular functions of vitamin B12 in chronic toxigenic mold exposures, ScientificWorldJournal 7:1649-57 (2007).

*The author has kindly given his permission to reprint this article at LymeInfo.