No folic acid

November 21, 2010

Folic acid and autism take another look

Anon DoR Nov.22-09

In 1991, CDC recommended folic acid supplementation for women who previously had

had an infant or fetus affected by an NTD and who planned to have more children

(1).

CDC recommended that these women take a 4-mg daily dose of folic acid (under a

physician's supervision) beginning at least 1 month before conception and

continuing throughout the first trimester of pregnancy. (2)However the data on

folic acids reduction in Spinal Bifida and NTD is not as impressive as one may

think. Advances in technologies and elected abortions may in fact be the true

decline in these disorders.

Similarly the numbers of autistic type disorder have increase with women's

increase in folic acid supplementation.

Peruvian women taking prenatal supplementation were found to have a lowered zinc

status.(3) Zinc is important for neuronal growth and immune function. Zinc is

also recognized as an anti-oxidant. Folic acid is capable of depleting zinc and

iron competes for zinc. This could possibly leave a child in a vulnerable state.

Improving maternal zinc status through prenatal supplementation may improve

fetal neurobehavioral development(4)

Boris and Goldblatt found that 89% of their autistic study population was

positive for at least one snip in the MTHFR.(5)

High amounts of folic acid may result in high dihydrofolate which in turn

inhibits MTHFR.(6)

MTHFR is found to be involved in one carbon metabolism. One carbon metabolism is

responsible for detoxification,. Amino acid synthesis, fatty acid synthesis,

energy production ,and oxidative phosphorylation to name a few. It has been

found that folic acid interferes with one carbon metabolism(7)

In addition, Fetal adaptations to a high-folate environment may interfere with

folate metabolism postnatally, with serious consequences for the epigenetic

regulation of gene expression.(8)

Once one carbon metabolism is inhibited, the child is vulnerable to metals,

bacteria, and virus.

In many autistic patients reduced natural killer cell activity has been

identified. Folic acid has been shown to reduce natural killer cell activity in

post menopausal women.(9) Lower estrogen amounts ,in post menopausal women has

been clearly defined .Autistic disorder is much higher among boys than girls.

In sprue ,another common variant in autistic disorder, it has been found that

neurologic lesions have occurred during folic acid therapy. In pernicious anemia

neurologic lesions have been observed in patients receiving folic acid therapy.

Moreover, folic acid may interfere with glutamic acid metabolism making the

brain more susceptible to glutamate toxicity. Furthermore, Folic acid may

interfere with the nutrition of the spinal cord.(10)

Many of these children have gut motility issues and high levels of folic acid

will serve to in fact feed undesirable inhabitants if the intestine.

It is well established that excess folic acid in low B-12 status results in

cognitive decline(11)

Similarly, the 2004 PDR Nurses Drug Handbook states that folic acid may cause

altered sleep patterns, difficulty in

concentration,irritability,overactivity,depression,confusion,abdominal

distention, flatulence, and bronchial spasm in addition to, prolonged folic acid

therapy may also cause decreased vitamin B-12 levels.

Recent studies have also found that mothers whom in fact had taken folic acid

supplements had offspring who were at a higher risk for leukemia.

The dangers of folic acid supplementation in the unborn fetus and small child

must be examined.

1.CDC Use of folic acid prevention of spinal bifida and other

neuraldefects1983-1991MMRW1991:40:513-6

2.Folic acid to reduce the number of cases of spinal bifida and other neural

tube defects MMWR1992;41(no.RR-14):1-7

3. O'Brien KO, Zavaleta N, Caufield LE, Yang D, Abrams SA. Influence of prenatal

iron and zinc supplements on supplemental iron absorption, red blood cell iron

incorporation, and iron status in prenant Peruvian women. Am J Clin Nutr.

1999;69:509–15

4 Merialdi M; Caulfield LE; Zavaleta N; Figueroa A; DiPietro JA

Center for Human Nutrition, Department of International Health, The s

Hopkins School of Hygiene and Public Health, Baltimore, MD, USA.

AM J Obstet Gynecol.1999; 1809 (2 pt 1):483-90

5. http://www.nationalautismassociation.org/pdf/IOM-Bradstreet.pdf.

6.Is folate good for everyone?

,Kim,Refsim Americam Journal of clinical nuritionVol.87,no.3,517-533 march

2008

7. Sauer, B. Mason, Sang-Woon Choi too much folate: A risk for cancer

and cardiovascular disease? Current opinion in clinical nutrition and metabolic

care 2009,12:30-36

8. C Sugden - Nutrition research reviews, 2006 - Cambridge Univ Press

9.Aron M. Troen ,Breeana ,Bess Sorensen ,Mark H. Wener, Abbey ston,

Brent

Wood, Selhub, Anne McTiernan, Yutaka Yasui, Evrim Oral, D. Potter,

Cornelia M. Ulrich J. Nutr. 136:189-194, January 2006

10. Anonymous. A warning regarding the use of folic acidNEJM;237;713-5

11. Martha Savaria , F Jacques, Irwin H Rosenberg and Selhub

American Journal of Clinical Nutrition, Vol. 85, No. 1, 193-200, January 2007

HIGH BLOOD PRESSURE AND KIDNEY DISORDER

The blood pressures of the rats are recorded

on table 1. After six weeks of treatment, the

rats receiving pteroylglutamic acid had uniformly

developed a significant hypertension "

Although the kidneys of treated rats were

equal in weight to those of controls, the renalcortex surface in 15 of the 17

animals receiving

pteroylglutamic acid was dotted with whitish,

slightly contracted scars of from 0.5 to 2.0

mm. in diameter. These areas extended 1.0

to 3.0 mm. into the cortical parenchyma as

small wedge-shaped lesions containing nu-merous fibroblasts. Cells of the

proximal

and distal convoluted tubules within and

immediately adjacent to these regions were

usually moderately shrunken, with pyknotic

nuclei and eosinophilic cytoplasm. The remainder

of the renal cortex and the medulla,

despite the number and extent of cortical scars,

compared favorably with that of the control

animals. Sections of the kidneys from one

rat treated with pteroylglutamic acid showed

rare atrophic glomeruli, but the other animals

failed to demonstrate this change. Occasional

dilatation of the convoluted tubules bordering

the scarred portions was observed in approximately

50 per cent of the animals, but casts

in the renal tubules were not observed.

The tubular damage observed in these

animals generally agrees with that previously

described by others in kidneys of guinea pigs10

and rats " treated with pteroylglutamic acid.

The mechanism by which a significant hypertension

is obtained in rats treated with pteroylglutamic

acid is at present obscure. Its associatiotn

with renal lesions possibly suggests a renal

factor comparable to that brought about by

interference with renal blood flow, as with

renal artery clamps, perinephric packs, or

renal ligation. An excess of dietary pteroylglutamic

acid, however, is associated with a

reduced activity of liver d-amino acid oxidase

and xanthine oxidase in the chick,12 13 and

diminished xanthine oxidase activity in the

rat.'4 Liver choline oxidase in the rat may also

be altered by an increase in dietary pteroylglutamic

acid.'4 It is conceivable that large

amounts of parenteral pteroylglutamic acid

might similarly interfere with the activity of

certain renal or other enzyme systems that

normally may inactivate endogenous hypertensive

factors, and in this manner induce a

sustained blood pressure elevation. Another

possible explanation of the hypertension is

suggested by recent demonstrations that

pteroylglutamic acid is imminently concerned

in transmethylation and the synthesis of

choline and methionine.1 " - " 1 In addition, under

certain specific experimental conditions, the

administration of pteroylglutamic acid accelerates

methylation of a toxic substance and

results in a consequent loss of available methyl

groups from the body.'9 In these circumstances,

the development of a yellow, fat-infiltrated

liver and a reduced growth rate suggests a

choline deficiency. This possible antilipotrophic

nature of pteroylglutamic acid under induced

conditions is of interest. In the present study,

pteroylglutamic acid may have accelerated

transmethylation in the body to a degree

sufficient to induce a significant over-all deficiency

of accessible methyl groups. The onset

of hypertension subsequent to a brief transient

period of choline deficiency in early life is well

established in rats. " " By producing a relative

insufficiency of choline, or other methyl donator

substances, administration of pteroylglutamic

acid may result in hypertension perhaps

by a metabolic action less direct than specific

enzyme inhibition.

http://circ.ahajournals.org/cgi/reprint/5/6/903.pdf

A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor

Outcome in Hemodialysis Patients

Kamyar Kalantar-Zadeh*,, Gladys Block, H. Humphreys, J.

McAllister and D. Kopple*,||

*Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance,

California, and Geffen School of Medicine at UCLA, Los Angeles,

California; Division of Public Health Nutrition and Epidemiology, School of

Public Health, University of California, Berkeley, California; University of

California, San Francisco, San Francisco, California, and Division of

Nephrology, San Francisco General Hospital, San Francisco, California; DaVita,

Inc., Torrance, California; and ||UCLA School of Public Health, Los Angeles,

California

Correspondence to Dr. Kamyar Kalantar-Zadeh, Departments of Medicine and

Pediatrics, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center,

Harbor Mailbox 406, 1000 West Carson Street, Torrance, CA 90509-2910. Phone:

310-222-3891; Fax: 310-782-1837; E-mail: kamkal@...

ABSTRACT. An increased level of total plasma homocysteine (tHcy) is a risk

factor for poor cardiovascular outcome in the general population. However, a

decreased, rather than an increased, tHcy concentration may predict poor outcome

in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse

epidemiology. Associations were examined between tHcy level and markers of

malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization

and mortality in 367 MHD patients, aged 54.5 ± 14.7 (mean ± SD) years, who

included 199 men and 55% individuals with diabetes. tHcy was 24.4 ± 11.8 µmol/L,

and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 µmol/L). tHcy had

weak to moderate but statistically significant bivariate and multivariate

correlations with some laboratory markers of nutrition (serum albumin,

prealbumin, creatinine, and urea nitrogen) but no significant correlation with

serum C-reactive protein or two

proinflammatory cytokines (IL-6 and TNF-). During 12 mo of follow-up, 191 MHD

patients were hospitalized, 37 died, nine underwent renal transplantation, and

38 transferred out. Hospitalization rates were significantly higher in patients

with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was

significantly higher compared with other three quartiles (6.5 to 9.8%;

Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile,

even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence

interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive

nutritional marker in MHD patients with no association with inflammatory

measures. Despite a very high prevalence of hyperhomocysteinemia in MHD

patients, lower values of tHcy are paradoxically associated with increased

hospitalization and mortality. The lowest tHcy quartile confers a twofold

increase in risk of death independent of hypoalbuminemia.

The nutritional feature of tHcy in MHD patients may explain its reverse

association with outcome.

J. Am. Soc. Nephrol. 2004 15: A26-A29

http://jasn.asnjournals.org/cgi/content/abstract/15/2/442

CARDIAC

Too much folate: a risk factor for cancer and cardiovascular disease?

Sauer J, Mason JB, Choi SW.

Vitamins and Carcinogenesis Laboratory, Mayer USDA Human Nutrition Research

Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.

PURPOSE OF REVIEW: The intent of this evidence-based review is to analyze the

role of folate in chronic diseases, focusing on cancer and cardiovascular

disease. RECENT FINDINGS: Low folate status has been shown to be a risk factor

for cancer and cardiovascular disease. Although epidemiological data suggest an

inverse association between folate status and disease risk, intervention studies

give equivocal results, suggesting the response to folate intake does not follow

a linear continuum. Moreover, recent folate intervention trials raise concern

about possible adverse effects of folate supplementation and suggest that too

much folate in inopportune settings may be potentially harmful in individuals at

higher risk for cardiovascular disease and cancer. SUMMARY: Although folate

intake at sufficient levels appears to be an effective cancer chemopreventive

strategy, high-dose supplementation of folate has generally not been effective

in reducing recurrence of

cardiovascular events or colorectal adenomas in clinical intervention trials.

Although controversial, high folate status achieved through folate fortification

or supplementation may increase the risk of certain chronic diseases among

certain individuals, possibly by interfering with the homeostasis of one-carbon

metabolism. Further research is urgently needed to accurately define the

relationship between supraphysiological intake of folate and chronic diseases.

PMID: 19057184 [PubMed - indexed for MEDLINE]

HEP_B HEAVY METALS MIXED WITH SACCHAROMYCES LOADED FOLATE

http://www.inchem.org/documents/pims/pharm/folicaci.htm#SectionTitl...

" Folic acid is incompatible with oxidizing and reducing

agents and with heavy metal ions (McEvoy, 1990). "

" It should be given with caution to patients with abnormal

renal function "

CONVULSIONS ATAXIA FOLIC ACID NEUROTOXICITY IN THE PYRIFORM CORTEX AND

AMYGDALA

Folic acid is relatively non-toxic. Toxicity studies in

mice showed that folic acid could cause convulsions,

ataxia and weakness. Histopathological studies in some

strains of mice showed that toxic doses may also cause

acute renal tubular necrosis. A possible relationship

between folic acid neurotoxicity and cholinergic

receptors in the pyriform cortex and amygdala has been

shown (McGeer et al, 1983).

FOLATE BRAIN LESIONS

J Child Neurol. 2010 Mar 31. [Epub ahead of print]

Maternal Methylenetetrahydrofolate Reductase (MTHFR) Homozygosity and Neonatal

Outcome: Follow-Up of 42 Pregnancies at Risk.

Pogliani L, Muggiasca L, Arrigoni L, Rossi E, Zuccotti G.

Department of Pediatrics, Università di Milano, Luigi Sacco Hospital, Milan,

Italy.

Abstract

From February 2006 to March 2008, 42 pregnant women homozygous for the

677CT-methylenetetrahydrofolate reductase (MTHFR) allele were recruited in our

obstetrics service for pregnancy at risk. All had antithrombotic prophylaxis

with low-dose aspirin and/or low-molecular-weight heparin, supplemented with

folic acid. In all, 2 women lost the fetus and 4 were lost to follow-up before

delivery. A total of 36 women delivered term infants who all underwent

transfontanellar ultrasonography within 24 hours of birth. Six (16.6%) had

ischemic or hemorrhagic cerebral lesions. No differences were observed in

gestational age, birth weight, or umbilical cord pH between the 30 healthy

infants and the 6 with cerebral lesions. Neonatal outcomes were negative in

spite of maternal folic acid supplementation and antithrombotic prophylaxis

during pregnancy. This suggests a relationship between maternal homozygous

mutation in the 677CT-MTHFR allele and neonatal cerebral

lesions.

PMID: 20357240 [PubMed - as supplied by publisher]

MYCOSIS

Antifolates as antimycotics? Connection between the folic acid cycle and the

ergosterol biosynthesis pathway in Candida albicans.

Navarro-Martínez MD, Cabezas-Herrera J, Rodríguez-López JN.

Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología

Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo,

Murcia, Spain.

The increased incidence of invasive mycoses and the emerging problem of

antifungal drug resistance have encouraged the search for new antifungal agents

or effective combinations of existing drugs. Infections due to Candida albicans

are usually treated with azole antifungals such as fluconazole, ketoconazole or

itraconazole. Whilst azoles may have little or no toxicity, they generally offer

rather poor fungicidal activity. Even in the absence of resistance, treatment

failures or recurrent infections are not uncommon, especially in

immunocompromised individuals. Here we demonstrate that the non-classical

antifolate pyrimethamine shows synergy with azole antifungal compounds and

interferes with the ergosterol biosynthesis pathway in C. albicans. By

disturbing folate metabolism in this fungus, pyrimethamine can inhibit

ergosterol production. The molecular connection between the folic acid cycle and

the ergosterol biosynthesis pathway is discussed and we show that the

filamentous form of this fungus is more susceptible to methotrexate than the

yeast form because the drug is more effectively transported through the membrane

of the filamentous form. When used to treat the hyphal form, methotrexate showed

synergy with other antifungals such as azoles and terbinafine. This finding

could have important clinical applications, as a combination of azoles with

antifolates and/or inhibitors of folic acid synthesis could represent an

attractive alternative for the treatment of C. albicans infections.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 17046206 [PubMed - indexed for MEDLINE

FOLATE AND YEAST

Growth inhibition of Candida albicans by folate pathway inhibitors. Their

potential in the selection of auxotrophs.

Henson OE, McClary DO.

Growth studies were conducted on C. albicans in a glucose - salts - biotin (GSB)

medium in the presence of folate inhibitors. Sulfanilamide inhibited growth

which was restored by PABA or tetrahydrofolate (THF). Aminopterin inhibited

growth to about the same level as did sulfanilamide, but this inhibition was not

reversed with PABA nor THF, singly or in combination. Inhibition by combined

sulfanilamide and aminopterin was synergistic, reducing growth by more than 90%

for 48 h. The sulfanilamide component of the combined inhibition was reversed by

PABA or THF to the level of that of aminopterin alone. Cytochrome synthesis was

not affected by the inhibitors, but marked increases occurred in

alpha-ketoglutarate, malate, isocitrate, and pyruvate dehydrogenases, especially

in the presence of both inhibitors. The pyrimidines in combination with

sulfanilamide were as inhibitory as was the combination of aminopterin and

sulfanilamide, but they had no effect when added alone or in combination with

aminopterin. Unlike the pyrimidines, the purines stimulated about a 50% recovery

from inhibition by either of the inhibitors. Growth inhibition by combined

sulfanilamide and aminopterin was overcome by about 50% by the addition of the

THF-mediated end-produits: deoxythymidylate, adenine, histidine and methionine.

The use of GSB medium containing adenine, histidine, methionine and the folate

inhibitors but without deoxythymidylate resulted in thymineless death of

prototrophic cells providing a method for the selection of auxotrophic mutants.

PMID: 386943 [PubMed - indexed for MEDLINE]

ANEMIA ICP AND BRAIN HERNIATION

Craniocephalic Disproportion with Increased Intracranial Pressure and Brain

Herniation: A New Clinical Syndrome in Anemic Patients: Report of Two Cases

Rengachary, Setti S. MD; Blount, MD; Heros, Deborah MD; Bowers,

MD; Truwit, MD

Abstract

OBJECTIVE AND IMPORTANCE: We describe a new clinical syndrome in two patients

with chronic anemia. The major manifestation of the syndrome is herniation of

the brain resulting in death caused by long-standing craniocephalic

disproportion. The disproportion was caused by extreme thickening of the cranium

because of erythroid hyperplasia.

CLINICAL PRESENTATION: Two patients with known chronic anemia presented with

chronic increase in intracranial pressure with acute deterioration resulting in

brain herniation.

INTERVENTION: Despite maximum medical therapy, both patients died as a result of

uncontrollable increase in intracranial pressure.

CONCLUSION: Patients with chronic anemia presenting with progressive headaches

should be monitored for this newly described clinical phenomenon

Reynolds 1972

" There is evidence that treatment with folic acid for three months or longer may

result in a significant fall in B-12 levels sometimes to subnormal values "

" 2004 PDR Nurses Drug Handbook states that folic acid may cause altered sleep

patterns, difficulty in

concentration,irritability,overactivity,depression,confusion,abdominal

distention, flatulence, and bronchial spasm in addition to, prolonged folic acid

therapy may also cause decreased vitamin B-12 levels "

Re safety and FA " Careful review

of that research shows that after giving folic acid to

treat

" pernicious anaemia " there was sometimes brief

temporary symptomatic neurological improvement

before the more fl orid and sometimes explosive

deterioration,9,28 and after the obvious but suboptimal

haematological improvement there was commonly alater

insidious haematological relapse.8,28 A similar

number of patients have neurological and haematological

relapse, although often dissociated (fi gure 2).8 In other

words, both the nervous system and the blood may show

improvement and relapse but to diff erent degrees and at

diff erent rates, which may in turn refl ect profound

diff erences in structure, function, and cellular turnover

in the two tissues.

Patients with neurological complications of vitamin-B12

deficiency have significantly higher serum folate

concentrations than those without such CNS disorders.37,38

full:

http://www.direct-ms.org/pdf/NutritionMS/B12%20folic%20acid%20nervous%20system.p\

df

DEMYELINATION DUE TO B-12 DIFICIENCY

Surtees1

(1) Institute of Child Health, London, UK

Summary In humans, subacute combined degeneration of the spinal cord and brain,

a primary demyelinating disease, is caused by cobalamin or

methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis

suggest that dysfunction of the methyl-transfer pathway may be the cause.

Compelling evidence for this comes from the study of inborn errors of cobalamin

metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin,

is associated with demyelination. Recent studies have focused upon inborn errors

of the methyl-transfer pathway. Cerebrospinal fluid concentrations of

metabolites of the methyl-transfer pathway have been measured in humans with

sequential errors of the pathway and correlated with demyelination demonstrated

on magnetic resonance imaging of the brain. This has provided new data

suggesting that deficiency ofS-adenosylmethionine is critical to the development

of demyelination in cobalamin deficiency.

http://www.springerlink.com/content/xt6r43x857485236/

RISK OF NEUROLOGICAL COMPLICATIONS

IN PERNICIOUS ANAEMIA

TREATED WITH FOLIC ACID

BY

M. C. G. ISRAELS, M.D., M.Sc., F.R.C.P.

AND

JOHN F. WILKINSON, M.D., M^Sc., Ph.D., F.R.C.P.

(From the Department of Haematology, University and Royal

Infirmary, Manchester)

The identification and synthesis of pteroyl-y-glutamic acid

(folic acid*) by Angier et al. (1945, 1946) led to the early

recognition of its quite unexpected and remarkable effects

in the treatment of pernicious anaemia ( et al., 1945)

and of nutritional macrocytic anaemia (Spies et al., 1945).

The results in pernicious anaemia were very striking

at first, as many workers reported, including ourselves

(Wilkinson, Israels, and Fletcher, 1946). It soon became

evident, however, that even when the blood counts were

restored to normal levels relapses were occurring, and

signs of involvement of the peripheral nerves, such as paraesthesiae

and numbness in the limbs, and of the spinal

cord tracts, like ataxia and loss of vibration sense, might

not be improved or might become worse.

Even more important, however, was the fact that

some patients who had not previously shown signs of

nervous system disturbances developed such signs, often

very acutely, after being treated with folic acid for variable

periods. Since 1946 several groups of workers

have become aware of this disquieting fact, and in consequence

the widespread enthusiasm for folic acid, at least

for the treatment of pernicious anaemia, has been rapidly

waning.

In Table I we have included all the available references

to the development of subacute combined degeneration of

the spinal cord in patients with pernicious anaemia, or the

worsening of neurological symptoms already present, after

treatment with pteroyl-y-glutamic acid.

From a careful study of the various reports it was

obvious that many of them referred to the same groups

of cases, since some authors have published their results

and cases in several journals, often without cross-references,

and in some reports no details are given at all, other than

*In this paper folic acid is used synonymously with and refers to

the synthetic pteroyl-y-glutamic acid.

Folic acid treatment was immediately discontinued, and

she was given liver extract intramuscularly and 30 g. of

desiccated stomach daily by mouth. After one month her walking

was improved, but the right plantar response was still

extensor; after two months she was ambulant again and both

plantar responses were flexor; after eight months all symptoms

had disappeared and she has remained well since.The results therefore show that

in a three-year period

80% of the patients who were being treated with folic

acid had developed or had increased signs and symptoms

of nervous system disease that could be quite quickly controlled

in the early stages by treatment with intramuscular

liver extracts or oral desiccated stomach preparations.

Thus there is obviously serious risk that patients with pernicious

anaemia treated solely with folic acid may develop

signs of disturbance of the central nervous system, or that

any initial cord involvement or peripheral neuritis may get worse.Consequently,

it is our

considered opinion that folic acid ordinarily should-not be

used in the treatment of pernicious anaemia, and never in

subacute combined degeneration of the spinal cord.Therefore, whatever the

circumstances, folic acid, if used

at all, should be replaced by liver or stomach as soon as

possible, and those patients having folic acid should be

seen at frequent and regular intervals so that the onset of

neurological complications can be corrected without delay.its use was allowable

in the treatment of other

megaloblastic anaemias that do not develop cord lesions,

like those occurring in sprue, steatorrhoea, and pregnancy.This must now be

reconsidered carefully in view of the

recent observation by Meyer (1948) that combined system

disease occurred in a patient with macrocytic anaemia

secondary to ulcerative colitis of long standing. After treatment

with folic acid for 18 months he quite quickly

developed ataxia, loss of vibration and position sense in the

legs, and positive pyramidal signs. These neurological complications

appeared when the patient's haemoglobin level

was normal and his weight satisfactory. son and

Girdwood (1948) have also reported the onset of neurological

signs in two patients with idiopathic steatorrhoea who

were having folic acid treatment; the signs in these patients

could have been due to peripheral neuritis, and no pyramidal

lesion was detected. It is only reasonable to point

out that this neurological complication of non-ian

types of anaemia is extremely rare.

full free

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2051766/pdf/brmedj03650...

FOLATE AND FATTY ACID METABOLISM

Abnormal Fatty Acid Metabolism in Peripheral

Nerves of Patients with Pernicious Anemia

INTRODUCTION

The administration of vitamin B12 to patients with pernicious

anemia (PA)' results in correction of the hematopoietic

abnormalities as well as stabilization or improvement

in the neurologic lesions. It has been known

for some time that folic acid administration is also capable

of repairing the megaloblastic state (1) but that it

fails to improve and may in fact worsen the neurologic

disease (2, 3). The explanation for the folic acid effect

is thought to be as follows: In man vitamin B12 is

known to participate in the methyltransferase reaction

(Ns-methyltetrahydrofolate methyltransferase) where homocysteine

conversion to methionine provides tetrahydrofolate

for a variety of chemical reactions (Fig. 1)

(4). The source of folate in this reaction is the storage

form of folate, N -methyltetrahydrofolic acid. The clinical

expression of vitamin B12 deficiency, via interference

with this pathway, is based upon the need of B12 as a

coenzyme for the methyltransferase reaction. Thus B12

deficiency results in a " trapping " of this storage folate

reducing available active folate coenzyme forms.

free full

http://ukpmc.ac.uk/picrender.cgi?artid=153071 & blobtype=pdf

FOLATE FORTIFICATION DANGERS

Folic acid fortification: a double-edged sword

Lucock M, Yates Z.

School of Environmental & Life Sciences, University of Newcastle, P.O. Box 127,

Brush Road, Ourimbah, NSW 2258, Australia. Mark.Lucock@...

Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):555-64.

PURPOSE OF REVIEW: To examine the impact of folic acid fortification, including

its use as a functional food component, on human health. RECENT FINDINGS: There

is a consensus view that folic acid supplementation has numerous health

benefits, many of which are significant in their impact. However, emerging

evidence suggests that increased population exposure to folic acid may also have

a negative impact with respect to certain developmental and degenerative

disorders. As examples, presently much attention is focused on the role of folic

acid fortification augmenting colon cancer risk, whereas earlier in the life

cycle, the vitamin may additionally influence insulin resistance. Without

question, conditions that are influenced by folic acid are both diverse and many

- from concerns relating to cognitive decline, breast cancer and vascular

disease through to preconceptional issues where maternal folate levels might

conceivably alter the phenotype of

offspring via epimutations. SUMMARY: The highly complex and critical biological

importance of folic acid-related molecular nutrition makes it a difficult

micronutrient to deploy as a simple intervention at a population level - it has

far too many biochemical spheres of influence to predict effects in a

generalized way. Additionally, several gene variants and other nutrients are

interactive factors. It is, therefore, hardly surprising that the scientific

community does not have a true consensus view on whether mandatory fortification

is appropriate as a population measure. This latter point not withstanding, any

ultimate decisions on fortification should be well rooted in scientific fact

rather than political expediency.

FOLATE AND BLOOD BRAIN BARRIER

" focal epileptic discharges may result from accumulation of folate at the site

of the focus as a result of local damage to the blood brain barrier "

Obbens 1973

FOLIC ACID IN BRAIN METABOLISM

It is suggested that folic acid may interfere with the metabolism of 1(+)

glutamic acid in the central nervous system and possibly disturb the formation

or function of acetylcholine.

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/3/1/68

WITH FOLATE DISTURBANCE OF ACETYLCHOLINE WE LOOK NOW TO ACETYL CHOLINE

METHIONINE SAH-SAM

Choline-related supplements improve abnormal plasma methionine-homocysteine

metabolites and glutathione status in children with cystic fibrosis.

Innis SM, son AG, Melynk S, SJ.

Department of Paediatrics, University of British Columbia, Vancouver, BC,

Canada. sinnis@...

BACKGROUND: Liver triacylglycerol accumulation and oxidative stress are common

in cystic fibrosis (CF) and also occur in choline deficiency. Previously, we

showed an association between elevated plasma homocysteine, reduced ratios of

S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) and of

phosphatidylcholine to phosphatidylethanolamine, and phospholipid malabsorption

in children with CF. OBJECTIVE: The objective was to address a possible relation

between altered methionine-homocysteine metabolism and choline metabolism in

children with CF. DESIGN: Children with CF were assigned without bias to

supplementation with 2 g lecithin/d (n = 13), 2 g choline/d (n = 12), or 3 g

betaine/d (n = 10) for 14 d. Plasma concentrations of methionine, adenosine,

cysteine, cysteinyl-glycine, glutathione, glutathione disulfide (GSSG), and

fatty acids; SAM:SAH; and red blood cell phospholipids were measured within each

group of children with CF before and after

supplementation. Plasma from healthy children without CF (n = 15) was analyzed

to obtain reference data. RESULTS: Children with CF had higher plasma

homocysteine, SAH, and adenosine and lower methionine, SAM:SAH, and

glutathione:GSSG than did children without CF. Supplementation with lecithin,

choline, or betaine resulted in a significant increase in plasma methionine,

SAM, SAM:SAH, and glutathione:GSSG and a decrease in SAH (n = 35).

Supplementation with choline or betaine was associated with a significant

decrease in plasma SAH and an increase in SAM:SAH, methionine, and

glutathione:GSSG. Supplementation with lecithin or choline also increased plasma

methionine and SAM. CONCLUSION: We showed that dietary supplementation with

choline-related compounds improves the low SAM:SAH and glutathione redox balance

in children with CF.

FOLATE AND BEHAVIOR AND GASTRO

TOXICITY OF FOLIC ACID GIVEN IN PHARMACOLOGICAL DOSES TO HEALTHY VOLUNTEERS

Original Text Hunter a, Joanna a, H.F. Oakeley b, D.M. s c

Abstract

A trial to elucidate the effect of folic acid in pharmacological doses (15 mg.

daily) on serum-vitamin-B12 levels in a group of fourteen healthy volunteers was

abandoned after 1 month of a projected 3-month period because of the unexpected

development of increasingly disturbing toxic effects in the majority. Most of

the subjects experienced mental changes, sleep disturbance and gastrointestinal

symptoms. Possible mechanisms of these effects are discussed.

Subacute combined degeneration of the cord, dementia and parkinsonism due to an

inborn error of folate metabolism.

P T Clayton,

I ,

B Harding,

K Hyland,

J V Leonard,

R J Leeming

Abstract

A 2-year-old girl with 5,10-methylenetetrahydrofolate reductase deficiency

developed subacute combined degeneration of the cord and a leuco-encephalopathy

which was confirmed at necropsy. Total folate concentrations in serum, red cells

and CSF were markedly reduced whereas vitamin B12 concentrations were normal. In

addition the patient had Parkinsonism and reduced concentrations of homovanillic

acid, 5-hydroxyindoleacetic acid and total biopterins in cerebrospinal fluid.

Folic acid administration was accompanied by fits and acute deterioration in the

movement disorder. At necropsy the basal ganglia showed no detectable

abnormality.

http://www.ncbi.nlm.nih.gov/pubmed/3755752

Science NewsLow Levels Of Salivary Cortisol Associated With Aggressive Behavior

(Jan. 20, 2000) — Consistently low salivary levels of the stress hormone

cortisol in boys aged 7 to 12 are associated with early onset and persistence of

extremely aggressive behavior report researchers from the University of Chicago

in the Archives of General Psychiatry.

In a four-year study of boys with behavioral problems, those with consistently

low cortisol levels began antisocial acts at a younger age, exhibited three

times the number of aggressive symptoms, and were three times as likely to be

singled out by their classmates as mean or combative as those who had higher or

fluctuating cortisol concentrations.

The finding may help psychiatrists better understand differences between

adolescent males undergoing a short-term dalliance with delinquent behavior and

those with severe and lasting conduct disorder, which is notoriously difficult

to treat. Children with persistent conduct disorder tend to remain disruptive

for decades and account for a hugely disproportionate percentage of total crimes

and violent acts.

The finding also suggests that there is a " lasting biological and not just

parental or short-term environmental component to this type of chronic

antisocial behavior, " said McBurnett, Ph.D., assistant professor of

psychiatry at the University of Chicago and lead author of the study. " Children

with persistent conduct disorder may have genes that predispose them to produce

certain hormones differently, or their hormone production may have been altered

before or soon after birth. "

For four years, the researchers followed 38 boys who had been referred to a

psychiatric clinic for disruptive behavior. They collected saliva samples from

each boy in years two and four of the study. Through psychiatric evaluations and

interviews with parents and teachers, the researchers assessed the boys'

aggressive behaviors and tallied symptoms such as starting fights, using

weapons, being cruel to people or animals, stealing, or forcing sexual acts.

Each child in the study was also evaluated by his peers at school; classmates

were asked to rate all their fellow students on several behavioral categories,

including naming the three boys in class who were meanest, and fought most.

The researchers found that salivary cortisol levels were " strongly and inversely

related to aggressive conduct disorder, peer aggression nominations and

oppositional defiant disorder. " The 12 children with low cortisol levels on both

samples averaged 5.2 symptoms of conduct disorder, compared to 1.5 such symptoms

in the 26 boys who had a higher level on either sample. More than one third of

boys with low cortisol were nominated by their peers as the " meanest " in the

class, compared with 10.5 percent of boys who had at least one higher cortisol

reading.

Eleven of the 12 boys with consistently low cortisol developed aggressive

symptoms before age ten. Less than half of those with at least one higher

cortisol level showed symptoms before age ten.

The groups with low, varied or high cortisol levels all had similar IQs,

socioeconomic and ethnic characteristics.

Although the mechanism connecting cortisol levels to aggressive behavior is

unclear, McBurnett suspects that variation in levels may serve as a marker for

abnormalities in the production of various stress hormones that influence the

body's response to a challenge or confrontation.

Cortisol is secreted in response to stressful or threatening situations. Low

levels may indicate how these young males will respond to potentially stressful

situations, suggests McBurnett. " Boys with consistently lower cortisol levels

may not be as afraid of retribution, " he suggested. " In many aggressive

children, the system that responds to the threat of punishment does not react

normally.

They may not feel stress in the same way and so they don't avoid stressful

situations. "

Other researchers contributing to this report include Lahey, Ph.D., and

Rathouz, Ph.D., of the University of Chicago, and Rolf Loeber, Ph.D., of

the University of Pittsburgh and Free University, Amsterdam, the Netherlands.

Support for the research was provided by the National Institutes of Health.

EXCESS FOLATE AND TOLOMERE LENGTH CANCER INCREASES

Ligi 09 Telomere Length in

> PBMCs Folate Status in Men

>

> > " Human chromosomes are capped by telomeres, which

> consist of tandem repeats of DNA and associated proteins.

> The length of the telomeres is reduced with increasing cell

> divisions except when the enzyme telomerase is active, as in

> stem cells and germ cells. Telomere dysfunction has been

> associated with development of age-related pathologies,

> including cancer, cardiovascular disease, Alzheimer's

> disease, and Parkinson's disease. DNA damage in the

> telomeric region causes attrition of telomeres. Because

> folate provides precursors for nucleotide synthesis and thus

> affects the integrity of DNA, including that of the

> telomeric region, folate status has the potential to

> influence telomere length. Telomere length is epigenetically

> regulated by DNA methylation, which in turn could be

> modulated by folate status. In this study, we determined

> whether folate status and the 677C > T polymorphism of

> the methylene tetrahydrofolate reductase (MTHFR) gene are

> associated with the telomere length of peripheral blood

> mononuclear cells in healthy men. The results of our study

> showed that plasma concentration of folate was associated

> with telomere length of peripheral blood mononuclear cells

> in a nonlinear manner. When plasma folate concentration was

> above the median, there was a positive relationship between

> folate and telomere length. In contrast, there was an

> inverse relationship between folate and telomere length when

> plasma folate concentration was below the median. The MTHFR

> 677C > T polymorphism was weakly associated (P = 0.065)

> with increased telomere length at below-median folate

> status. We propose that folate status influences telomere

> length by affecting DNA integrity and the epigenetic

> regulation of telomere length through DNA methylation. "

MORE FOLATE CANCER

http://bloodjournal.hematologylibrary.org/cgi/content/abstract/103/...

Here, we provide additional evidence on the protective role of these

polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric

cancer. A case-control study was conducted in 270 ALL patients and 300 healthy

controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298

individuals were associated with reduced risk of ALL (crude odds ratio [OR] =

0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6;

respectively). Further stratification in patients born before and after January

1996 (approximate time of Health Canada recommendation for folic acid supplement

in pregnancy) revealed that the protective effect of MTHFR variants is

accentuated and present only in children born before 1996. eg protective against

cancer only in the group whom was not subjected to folate during development

The reluctance to proceed to mandatory food fortification with folic acid in

Europe has been fuelled primarily by concern regarding the potential risk of

masking the symptoms of pernicious anaemia caused by vitamin B12 deficiency. If

undiagnosed, there is potential for irreversible neurological damage in those at

high risk of this This work was completed on behalf of the EuroFIR Consortium

(FOOD-CT-2005-513944) and funded under the EU 6th Framework Food Quality and

Safety Programme deficiency, namely the elderly. Fortifying flour with vitamin

B12 along with folic acid does not seem to be a feasible option as the high dose

of B12 required to improve status among elderly people could put others in the

population at risk of excess intakes. Any action on fortification with folic

acid would, however, need to consider the adequacy of arrangements to routinely

detect B12 deficiency. There have been some reports of possible increases in

twinning associated with

periconceptional folic acid but this association is thought by many researchers

to be due to the confounding effect of folic acid supplementation being much

more common among women using assisted reproductive technology and the fact that

use of this technology may be significantly under-reported (Berry et al. 2005).

There is concern, however, about the possibility that high intakes of folic acid

may enhance the development of undiagnosed pre-malignant and malignant lesions.

EPIGENETIC CHANGES

Is folic acid good for everyone?1,2

A 1, Young-In Kim1 and Helga Refsum1

Fortification of food with folic acid to reduce the number of neural tube

defects was introduced 10 y ago in North America. Many countries are considering

whether to adopt this policy. When fortification is introduced, several hundred

thousand people are exposed to an increased intake of folic acid for each neural

tube defect pregnancy that is prevented. Are the benefits to the few outweighed

by possible harm to some of the many exposed? In animals, a folic acid–rich diet

can influence DNA and histone methylation, which leads to phenotypic changes in

subsequent generations. In humans, increased folic acid intake leads to elevated

blood concentrations of naturally occurring folates and of unmetabolized folic

acid. High blood concentrations of folic acid may be related to decreased

natural killer cell cytotoxicity, and high folate status may reduce the response

to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and

cancer. In the

elderly, a combination of high folate levels and low vitamin B-12 status may be

associated with an increased risk of cognitive impairment and anemia and, in

pregnant women, with an increased risk of insulin resistance and obesity in

their children. Folate has a dual effect on cancer, protecting against cancer

initiation but facilitating progression and growth of preneoplastic cells and

subclinical cancers, which are common in the population. Thus, a high folic acid

intake may be harmful for some people. Nations considering fortification should

be cautious and stimulate further research to identify the effects, good and

bad, caused by a high intake of folic acid from fortified food or dietary

supplements. Only then can authorities develop the right strategies for the

population as a whole.

Key Words: Folate • folic acid • vitamin B-12 • fortification • supplements •

cancer • antifolates • cognition • epigenetics • public health

http://www.ajcn.org/cgi/content/full/87/3/517

The data reported by Pfeiffer et al (26) show that the section of

theUSpopulation with the highest blood concentrations of folate

after fortification is children aged5 y, 43% ofwhomhad serum

folate concentrations 45.3 nmol/L. Ten percent of these children

had concentrations 77.3 nmol/L. We can estimate the

intake of folic acid equivalents needed to achieve these concentrations

from the formula provided by Quinlivan and

(25): 43% of children aged5 y are consuming the equivalent of

780 g folic acid/d, ie, double the proposed tolerable upper

limit (300–400 g/d) for children of that age. It is striking that

10% are consuming1320 g folic acid/d, which is well above

the tolerable upper limit of 1000g/d for adults. The next highest

blood concentrations were found in children aged 6–11 y; the

third highest concentrations occurred in those aged 60y, of

whom 38% had45.3 nmol/L. We simply do not know whether

these concentrations may cause harm, but it must be of concern

that such high concentrations occur, particularly in children at a

rapid stage of development, when it likely that epigenetic

changes are occurring in many tissues. A recent study in mice

showed that varying the methyl donor status of the postweaning

diet in mice could influence the methylation status and the expression

of imprinted genes (180). Could the same thing happen

in young children?

Hereditary Folate Malabsorption.

Goldman ID, Min SH, Sandoval C, Kronn D.

In: Pagon RA, Bird TC, Dolan CR, s K, editors. GeneReviews [internet].

Seattle (WA): University of Washington, Seattle; 1993-.

2008 Jun 17.

Excerpt

Disease characteristics. Hereditary folate malabsorption (HFM) is characterized

by impaired intestinal folate absorption and impaired folate transport into the

CNS. Findings include poor feeding and failure to thrive, anemia often

accompanied by leukopenia and/or thrombocytopenia, diarrhea and/or oral

mucositis, hypoimmunoglobulinemia, and infection with unusual organisms.

Neurologic manifestations include seizures and developmental delay in infants.

Ataxia and cognitive impairment may occur in older untreated individuals.

Diagnosis/testing. Diagnosis of HFM is confirmed by impaired absorption of an

oral folate load and low cerebrospinal fluid (CSF) folate concentration (even

after correction of the serum folate concentration). SLC46A1, encoding the

proton-coupled folate transporter (PCFT) protein, a member of the superfamily of

facilitative carriers, is the only gene known to be associated with HFM.

Sequence analysis has identified either homozygous or

compound heterozygous mutations in all 11 families tested to date. Management.

Treatment of manifestations: for systemic manifestations of folate deficiency,

low-dose parenteral (intramuscular) (1.0 to 5.0 mg/day) or high-dose oral

(~150-200 mg/day) 5-methyltetrahydrofolate (5-methylTHF) (Metafolin®) or

5-formyltetrahydrofolate (5-formylTHF) (folinic acid or Leucovorin®); neurologic

signs can be more difficult to correct. Prevention of primary manifestations:

Early treatment with 5-methylTHF or 5-formylTHF before symptoms appear can

prevent the metabolic consequences of folate deficiency. Surveillance: to assess

adequacy of treatment, periodic complete blood counts and measurements of the

concentrations of serum and CSF folate. Testing of relatives at risk: for sibs

of a proband, molecular genetic testing when the family-specific disease-causing

mutations are known; otherwise, assessment of intestinal absorption of folate

and CSF folate concentration.

Other: Folic acid should not be used for treatment of HFM; it is not a

physiologic folate and binds irreversibly to the folate receptors that transport

folates into cells. Genetic counseling. HFM is inherited in an autosomal

recessive manner. Heterozygotes (carriers) are asymptomatic and do not have

evidence of folate deficiency. At conception, each sib of an affected individual

has a 25% chance of being affected, a 50% chance of being an asymptomatic

carrier, and a 25% chance of being unaffected and not a carrier. In families in

which the disease-causing mutations are known, carrier testing for at-risk

relatives and prenatal testing for pregnancies at increased risk may be possible

through laboratories offering custom genetic testing.

PMID: 20301716 [PubMed]

http://www.ncbi.nlm.nih.gov/pubmed/20301716

GENDER DIFFERENCE

Effect of maternal multiple micronutrient supplements on cord blood hormones: a

randomized controlled trial.

Roberfroid D, Huybregts L, Lanou H, Henry MC, Meda N, Kolsteren P.

Child HealthNutrition Unit Department of Public Health Institute of Tropical

Medicine Antwerp Belgium.

Abstract

BACKGROUND: Fetal growth improves in pregnant women who take daily maternal

multiple micronutrients [united Nations International Multiple Micronutrient

Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone. OBJECTIVE:

Our objective was to test whether such an effect was mediated by changes in

concentrations of cord hormones. DESIGN: In a double-blind, controlled trial

carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive

UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth

factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in

a subsample of 294 live single newborns. We performed mediation analysis with an

Aroian test. RESULTS: UNIMMAP supplementation had no significant effect on cord

hormone concentrations. However, UNIMMAP supplementation significantly affected

concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male

newborns. In these

infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth

weight was mediated through IGF-I, whereas for female newborns, this proportion

was negligible. UNIMMAP supplementation also increased cortisol concentrations

by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02).

Growth-retarded babies had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin

(P = 0.04) than did infants with normal growth. Offspring of primiparae had

reduced IGF-I and insulin concentrations, and their cortisol concentrations were

25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin,

and insulin than did female newborns. CONCLUSIONS: UNIMMAP supplementation had

sex-specific effects on cord IGF-I and leptin concentrations that were of

unclear clinical significance. Other pathways may have been involved in the

action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae

could be related to constrained

fetal growth. Confirmatory studies are warranted. This trial was registered at

clinicaltrials.gov as NCT00642408.

http://www.ncbi.nlm.nih.gov/pubmed/20375185