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Participation in Genetic Study

led by Dr. Maritha Kotze

 will be posted here as they
become available for dissemination



The significance of this project lies in the recognition of a possible new subtype of MS, which may be treatable by iron supplementation. Further studies of patients with this phenotype may provide the missing link between environmental triggers (e.g. infections, hormones, heavy metal intoxication), autoimmunity and genetic factors in the etiology of MS, via the heme biosynthesis pathway.

As evidenced by several years of research, family history, and a long series of laboratory tests, this particular form of MS appears to be hereditary and biochemical. The nervous system damage may be related to a derangement of heme synthesis in the liver during periods of anemia.

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Current Research Status


Dr. Maritha Kotze,  managing director of GeneCare Molecular Genetics and a supervisor of PhD candidates at the University of Stellenbosch in South Africa, is leading the attempt to identify a gene responsible for "hereditary biochemical multiple sclerosis" (HBMS). Roberta (Bobbie) N. Rooney is a co-investigator on this project and the designer of this website.

We are working in collaboration with Prof. Hans Will of the Heinrich-Pette-Institute at the University of Hamburg, Hamburg, Germany and Dr. C. Heesen (neurologist) Universitatskrankenhaus, Eppendorf, Germany, along with Dr. J. Cohen (neurologist) at the Mellen Center of the Cleveland Clinic in Cleveland, Ohio, USA. Several South African neurologists are also working with us. JNP de Villiers is a team member who will be registering for a PhD study on this project.


  • Kotze MJ, Rooney RN: Hereditary biochemical multiple sclerosis: A new subtype of multiple sclerosis characterized by porphyria-like symptoms? Am J Hum Genet (10/97 Suppl) :A255 (Abstract 1482).
  • Kotze MJ, de Villiers JNP, Groenewald JZ, et al. Molecular analysis reveals a high mutation frequency in the first untranslated exon of the PPOX gene and largely excludes variegate porphyria in a subset of clinically affected Afrikaner families. Mol Cell Probes 1998;12:293-300.
  • Reich B, Ehlers I, Will H, Heesen C, de Villiers JNP, Rooney RN, Kotze MJ. Autoantibodies against nucleolar structures correlate significantly with an unusual association between multiple sclerosis and porphyria symptoms. J Neuroimmunol 1998;90 (Suppl):77.
  • Rooney RN, Kotze MJ, de Villiers JNP, Hillermann R, Cohen JA. Multiple sclerosis, porphyria-like symptoms and a history of iron deficiency anemia in a family of Scottish descent. Am J Med Genet 1999 Sep;86(2):194-196 .
  • Maritha J. Kotze, J. Nico P. de Villiers, Roberta N. Rooney, Johanna J. Grobbelaar, Erna P. G. Mansvelt, Christianne S. H. Bouwens, Jonathan Carr, Ilse Stander, Lana du Plessis Analysis of the NRAMP1 Gene Implicated in Iron Transport: Association with Multiple Sclerosis and Age Effects BCMD 2001;doi:10.1006:44-53

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Research History


This condition has always included symptoms beyond those commonly associated with MS. Due to the occasional hive-like skin rash following sun exposure and the abdominal pain and digestive disturbances that have always accompanied flares, it was early suspected that the cause of the nervous system damage was porphyria. (Click here to travel to another site explaining porphyria). Porphyria is a broad term referring to any of several hereditary disturbances in the liver's heme-making processes. Heme synthesis commences in the liver in response to the presence of toxins requiring neutralization (stress hormones, alcohol, sulfonomide medications, infection byproducts, barbiturates, etc.). The acute porphyrias damage nerves.

 Porphyrin levels were frequently abnormal, but were not diagnostic of any of the known porphyrias, as ascertained by porphyrinologists, who are experts in heme synthesis and the porphyrias.

 The first 11 years after diagnosis were spent learning about the porphyrias and heme synthesis. There were also multiple tests done to measure porphyrin levels.

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Family Medical History


Briefly, the family history as it pertains to this illness contains several forebears and close relatives who exhibited the introductory symptoms of porphyria. The family members affected include the index case, her father, grandmother, aunt, and first cousin. All had the photosensitive skin rash. Of these, the index case, her father, and cousin are known to have had the acute abdominal pain. Her aunt died many years ago at age 42 after having experienced weakness in her arms. She was never correctly diagnosed and her death is apparently attributable to this illness and iatrogenic causes. The cousin, who is her daughter, and the index case have both experienced disability. The cousin has no diagnosis except to be told that she probably suffered the same unidentified illness that her mother had. The index case was diagnosed as having MS.

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Telltale Symptoms


The following list contains several symptoms that have been associated with this disease, not all of them considered typical of MS. The index case has experienced all of them and so have others of her affected kin.

  • CNS Damage and Disability
  • Overall Pallor and Local Cyanosis (bluish nailbeds)
  • Severe to Mild Abdominal Distress During Flares
  • Constipation During Flares (can also be diarrhea instead)
  • Weight Loss During Flares
  • Flare During Last Trimester of Pregnancy
  • Dark, Reddish Urine During Flares
  • Sun Induced Rash Following Flares
  • Abnormally Strong Craving For Salt
  • Tendency To Low Blood Pressure
  • Bright Flashes of Light in the Peripheral Vision

    Regarding this last symptom, a prominent Immunologist who specializes in MS has stated that an immune system attack on the CNS cannot cause this symptom. It has long been known, however, that the acute porphyrias CAN cause this symptom by causing spasms of the retinal artery.

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    Biochemistry of CNS Damage


    The ultimate cause of this illness appears to be an inherited reduced ability to absorb iron (click here to travel to another site explaining iron metabolism by a biochemist) resulting in a tendency to chronic anemia. The impact of low iron availability during heme synthesis by the liver may cause a derangement of the heme biosynthetic pathway that promotes CNS damage in a manner similar to that seen in the acute porphyrias. The main difference in this case is that only the CNS is damaged whereas in the acute porphyrias, the peripheral and/or central nervous systems fall prey.

     Another differentiating characteristic between this MS and the acute porphyrias is that porphyrin precursor levels, delta Aminolevulinic Acid (ALA) and Porphobilinogen (PBG), need not be elevated for the damage to occur. It is suspected that it is the proportion of precursors in relation to Uroporphyrins that is cogent. We have prepared some diagrams that compare normal heme synthesis (diagram 1) to the proposedMS heme synthesis (diagram 2) .

    In order to arrive at this understanding, it has been necessary to build upon what is currently known to medical science about the dynamics of heme synthesis. An association of decreased productions of Uroporphyrinogen 3 Synthase and Uroporphyrinogen Decarboxylase has been noted in the presence of excess iron. We propose that the converse may also be true: insufficient iron availability may be associated with increased production of both of these enzymes. The result of high productions of both of these enzymes, as illustrated in (diagram 2) , could be an overabundance of Coproporphyrins and a shortage of Uroporphyrin 1. (The porphyrins are the measurable slough from the porphyrinogens that appear in (diagram 1) and (diagram 2) )

     It has previously been established that in the liver, excess accumulations of any of the porphyrins occurring along the chain of reactions that culminate in heme synthesis are associated with an acute, or neurotoxic, porphyria. The exception is the Uroporphyrins. Uroporphyrins can be present in unlimited amounts and, while associated with dermal photosensitivity, are never associated with nervous system damage. The nervous system damage has been associated with the excesses of porphyrin precursors, ALA and PBG. Each of the porphyrias is characterized by an excess of whichever porphyrin immediately precedes the interruption as well as excesses of the precursors. Uroporphyria (commonly known as Porphyria Cutanea Tarda, or PCT) is the sole exception.

     One explanation might be that the Uroporphyrins can be present in limitless amounts and never be associated with nervous system damage because they are the buffers that nullify or prevent the neurotoxic processes evoked by the precursors. It may, therefore, not simply be excesses of precursors that evoke nervous system damage, but instead, the disproportion between the precursors and the Uroporphyrins that is responsible for the damage. If the precursors numerically overwhelm the Uroporphyrins, the result may be nervous system damage.

     It may be that this condition results in damage to only the CNS because, as illustrated by (diagram 1) and (diagram 2) , only Uroporphyrin 1 levels are in significantly low proportion. This may be important to allowing CNS damage because it is the smaller of the 2 uroporphyrin isomer molecules, and is therefore the one more capable of crossing the blood-brain barrier and offering it's protection to the CNS. Without the buffering offered by sufficient amounts of the Uroporphyrin1 molecules, the CNS is left vulnerable to the neurotoxic ravages evoked by the precursors. An alternative explanation might be that Uroporphyrin I inhibits production of PBG, especially if excess PBG proves to be the culprit in CNS damage, while excess ALA may prove responsible for peripheral nervous system damage. There may be other possible explanations. Until the testing is completed, the only sureties in the index case are that this illness is a result of chronic anemia and may cause a disturbance of the heme biosynthesis pathway resulting in CNS damage and that the way to treat it is through iron supplementation.

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    Relationship to Autoimmune MS


    This research could lead not only to identifying the cause of this illness, but to possibly explaining the establishment of autoimmune 'MS as well. Anyone can become anemic. If there is a concurrent demand for heme synthesis by the liver, all of the above principles would apply and CNS damage may occur. Since our index case is frequently anemic when not taking iron supplements, this has occurred often enough in her case to add up to disability. In the person who absorbs iron normally, this would likely transpire seldom enough that they would remain unaware of any CNS damage that had occurred. Their immune system, however, might not remain ignorant of the damage and would perform its normal function of mopping up its residue. It may be at that point that the immune system accidentally targets an inappropriate component of the CNS damage residue (like myelin basic protein) and autoimmune MS would thus become established.

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    How This Thesis Makes Sense of MS Epidemiology


    Understanding all of the above, it is not difficult to explain many of the mysteries associated with MS. For instance, it is not hard to understand why all forms of MS occur more frequently in females than in males, given the greater female tendency to anemia. It is not hard to understand the higher incidence of MS in people of Northern European descent, given that our index case's genetic background is Scottish. It is not hard to understand that all forms of MS are exacerbated by things like stress hormones, alcohol, infection byproducts, etc., all provocateurs of heme synthesis by the liver. It is not hard to understand that MS could occur in clusters in areas high in environmental toxins. The list goes on. It is even a possibility that the principles outlined above are contributors to the CNS damage seen in pernicious anemia. Also, one could expect an increased number of cases of MS in modern times because of:

    1. Discontinuance of cooking in iron pots
    2. Removal of iron from the water supply
    3. Increased environmental toxins

    If these principles stand up to testing, it may be prudent that virtually all MS patients be kept on a regimen that ensures continuously adequate iron supplies. 'MS is probably not caused by a specific virus but yet it is caused by any or all viruses. It is caused by anything that has to be neutralized by the liver when there is not sufficient iron available to support safe heme synthesis.

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  • Treatment


    Prior to understanding the biochemistry of this ailment, the index case had been experiencing a pattern of having an exacerbation about once every 6 months. Once she started taking the iron supplements, she was free of exacerbations for almost 4 years. She then suffered an exacerbation when she began experimenting with reducing the iron supplement and taking the hormone called melatonin, a mistake that won't be repeated. The key seems to be to get enough iron to "cover" any toxins.  Toxins might be natural hormones produced and needed by the body, medications, alcohol, byproducts of infection or some sort of illicit toxin. Fortunately, she has made a full recovery from this exacerbation.

     There are some things to keep in mind for anyone considering iron supplementation: first of all, please check with your physician to make sure that you do not have Hemochromatosis , a dangerous hereditary condition that causes overabsorption of iron. Only tablets or pills should be used because liquid iron supplements, unless monitored by a physician, can also cause iron overload, even in persons who do not have hemochromatosis.. If you do not have Hemochromatosis and you wish to boost your iron levels, a daily multivitamin/mineral supplement is very important to enhancing iron absorption.

    The RDA (recommended daily allowance, USA) for iron has recently been increased from 11 mg to 15 mg. The combination of a 65 mg iron tablet (preferably not iron sulfate as that form can adversely affect the taste of foods) and a good multivitamin/multimineral tablet has been fully effective in halting exacerbations in our index case. Since this regimen can at first be difficult to adjust to for some people, it is advised that it be introduced gradually by starting with the vitamin/mineral tablet and then introducing the iron a couple of weeks later. The iron could even be introduced by first using a 30 mg or so tablet and then increasing later to 50 or 60 mg. For a patient who does not have a low ability to absorb iron, just the vitamin/mineral tablet may be sufficient by itself.

    To prevent the constipation that iron supplementation sometimes encourages, it may be useful to follow a low fat diet, increase fiber intake with things like raisin bran cereal or popcorn, etc. and take additional vitamin C, especially at bedtime when it can remain in your system for a longer period. Snack products containing the fat substitute called Olestra may also be useful to some.

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