Cobalamin Deficiency, Methylation and Neurological Disorders by po2378


									        Cobalamin Deficiency, Methylation and
               Neurological Disorders
                          G.E. Schuitemaker, M.D. and A.J. Hoogland 1

     An article in the New England Jour-                   ficiency are paleness and fatigue. In general,
nal of Medicine from 1988 drew the                         deficiency is diagnosed on the observation
attention to a scant discerned problem:                    of enlarged red blood cells (macrocyto-
neuropsychiatric disorders due to vitamin                  sis). However this symptom cannot be
B12 (cobalamin) deficiency occured in pa-                  distiguished from folate deficiency. The
tients, mainly elderly, who didn’t present                 general opinion is that distinction usually
with hematological deviations.1 After ad-                  only manifests after several years, when
ministration of vitamin B12, the symptoms                  neuropsychiatric symptoms come forward:
disappeared in practically all patients. The               tingling hands and/or feet (always sym-
research demonstrated that in daily prac-                  metrical), boredom, fatigue and lethargy,
tice a deficiency of vitamin B12 is often                  shortness of breath, palpitations, sore
not recognized as the cause of severe and                  mouth with a thick, often painful tongue.
frequently occuring psychiatric disorders.                 Frequently a pale complexion with soft yel-
Advanced research confirmed these results.2                low discoloration (because of a deteriorated
Other research points out the danger of                    liver function) is seen. Irritability, loss of
undiagnosed vitamin B12 deficiency, espe-                  memory, mild depression and mood swings
cially in pernicious anaemia.                              can also be observed.

B12 Status and Pernicious Anemia                           B12 Deficiency and Alzheimer’s Disease
      Pernicious anemia is an autoimmune                        New methods to assess vitamin B12 sta-
disease with the principle characteristic be-              tus show that vitamin B12 deficiency occurs
ing that the stomach is not able to produce                much more often than was previously as-
intrinsic factor necessary for adequate                    sumed.4 Assessment of the methylmalonic
resorption of vitamin B12 from food. The                   acid level is a precise method to determine
disease shows a megaloblastic blood picture                possible existence of vitamin B12 deficiency,
as a result of a chronic lack of vitamin B12.              if necessary supported by assessment of
Suprisingly, the research shows only a slight              homocystein and cystathionin.
connection between low vitamin B12 status                       When these assessments are performed
and pernicious anaemia.3 Yet vitamin B12                   in elderly people, high percentages are
blood levels are important for the diagno-                 often found, which indicates the existence
sis of pernicious anaemia. For this reason                 of deficiencies of the vitamins cobalamin,
pernicious anaemia is often missed. Fur-                   folic acid and pyridoxal phosphate (vitamin
thermore, a correct diagnosis is hindered                  B6) in the elderly.5
by the rather aspecificity of vitamin B12 de-                   Ten percent of all people between 65
ficiency, and such a deficiency manifesting                and 75 years old, 20% of those between
itself over the long term. Also the general                75 and 85 years old and 30% of all those
opinion that storage of this vitamin in the                over 85 years old suffer from some sort
human body is sufficient to supply it for                  of dementia.6 The literature provides ex-
three to six years does not help in diagnos-               tended information on the deteriorated
ing pernicious anemia adequately.                          vitamin B12 status in patients with senile
      The first symptoms of a cobalamin de-                dementia of the Alzheimer type (SDAT).
                                                           Van Tiggelen described subnormal levels
1. Ortho Institute, P.O. Box 82, 7080 AB Gendringen, The
                                                           of vitamin B12 in the cerebrospinal fluid

                       Cobalamin Deficiency, Methylation and Neurological Disorders

of SDAT patients, in spite of normal se-        Methylation is Part of Many Processes
rum levels.5,7 Later others described B12            Methyltransferases take part in a
anomaly in SDAT patients.8,9 To clarify         large number of body processes,including
connections mentioned above one should          regulation of protein structure, regula-
first gain some insight into the reactions of   tion of DNA expression, production of
methylation (Figure 1)10                        phos-pholipids, and production of certain
                                                hormones and neurotransmitters.10 There
Methylation                                     are also indications that methylation of
     In the body cobalamin is active in two     phospholipids is the common mechanism
forms. As adenosylcobalamin, a cofactor of      of receptor signalling across cell mem-
the enzyme methylmalonyl-CoA-mutase,            brane.13
or as methylcobalamin, a cofactor of the             Methyltransferases transfer a methyl
enzyme methionine synthase.                     group away from S-adenosylmethionine
     The first form (adenosylcobalamin)         (SAM) forming S-adenosyl-homocystein
is involved in conversion of methylmalo-        (SAH). SAH is a strongly competitive
nyl-CoA (MM-CoA) into succinyl-CoA.             inhibitor of methyltransferases and ac-
In case of shortage of vitamin B12 this         cumulation of SAH in the cell will inhibit
conversion takes place insufficiently           methylation reactions. The ratio between
and a different conversion takes place of       these two compounds is called the methyla-
MM-CoA, namely in methylmalonic acid            tion ratio. A low ratio indicates inhibition
(MMA). A raised MMA-level can serve as          of methylation.
an exclusive rate of vitamin B12 deficiency.         SAH is broken down by S-adenosyl-
This conversion is particularly important       homocysteinhydrolase into homocysteine
in the brain and is known as the propionate     and adenosine. Adenosine is rapidly
metabolism.11,12                                metabolised into, for example, inosine.
     The second form of vitamin B12 (meth-      Homocysteine has three elimination path-
ylcobalamin) is co-enzyme of methionine-        ways: remethylation to methionine (the
synthase. This is an important enzyme in        main elimination route), breakdown to
the reaction which transfers a methyl group     cystathionine or excretion from the cell.
from 5-methyl tetrahydrofolate (5-MTHF)
to homocysteine, forming methionine.            Remethylation in the Brain
This reaction is the key reaction of the so          Remethylation of homocysteine is
called methylation, a series of reactions       possible in two ways. The first is by way of
in the body transferring methyl groups.         the above mentioned enzyme methionine
In these reactions S-adenosyl methionine        synthase, but remethylation can also take
(SAM) is used as methyl donor by methyl-        place by way of the enzyme betaine meth-
transferase enzymes. SAM is synthesized from    yltransfersase. This enzyme is present in
methionine.11,12                                only a few organs, such as liver and kidneys
                           Figure 1. The Methylation Process

Journal of Orthomolecular Medicine           Vol. 11, No. 4, 1996

and is not present in the brains. In this case    of SAM to SAH are found after exposure
methylation reactions depend totally on           to nitrogen oxides. Adequate supply of
functioning of methionine synthase.10             methionine appears to be able to prevent
      When both remethylation pathways            neuropathy at least partly.15 The addition of
fail, homocysteine is converted with dif-         S-adenosyl methionine itself appears in sev-
ficulty into cystathionine , and cysteine         eral studies to have many beneficial effects
because the regulating enzyme is activated        on the central nervous system, especially
by high levels of SAM, and these are lack-        on the monoamine neurotransmitter me-
ing. Consequently SAH and homocysteine            tabolism and receptor systems. Provision
accumulate, the ratio between SAM                 of these methyl donors is responsible for
and SAH (methylation ratio) is low and            the remyelination observed in patients with
methylation is inhibited.10 The brain is          inborn disorders of folic acid metabolism
capable of remethylation of homocysteine          and methylation.16
exclusively by way of methionine synthase
and in case of disfunctioning methionine          Affected Liver is an Extra Risk Factor
synthase enzyme is totally dependent on                In patients with affected liver func-
plasma methionine supply, derived from            tion, such as in alcoholics, chronic pheny-
food or from organs such as the liver, which      toin users and patients exposed to hepato-
has the disposal of an alternative synthesis      toxic chemicals with neurotoxic potential,
pathway. If this supply also fails, clinical      abnormally low levels of cobalamin are
symptoms manifest.                                found in cerebrospinal fluid.7,17 This could
                                                  be indicative of an abnormal conversion
Neuropathy Caused by B12 Deficiency               of neurologically active cobalamin by the
     Neuropathy as a complication of co-          affected liver, for example by changed ac-
balamin deficiency is characterized by demy-      tivity of microsomal liver enzymes.18-20 In
elinisation of the posterolateral nerves of the   patients with predominantly neurological
spine. At first it was thought to be due to a     symptoms of cobalamin deficiency, higher
disturbance of the enzyme methylmalon-            serum levels of cobalamin analogues are
CoA-mutase. Shortage of adenosylcobala-           found than in patients with hematological
min may inhibit the enzyme, which may             symptoms.21 This finding is supported by
result in production of abnormal fatty            data derived from studies of alcoholics.22
acids. Incorporation of these defective
fatty acids in myelin may lead to demy-           Interaction with Thiamine Metabolism
elination.14                                           It is possible that functional vitamin
     Recent evidence however points to a          B12 deficiency blocks resorption, transport
mechanism by way of the enzyme methio-            and biological activity of thiamine. In
nine synthase by methylcobalamin. The             particular, methylcobalamin deficiency
most important proof of this is derived           could induce reduction of the intestinal
from experiments with nitrogen oxides.            alkaline phosphatase level, blocking intes-
Nitrogen oxides are strong inhibitors of          tinal resorption and possibly also biological
the enzyme methionine synthase. They              activation of thiamin.23,24 Deficiency of
inactivate methylcobalamin by oxidation           biological active thiamine in the brains
of monovalent cobalt groups to cobalt             is connected with a range of neurological
oxide, which then forms biological inactive       diseases, as is known from brain research
cobalamin analogues. Exposure to nitrogen         in chronic alcoholics.
oxides (also in anaesthesia) results in neu-
ropathy in humans, primates, fruitbats and        Folic Acid
pigs.15 In cerebrospinal fluid and neural             Folate deficiency is common in elderly.
tissue of these animals extremely low ratios      Research among 1250 randomly selected

                       Cobalamin Deficiency, Methylation and Neurological Disorders

elderly persons showed that 8% had low             syndromes and can occur without reduced
serum folate levels.25 Alcoholics, too, run        serum level or hematological deviations.
a higher risk of folate deficiency because         Assessment of the methylmalonic acid
alcohol specifically affects the formation         level is a specific and reliable method to
of tetrahydrofolate. At first, effects of folate   determine vitamin B 12 status. Elderly
deficiency are indistinguishable from vita-        people often appear to have abnormal me-
min B12 deficiency. Differentiation between        thyl malonic acid levels, which indicates
these deficiencies is possible only after a        disturbed methylation. Senile Alzheimer’s
long period, when vitamin B12 deficiency is        dementia, too, is often accompanied by an
visible by degeneration of nerve tissue.           affected B12 status.
     The biologically active form of folic               The brain has available, in constrast to
acid in the body is 5-methyltetrafolate            organs such as the liver, only one method
(5-MTHF), mentioned before as a methyl             to remethylate homocysteine to methio-
donor for the enzyme methionine synthase,          nine. However B12 deficiency inhibits the
that converts homocysteine to methionine.          enzyme responsible for this conversion,
The body, as mentioned, has at its disposal        and the brain, therefore, becomes totally
alternative supply routes for methyl groups        dependent on supply of methionine in the
in case of insufficient supply of folic acid.      blood. When this supply fails, neuropathy,
But in longstanding folate deficiency these        among other things, may develop. Folic
protective mechanisms, too, may fail and           acid as methyl donor is an important fac-
result in neurological disorders. Folic acid       tor in methylation and also in converting
can act in methylation reactions in other          vitamin B12 into a biological active form.
ways. Several interactions are documented                A complicating factor when the liver
between vitamin B12 and folic acid, which          is affected by alcohol or toxic substances.
suppose that folic acid, or rather 5-MTHF,         As a consequence vitamin B12 is probably
plays a part in the conversion of cobala-          converted abnormally, through which bio-
min to methylco-balamin.26 This theory             logical inactive cobalamin analogues enter
is supported by clinical observations of           the bloodstream. Disturbance of vitamin
patients with a neuropsychiatric syndromes         B1 metabolism may also contribute to
which are responsive to folate. In research        development of neurological symptoms in
in elderly patients with depression as-            vitamin B12 deficiency.
sociated with mild dementia, 5-MTHF
supplements remedied symptoms in 45%               References
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