Ear Infection

November 19, 2004

> My question is if he gets an antibiotic, should I ask for a

> prescription for Nystatin.

Yes.

I have GSE which I havent used with him

> yet. I tasted it today. YUCK- I have warts all over my hands and

> have been to Dr. 5 times to have them burned off and they are still

> here even after a bunch of home treatments. I read where GSE helped

> cure someone's warts so i figured Id try it first.

I have not read that GSE worked on a viral issue, altho you can

certainly try it.

I recently started olive leaf extract myself [when I had the flu last

month] and I have noticed that two small warts are gone.

>> I can still give

> him the Culturelle also right?

Yes.

Dana

November 19, 2004

Thanks Dana: I just got back from Doctor. He has double ear infections.

She gave me Diflucan, she felt it was easier. I have been thinking about

all this yeast and viral issues. My son very rarely had infections or

antibiotics when he was young. He has had quite alot in the past 2 years

with ear issues. Either infections from colds or swimmers ear. Now it

seems funny to me that his OCD has gotten way out of control in the past two

years. I thought of this when you brought up that alot of parents have felt

that OCD is connected to Viral issues. So this should be very interesting

indeed to see how he progresses with the OCD. When he is better from ears I

will have to try the OLE to see what happens. I was feeling a bit down as I

have not really seen positives with the enzymes, but his BM are much more

consistent, still watery and sponge like with the exception of the one day

they were beautiful LOL. I did get a chance today to talk with his aide at

school and she noticed that his OCD is better (not at home) his anxiety a

bit higher, but other than that no real problems (also circle walking more

she included this in anxiety). THanks for your help Eileen

>From: " danasview " <danasview@...>

>Reply-

>

>Subject: Re: Ear infection

>Date: Fri, 19 Nov 2004 15:21:41 -0000

>

> > My question is if he gets an antibiotic, should I ask for a

> > prescription for Nystatin.

>

>Yes.

>

> I have GSE which I havent used with him

> > yet. I tasted it today. YUCK- I have warts all over my hands and

> > have been to Dr. 5 times to have them burned off and they are still

> > here even after a bunch of home treatments. I read where GSE helped

> > cure someone's warts so i figured Id try it first.

>

>I have not read that GSE worked on a viral issue, altho you can

>certainly try it.

>

>I recently started olive leaf extract myself [when I had the flu last

>month] and I have noticed that two small warts are gone.

>

> >> I can still give

> > him the Culturelle also right?

>

>Yes.

>

>Dana

>

November 21, 2004

> Thanks Dana: I just got back from Doctor. He has double ear

infections.

> She gave me Diflucan, she felt it was easier.

Diflucan is an anti-fungal, so far as I know. So she determined that

these infections were fungus/yeast based? My kids will get yeast in

their ears also. Is the Diflucan working? It can be hard on the

liver, so watch for that.

>>I have been thinking about

> all this yeast and viral issues. My son very rarely had infections or

> antibiotics when he was young. He has had quite alot in the past 2

years

> with ear issues. Either infections from colds or swimmers ear.

Chlorine can really aggravate yeast issues

http://www.danasview.net/chlorine.htm

For my son, milk will cause excessive ear wax, even with enzymes, even

after being fully chelated. So you might want to reduce or remove

milk. I don't give my son glasses of milk, etc, but I do allow

butter, cheese, and cream sauce and other things.

Dana

November 21, 2004

Hi Dana: No the doctor didnt tell me if she determined if the ear

infections were yeast based. I just asked her for a script for Nystatin and

she gave DiFlucan (1) tablet. I have not given it to him yet. I have been

giving him the Culturelle. I was going to give the DiFlucan today.

He does not drink milk. Has refused it since he is about a year old or so.

The only milk based product he likes is ice cream. Wont eat cheese or any

other dairy products either.

The chlorine is something I never knew, but I am learning alot that I never

knew before.

I suppose he is CF except for the occasional ice cream, which is not often.

Dinner last night was Hamburger (no bun) has always eaten it this way,

french fries (baked in oven) but they are store bought, string beans.

Thanks Eileen

>From: " danasview " <danasview@...>

>Reply-

>

>Subject: Re: Ear infection

>Date: Sun, 21 Nov 2004 15:39:24 -0000

>

> > Thanks Dana: I just got back from Doctor. He has double ear

>infections.

> > She gave me Diflucan, she felt it was easier.

>

>Diflucan is an anti-fungal, so far as I know. So she determined that

>these infections were fungus/yeast based? My kids will get yeast in

>their ears also. Is the Diflucan working? It can be hard on the

>liver, so watch for that.

>

> >>I have been thinking about

> > all this yeast and viral issues. My son very rarely had infections or

> > antibiotics when he was young. He has had quite alot in the past 2

>years

> > with ear issues. Either infections from colds or swimmers ear.

>

>Chlorine can really aggravate yeast issues

>

>http://www.danasview.net/chlorine.htm

>

>For my son, milk will cause excessive ear wax, even with enzymes, even

>after being fully chelated. So you might want to reduce or remove

>milk. I don't give my son glasses of milk, etc, but I do allow

>butter, cheese, and cream sauce and other things.

>

>Dana

>

November 21, 2004

Yes, you can give Culturelle and GSE in the same day. I wouldn't necessarily

give them at the same time of day, especially in the beginning as die-off is

difficult enough with one product, much less two at once. We give Culturelle

at night, as the die-off issues are easier to manage when they sleep through

the initial effects of it. GSE die-off can produce some real rage issues,

weepiness, etc. I'd do it when you know you have a couple of days when

you're not on a real tight time schedule. Most days I'm a drill instructor,

with routine, but when I know I'll be treating for something, I make the

time to explain " why " 50 toys can't go with us in the car, and why this is

not a tragedy worthy of crocodile tears. Things like this pop up all day and

night during die-off, but I know his body is hurting, the equivalent of a

massive headache, body ache, tummy ache, etc. So I take my time with him.

Sorry if this e-mail is too long, but boy is it worth all the trouble when

you can get things cleared up. Ex. My Mom has a terrible infection that

required two antibiotics and an inhaler for asthma like symptoms. My son

caught it from her. After 4 days of Olive Leaf extract, with no alleviation

of symptoms, and 2 days of Oil of Oregano, with fever gone, cough minimized,

draining already occurring, definitely worth the weepiness we experienced

for about 50 minutes prior to dinner last night. Good luck to everyone. Ask

your doctor about Calcium Butyrate if your child tests positive for

Clostridia, really made a difference here.

Ear infection

>

> Hi-Me again-My son is going to doctor tomorrow as I believe he has

> an ear infection. He stayed home today with a soar throat. When I

> got home from work he complained that his ear hurt and he was warm.

> My question is if he gets an antibiotic, should I ask for a

> prescription for Nystatin. I have GSE which I havent used with him

> yet. I tasted it today. YUCK- I have warts all over my hands and

> have been to Dr. 5 times to have them burned off and they are still

> here even after a bunch of home treatments. I read where GSE helped

> cure someone's warts so i figured Id try it first. I can still give

> him the Culturelle also right? Thanks Eileen

>

November 21, 2004

ear infections, allergy, autism & gluten

Date: 19 Jul 1995

Jack Challem, Editor of The Nutrition Reporter newsletter,

wrote:

>I'm sure you'll hear a lot of opinions. But I'll point to you to a

>specific journal citation that confirmed what people have been

saying for

>years. The fundamental cause of ear infections is allergy, which

causes fluid

>retention in the ear, which creates a great breeding ground for

bacteria. The

>most common allergens for small children are milk and wheat.

>Nsouli TM, " Role of food allergy in serious otitis media, " ls

of Allergy,

>September 1994;73:215-219.

This is quite interesting because the IgA antibodies formed in the

gut are transported to all mucous membranes in the body and may

react with appropriate antigens. Because intact antigens are taken

up into the blood postprandially (1) and we have also demonstrated

increased levels of IgA antibodies to gluten, gliadin and casein in

some autistic patients (2,3); I can easily see a possible

connection, where all mucosal membranes are irritated by the

circulating antigen reacting with deposited IgA antibodies.

References:

1: Husby S et al (1985) Scand J Immunol 22:83-92.

2: Reichelt Kl et al (1990) J Applied Nutr. 42:1-11

3: Reichelt KL et al (1994) Develop Brain Dysfunct. 7:71-85

November 21, 2004

Immunodeficiency, gastrointestinal Candidasis, wheat and diary

sensitivity, abnormal urine arabinose, and autism:

A Case Study

by Shaw, Ph. D., Great Plains Laboratory

Baptist, MD Ph.D., Speer Allergy Clinic &

Geenens, D.O.

Abstract

A child with autism was found to have complete IgA deficiency (serum

IgA <6 mg/dL; normal 33-235mg/dL), Candidiasis of the

gastrointestinal tract based on evaluation of stool testing,

elevated urine arabinose, and elevated serum antibodies to wheat and

dairy products. The pretreatment urinary arabinose concentration

(341 mmol/mol creatinine in this child was nearly six times the mean

value (60.4 mmol/mol creatinine, n=20) of normal children and over

ten times the median value (31.0 mmol/mol creatinine) of normal

controls. After antifungal therapy for 4 months, the urine was

retested. At the time the urine arabinose was measured at 51

mmol/mol creatinine, a value only 15% of the baseline sample.

Restriction of wheat and dairy products from the diet and antifungal

therapy led to a significant decrease in autistic behaviors and

increased rate of learning. The Childhood Autism Rating Scale

(CARS), an observational measure of various aspects of autism, for

the child has decreased from a rating of 43 (severely autistic)

prior to introduction of these therapies to a value of 29 (non-

autistic) after therapy.

Introduction

Studies done by the late Warren Ph.D. at Utah State University

and others indicate that most children with autism have a

substantial immune abnormality of some type (1-20). Kontstantareas

and Homatidis (21) at the University of Guelph in Ontario, Canada

found a high correlation between the prevalence of ear infections

and the incidence of autism. they found that the earlier the child

had an ear infection, the more likely that child had a more severe

form of autism. They also found that increased incidence of ear

infections was associated with a more severe rather than a mild form

of autism. Candida infection has been reported as consequence of

frequent antibiotic usage in both humans and animals (22-30) and an

abnormal increase in the sugar arabinose probably form Candida has

been reported in urine sample of two siblings with autism (31).

However, Candida infection may also be common in children with

immunodeficiencies who do not have an unusually high number of

infections treated with antibiotics. The patter of gastrointestinal

Candida overgrowth, immunodeficiency, metabolic disorder and autism

is well-illustrated in the medical history of the child evaluated by

us.

Previous medical evaluation

The child evaluated is a five year old Caucasian male with a normal

birth at term and normal apgar scores. Newborn metabolic screens

for phenylketonuria, hypothyroidism, galactosemia, and sickle-cell

disease were within normal limits. Both parents are college

graduates; both parents are considered socially well-adjusted. The

maternal grandmother suffered from multiple sclerosis and is now

deceased. The maternal grandfather died secondary to viral

cardiomyopathy; as a child he did not speak until three years of age

but then talked and developed normally. The paternal grandparents

are in good health.

The child was evaluated by a pediatric opthalmologist at six months

of age for intermittent crusting and tearing of the left eye which

was non-responsive to antibiotic drops. The patient had surgery for

the blocked tear-duct and a possible undescended testicle at 16

months. Exploratory surgery did not located the missing testicle;

the patient was put on porphylactic antibiotics after surgery. Up

to the age of three years, the patient had had only one or two ear

infections treated by antibiotics, a couple of colds, and an upper

respiratory infection. Immunizations were all on schedule. A

routine physical examination at 15 months of age assessed

development as normal although concerns about lack of speech were

expressed by parents. The MMR vaccine was administered at this

checkup. Assessment by the pediatrician at 18 months was a " healthy

1.5 year old " who " does not need to return until 2 years of age. "

Deficiency of expressive language was noted in the medical record

but the parents were not advised to seek additional consultation.

At a pediatric evaluation at 2 years of age, lack of expressive

language (only 5 words) was again noted by not follow-up was

recommended. At a pediatric evaluation at 2.5 years of age, no

expressive language was noted and the child was referred to a

hearing and speech clinic for evaluation. Diet was noted to consist

of bread, pancakes, milk peanut butter, and chicken. He was noted

to always have loose stools. The subsequent hearing evaluation

revealed normal hearing but recommended a developmental assessment

of the child. Three months later at the age of 27 months, the child

was diagnosed with autism by a developmental pediatrician at a

university autism clinic using DSM-IV diagnostic criteria;

developmental age was assessed as a t the 19-20 month level. At

this exam, otitis media was diagnosed and treated with Amoxicillin.

A MRI scan of the head revealed some atrophy of the frontotemporal

lobe. EEG and fragile X chromosome studies were normal. The child

was seen by a second university autism clinic in another state which

confirmed the original diagnosis. The parents of the child were

referred to support groups, to speech therapists, and to special

schools for education and behavioral modification but were not

referred for any evaluation of the child's immune or

gastrointestinal function.

When the child was 4.75 years of age, the parents decided to embark

on additional biochemical assessment of their child including

allergy assessment, routine chemistry and hematology, evaluation of

stool microorganisms, evaluation of immune function, and urine

organic acid testing.

Comprehensive food allergy testing for 96 foods were performed using

IgG specific enzyme linked immunoassay. The following allergens

were positive for IgG-specific enzyme linked immunoassay: barley,

gluten, heat, bran, cow's milk, cheeses (cheddar, cottage, and

Swiss), beef, grapefruit, orange, peanut, soybean, and sugar. The

IgA endomysial antibody test which is considered to be specific for

celiac disease was negative in this child.

Normal serum values were found for all of the following: glucose,

urea nitrogen, creatinine, total protein, albumin, total bilirubin,

alkaline phosphates, AST, ALT, LDH, calcium, phosphorus, blood lead,

sodium, potassium, chloride, bicarbonate, uric acid, triglycerides,

cholesterol, anion gap, thyroxine, antinuclear antibodies,

thryotropin (highly sensitive), iron, copper, magnesium, corisol,

zinc and ferritin. White cel count was slightly low (4900/mm3);

normal: 5500-15,500/mm3. Hemoglobin and hematocrit were normal.

The white cell differential was normal except for a slight elevation

of atypical lymphocytes. The absolute number and percentage of CD3,

Cd4, and CD8 cells, evaluated by flow cytometry were all within

normal limits.

Analysis of serum immunoglbulins revealed normal values for serum

IgG, IgM, IgE and IgG subclasses but undetectable values for serum

IgA (Table 1). Stool analysis revealed a 4+ overgrowth of Candida

parapsilosis; normal is 0 and the highest possible overgrowth is

4+. Antifungal sensitivity of the organism indicated sensitivity to

fluconzole, itraconazole, nystatin, ketoconazole, and garlic.

Bacteria in the stool sample usually considred beneficial were

Lactobacillus (2+) and Bifidobacteria (4+). Stool analysis also

revealed 3+ levels of gamma streptococci and 4+ hemolytic E. coli.

An evaluation of a urine sample by gas chromatography-mass

spectrometry as described previously (31) taken at the same time

indicated significant increases of the sugar arabinose as the major

abnormality; there were no abnormalities associated with any

recognized inborn error of metabolism.

Therapy

Because of elevated Candida in the stool sample, indicating a

gastrointestinal yeast overgrowth, the child was placed on 100,000

Units nystatin four times a day plus alternating weeks of Nizoral or

Diflucan (2mg/kg) and was also placed on a gluten and casein free

diet approximately two months after beginning antifungal therapy.

Both dietary and antifungal therapy are continuing five months

later. The pretreatment urinary arabinose concentration (341

mmol/mol creatinine in this child was nearly six times the mean

value (31.0 mmol/mol creatinine) of normal controls. After

antifungal therapy for four months, the urine was retested. At that

time the urine arabinose was measured at 51 mmol/mol creatinine, a

value only 15% of the baseline sample. With two additional months

of antifungal treatment, the urine arabinose value decreased to 26

mmol/mol creatinine. A follow-up stool test indicated the absence

of Candida in the sample.

Results of therapeutic interventions.

The mother of the child reports a significant increase in eye

contact, a significant decrease in self-stimulatory behavior, and

increased use of spontaneous language shortly after beginning

antifungal therapy. After beginning the casein and gluten free

diet, the mother reports the child was able to follow three step

verbal directions versus only one step directions previously. The

mother also reported increased learning speed in the schooling

program, increased verbal labeling, and increased spontaneous verbal

initiations. The score for the child on the Childhood Autism Rating

Scale (CARS), an observational measure of various aspects of autism

has decreased from a rating of 43 (severely autistic) prior to

introduction of these therapies to a value of 29 (non-autistic)

after therapy. Cutoff for autism is 30 or above. The child is now

considered by the assessment team at the sate university autism

clinic to be a high-functioning individual with autism. The child

can now parallel play with other children in class, demonstrates an

interest in peers, shares toys, and is engaging in some imaginative

play.

Discussion

Selective IgA deficiency.

The most striking laboratory abnormality of this child is the

absence of detectable IgA. IgA is the antibody that is involved

with protection of the lining of the nasal passages and intestinal

lining from microorganisms. Secretory IgA or sIgA is a special form

of the IgA antibody that is secreted to protect the mucosa, which is

the lining of the intestinal tract. Secretory IgA on a stool sample

from this child was also noted as deficient. Secretory IgA is

apparently secreted by the gall bladder and then trickles down the

bile ducts into the small intestine. Some children with autism such

as this one have very low or even completely absent levels of IgA

(1,20); in such cases there is probably also a deficiency of a

secretory IgA since IgA is derived from IgA.

This extremely common immunodeficiency occurs in 1 in 600 - 1000

persons of European ancestry (32). The causes of IgA deficiency are

not completely known. There are some cases in which the deficiency

runs in families while in other cases it does not. It has been

reported in association with abnormalities of chromosome 18, but

most individuals with IgA deficiency have no detectable chromosomal

abnormalities (32). IgA deficiency may also be cased by drugs or

viral infection (rubella, cytomegalovirus, toxoplasmosis) and may be

also be associated with intrauterine infections. Patients with IgA

deficiency are usually deficient in both subtypes of IgA, IgA1 and

IgA2.

In Gupta's study (2), 20% of the children with autism had a

deficiency of IgA and 8% lacked it completely. Warren and his

colleagues (1) also found that 20% of individuals with autism had

low serum IgA compared with none of the normal controls. Thus,

complete IgA deficiency in autism is somewhere between 48 to 80

times higher in the autism population compared to a normal Caucasian

population.

IgA replacement therapy cannot be used currently because the short

half-life of IgA would make it an extremely expensive therapy.

However, bovine colostrum, which is commercially available is high

in IgA and might be considered as a possible therapy for IgA-

deficient patients. IgG therapy can be used with patients with low

IgA values. If the IgA values are so low that they cannot even be

detected, however, giving IgG therapy is too risky. It is possible

that the immunodeficient person's body would produce antibodies

against IgA present in gamma globulin, causing potentially fatal

anaphylactic shock.

The clinical consequences of IgA deficiency range from severe

systemic infection to a perfectly healthy state. Many IgA-deficient

persons are never aware of their antibody deficiency while others

may have recurrent infections, allergic diseases, and autoimmune

diseases (32). This child with autism had significant Candidiasis

of the gastrointestinal tract despite the fact that the child had

only two courses of antibiotics during his lifetime. Thus,

intestinal Candidiasis following antibiotic therapy appears to be a

much greater risk in a child with immunodeficiency. The decrease in

symptoms of autism after antifungal therapy and gluten and casein

restriction have been noted in many children with autism (33). (The

authors are aware of three children with autism diagnosed at

university autism centers who are now considered symptom-free after

antifungal treatment and gluten and casein restriction).

The child being presented was never considered a " sickly " child by

the parents. It is possible that the difficult to treat eye

crusting may have been related to the IgA deficiency since IgA is

secreted in tears, saliva, and gastric juice; the deficient IgA in

the tears may have led to a grater number of eye infections. The

occurrence of multiple sclerosis in the maternal grandmother might

be of significance but she was never evaluated for IgA deficiency.

The remarkable spectrum of clinical manifestations of this

immunodeficiency may be related to variations in the ability to

replace IgA antibodies in the mucous secretions with IgM

antibodies. IgG2 and IgG4 subclass deficiencies are common in IgA

deficiency but were not present in this individual.

IgA deficiency and celiac disease

The incidence of selective IgA deficiency is 10 times higher in

patients with celiac disease compared to the general population

(34). The diagnosis of celiac disease cannot be excluded in an IgA

deficient child because the endomysial antibody test uses an IgA

antibody specificity and may yield false negative results in such

cases (35) so the possibility that the child may have celiac disease

cannot be excluded. The parents elected to place the child on a

wheat and dairy-free diet based on the ELISA-allergy test results so

a diagnosis of celiac disease by intestinal biopsy would not be

valid for this child. Positive IgG antibodies to gluten were found

in 100% of IgA-deficient persons with biopsy proven celiac disease

but who were negative by the endomysial antibody test (35). Most

children with autism are sensitive to both gluten, the major protein

in wheat and barley, and to casein, the major protein in cow's milk

(36-40). Elevation of IgG antibodies to wheat, barley and several

dairy products is common in autism even though most children with

autism do not have celiac disease (36-40).

Candidiasis and abnormal arabinose: possible implications in brain

structure and function

The exact biochemical role of elevated arabinose is unknown but a

closely related blood sugar alcohol, arabitol, has been used as

biochemical indicator of invasive Candidiasis (41-43) We have never

found elevated arabitol in thousands of urine samples tested,

including many sample with elevated arabinose and high yeast counts

in the stool. Elevated arabinose in the urine of two brothers with

autism was first reported by Shaw et al. in 1995 (31) and has since

then has been reported to prevalent in urine samples from people

with autism (33); values as high as 4000 mmol/mol creatinine have

been found in children with autism (unpublished data). We have

found arabitol but not arabinose in the culture media of multiple

isolates of Candida albicans isolated form stool samples of autistic

children (unpublished data). Presumably elevated arabitol in the

urine may only occur in systemic rather than gastrointestinal

Candidiasis since arabitol in portal blood is converted to arabinose

in the liver. Arabinose in the urine decreased markedly after

antifungal therapy, concomitantly with an elimination of stool

Candida. Arabinose, a sugar aldehyde or aldose reacts with the

epsilon amino group of lysine in a wide variety of proteins and may

form cross-links with arginine residues in an adjoining protein

(44), thereby cross-linking the proteins and altering both bilogical

structures and functions of a wide variety of proteins including

proteins involved in the interconnection of neurons. Decreased

clinical symptoms of autism after antifungal treatment would be due

to decreased arabinose and pentosidine formation, resulting in fewer

random neural connections (neural noise) and increased numbers of

neural connections that are oriented to the child's environment.

This adduct of arabinose, lysine, and arginine is called pentosidine

(Figure 1). The epsilon amino group of lysine is a critical

functional group of many enzymes to which pyridoxal (vitamin B-6),

biotin and lipoic acid are covalently bonded during coenzymatic

reactions (45); the blockage of these active lysine sites by

pentosidine formation may cause functional vitamin deficiencies even

when nutritional intake is adequate. In addition, this epsilon amino

group of lysine may also be important in the active catalytic site

of many enzymes. Protein modification caused by pentosidine

formation is associated with cross link formation, decreased protein

solubility, and increased protease resistance. The characteristic

patholigical structures called nerofibrillary tangles associated

with Alzheimer disease contain modifications typical of pentosidine

formation. Specifically, antibodies against pentosidine react

strongly to neurofibrillary tangles and senile plaques in brain

tissue from patients with Alzheimer disease (46). In contrast,

little or no reaction is observed in apparently healthy neurons of

the same brain.

thus, it appears that the neurofibrillary tangles of Alzheimer's

disease may be caused by the pentosidines. The modification of

protein structure and function caused by arabinose could account for

the biochemical and insolubility properties of the lesions of

Alzheimer disease through formation of protein cross links. Similar

damage to the brains of autistic children might also be due to the

the pentosidine cross-links. Since pyridoxal (vitamin B-6) reacts

with the same critical epsilon amino group of lysine, it is possible

that the beneficial effects of vitamin B-6 in autism reported in

multiple studies (48) may be mediated by prevention of further

pentosidine formation. Analysis of brain tissue of people with

autism for increased brain pentosidines could be invaluable in the

confirmation of this hypothesis.

Women with vulvovagnitis due to Candida were found to have elevated

arabinose in the urine (49); restriction of dietary sugar brought

about a dramatic reduction in the incidence and severity of the

vulvovaginitis. Thus, one of the mechanisms of action of antifungal

drug therapy for autism might be to reduce the concentration of an

abnormal carbohydrate produced by the yeast that can not be

tolerated by the child with defective pentose metabolism or an

inability to remove harmful pentosidines. Arabinose tolerance tests

should be able to rapidly determine if such biochemical defects are

present in children with autism.

A model for autism

The success of Gupota (2) in treating the autistic symptoms of

children with autism with gamma globulin therapy indicates an immune

abnormality in autism. Based on these findings and our findings of

abnormal arabinose and other organic acids in other children with

autism (31,33), we propose the following model for autism.

According to this model, immune deficiencies which may be genetic or

acquired lead to an increased frequency of infections which in the

United States are almost always treated with broad spectrum oral

antibiotic usage and greater proliferation of yeasts and antibiotic-

resistant bacteria, setting up a vicious cycle. These organisms

produce high amounts of abnormal carbohydrates such as arabinose and

Krebs cycle analogs such as citramalic and tartaric acids (31).

there is no inherent reason that dramatic biochemical changes in

multiple biochemical systems caused by microorganisms would not be

expected to alter brain structure and function. In PKU, correction

of the metabolic defect by restriction of phenylalanine during

infancy allows for normal development; retardation occurs if dietary

intervention occurs too late. If abnormally elevated metabolites

cause autism, then it is reasonable to think that elevations of

these compounds would have maximum negative impact during periods of

critical brain growth and development. As in PKU, metabolic

intervention in autism night only be possible in the early stages of

the disorder before the brain has matured. The differences in

severity of disease and individual differences in symptoms might be

due to different combinations of metabolites become abnormally

elevated, and the susceptibility of the individual developing

nervous system to the different microbial metabolites.

some children with autism have a history of frequent infections: two

different parents of children with autism indicated to the authors

that their children had over 50 consecutive infections

(predominantly otitis media) treated with antibiotics. However,

some children with autism such as the child presented here id not

have excessive use of oral antibiotics and was not considered to be

a " sickly child " by the parents or attending physicians. In this

child the underlying immune deficiency and two uses of antibiotics

apparently led to a persistent yeast overgrowth of the intestinal

tract.

Generic immunodeficiencies proposed as the major genetic factors in

autism.

Ritvo et al. (54) found a concordance rate for autism of 23.5% in

dizygotic twins and 95.7% in monozygotic twins, indicating a strong

genetic basis for autism. However, the results of the Stanford

autism genetics study of 90 families affected by autism (55)

indicate " that there are no genes with a major effect for autism.

This is, our analyses show that autism is almost surely not a simply

single major gene disorder, such as Huntington disease. Rather, the

analyses from these 90 families indicate that there are likely to be

a relatively large number of different genes related to

susceptibility for autism, each with a minor effect. " We suspect

that many of these " relatively large number of genes " are those that

regulate the immune system. We have been impressed with the large

number of studies that have indicated a wide number of abnormalities

of the immune system in autism (1-20) including IgG deficiency, IgA

deficiency, IgG subclass deficiency, myeloperoxiase deficiency (a

genetic defect in an enzyme of the leukocytes that produces

hypochorite ion to kill yeast), reduced natural killer cell

activity, markedly elevated serum levels of cytokines interleukin-12

and interferon-gamma, increased anti-myelin and serotonin receptor

antibodies, increased DR+ T cells, and a deficiency in complement

C4b. In addition, some immune abnormalities in autism have been

linked to adverse reactions to vaccinations (56). The two brothers

with autism in which abnormal arabinose and abnormal organic acids

were first reported (431) both had abnormally low concentrations of

serum IgG. Autism has also been diagnosed in other children with

defined inborn errors of metabolism such as biotinidase deficiency

and isovaleric acidemia (Lombard, Personal Communication) in which

yeast infections are common.

Efforts to locate a single autism gene would fail since any generic

factor that severely impairs the immune system may eventually lead

to the proliferation of antibiotic-resistant yeasts and bacteria

which then alter behavior of children at critical periods of

development through the excretion of abnormal microbial metabolic

products. Thus, autism appears to be a complex metabolic disorder

involving immune deficiencies, autoimmune abnormalities, abnormal

food sensitivities, and gastrointestinal microbial overgrowths that

may result in altered human metabolism and protein function.

Figure 1. Reaction of arabinose from yeast with amino groups of

lysine to form a Schiff base adduct. The rearranged Schiff base

then reacts with a guanido group on an arginine residue of a second

protein, resulting in tow different proteins crosslinked through a

pentosidine moiety.

Figure 2. Immunodeficiency model for autism. In this model,

immunodeficiencies lead to antibiotic use that stimulates yeast

overgrowth (primarily Candida) of the gastrointestinal tract.

Certain strains of Candida produce immunosuppressant compounds

called gliotoxins that further weaken the immune system and may lead

to additional infections. Arabitol produced by Candida in the

gastrointestinal tract is converted to arabinose in the liver.

Elevated arabinose then leads to pentosidine formation, leading to

increased neurofibrillary tangles in the brain.

Table 1. Serum immunoglobulins in child with autism

Immunoglobulins class Child's value Reference Range

IgG 833 mg/dL 593-1723 mg/dL

IgA <6 mg/dL 33-235 mg/dL

IgM 51 mg/dL 36-314 mg/dL

IgE 10 IU/ml 2-35 IU/ml

IgG-1 444 mg/dL 370-994 mg/dL

IgG-2 180 mg/dL 88-455 mg/dL

IgG-3 30 mg/dL 11-108 mg/dL

IgG-4 33 mg/dL 1-97 mg/dL

References