OJHAS Vol. 8, Issue 1: (2009
Assessment of Metabolic Parameters For Autism Spectrum Disorders
Ananth N Rao, Minakshi Koch, Suresh Kumar V, Sabyasachi Ghosh, Shobha G,
Laboratory, Narayana Hrudayalaya, Bangalore.
Dr. Ananth N. Rao,
Address For Correspondence
Rao AN, Koch M, Suresh Kumar V, Ghosh S, Shobha G. Assessment of Metabolic Parameters For Autism Spectrum Disorders. Online J Health Allied Scs.
Submitted: Jan 20, 2009; Suggested
revision Apr 10, 2009; Revised: Apr 17, 2009 Accepted: Apr
20, 2009 Published: May 5, 2009
Autism is a
brain development disorder that first appears during infancy or childhood,
and generally follows a steady course without remission. Impairments
result from maturation-related changes in various systems of the brain.
Autism is one of the five pervasive developmental disorders (PDD), which
are characterized by widespread abnormalities of social interactions
and communication, and severely restricted interests and highly repetitive
behavior. The reported incidence of autism spectrum disorders (ASDs) has increased
markedly over the past decade. The Centre for Disease Control and Prevention
has recently estimated the prevalence of ASDs in the United States
at approximately 5.6 per 1000 (1 of 155 to 1 of 160) children. Several metabolic defects,
such as phenylketonuria, are associated with autistic symptoms.
In deciding upon the appropriate evaluation scheme a clinician must
consider a host of different factors. The guidelines in this article
have been developed to assist the clinician in the consideration of
Autism, Biomarkers, Immunology, Metabolic profile
spectrum disorders are more common in the pediatric population than
are some better known disorders such as diabetes, spinal bifida, or
Down syndrome.(1) Prevalence studies have been done in several states
and also in the United Kingdom, Europe, and Asia. A recent study of
a U.S metropolitan area estimated that 3.4 of every 1,000 children 3-10
years old had autism.(2)
Many ASD children are highly attuned or even painfully sensitive to
certain sounds, textures, tastes and smells. Many children with ASD
have some degree of mental impairment. When tested, some areas of ability
may be normal, while others may be especially weak. One in four children
with ASD develops seizures, either starting in early childhood or adolescence.(3)
Seizures, caused by abnormal electrical activity in the brain, can
produce a temporary loss of consciousness (a “blackout”), a body
convulsion, unusual movements, or staring spells. Metabolic errors related
to autism include errors of carbohydrate metabolism (4), errors of peptide
metabolism (5), purine and pyrimidine disorders (6), and malabsobtion.(7) Autisms generally have abnormalities in related and overlapping
areas such as oxidative stress (8), decreased methylation capacity and
limited transsulfation (9,10), increased toxic burden-primarily of heavy
metals and especially of mercury (11,12), immunological dysregulation
with a unique inflammatory bowel disease and immune activation of glial cells in
the brain (13-16) and central nervous system hypo perfusion or abnormal
regulation of blood supply to the brain.(17)
data from the U.S and the U.K suggest that 1-2% of males under 12 may have
Metabolic profile and polymorphisms:
may be a biochemical, neurologic, hormonal, or immunologic biomarker
associated with the disease state. Thus, the abnormal metabolic profile
that was discovered in autistic children is an endophenotype that may
reflect subtle changes in gene products that regulate flux through methionine
transmethylation and transsulfuration pathways. Even small variations
in gene expression and enzyme activity, if expressed chronically, could
have a significant impact on downstream metabolic dynamics.(20)
controls, autistic children had a significant increase in the frequency
of the reduced folate carrier RFC-1 homozygous 80GG (33% vs. 26%) and
heterozygous 80GA (52% vs. 41%). Children with either the RFC-1 GA or
GG genotypes were approximately two times more likely to be autistic
(OR: 2.26 and 1.96, respectively). Importantly, a significant interaction
between heterozygous RFC-1 80GA genotype and both the MTHFR 677CT and
TT genotypes was observed among in the autistic children with odds ratios
of 3.24 and 4.4, respectively. In addition, an interaction between the
homozygous RFC-180GG and the MTHFR 677CT genotypes conferred a three
fold increase autism susceptibility. Finally, an interaction between
3 and 4 loci was found for the compound heterozygous MTHFR677CT/1298AC
and the RFC 80AG and GG genotypes. TheRFC-1 80 G allele is associated
with decreased intracellular folate transport and the MTHFR 677 T allele
reduces the synthesis of metabolically active folate. Together, common
variants in the RFC and MTHFR genes conferred greater susceptibility
to autism than either alone and suggest a potential etiologic role for
impaired folate-dependent one-carbon metabolism in the susceptibility
to autism. Consistent with low intracellular folate availability, methionine
levels were decreased among most autistic children. Thus, the metabolic
and genetic data support the possibility that the observed alterations
in methionine metabolism may be due, in part, to a genetic predisposition
for a functional folate deficiency.(20)
is the major transport protein required for the cellular uptake of vitamin
B12 by receptor-mediated endocytosis.(21) Previous studies indicate
that a common 776C>G transition in the TCN2 gene (proline>arginine)
decreases the binding affinity of TCN2 for vitamin B12 and reduces the
transport of B12 into cells.(22,23) Vitamin B12 is an essential cofactor
for the MS reaction and accepts the methyl group from 5-methylfolate
to generate methionine from homocysteine in the initial step of the
methionine transmethylation pathway. The frequency of the homozygous
TCN2 776GG variant was significantly increased among the autistic children
compared to controls (26% vs. 16%) and the GG variant was associated
with a 1.7-fold increased risk of autism. Although speculative, the
low methionine levels found in many autistic children support the possible
contribution of all three variant alleles, independently or combined,
to impaired methionine synthesis. In addition, children with a genetic
predisposition to impaired methionine synthesis would be especially
vulnerable to further reduction in enzyme activity with exposure to
endogenous or exogenous oxidative stress.(24)
genetic variant found to be significantly more frequent among autistic
children was the COMT 472 G allele. The methylation of dopamine by COMT
is an important mechanism for dopamine inactivation and dopaminergic
tone in the CNS.(25) The G>A transition at position 472 (valine>methionine)
has been shown to influence protein expression and enzyme activity in
an allelic dose/response manner.(26) The val allele is associated with
thermostability and high activity whereas the met allele is associated
with low activity and thermolability.(26) Compared with met carriers,
individuals homozygous for the val allele showed poorer attentional
control and performance on tests of executive cognition associated within
efficient precortical activity.(27) In other studies, the met allele,
which encodes the low activity variant, was associated with better performance
on tests of prefrontally mediated cognition.(28,29)The high activity
homozygous GG (val/val) genotype was present in 29% of autistic cases
and 20% of unaffected controls and was associated with a 1.74-fold increased
susceptibility to autism.
combined RFC-1 heterozygous 80GA and GST M1 null genotypes had a 3.78-fold
increased susceptibility to autism and children with both the RFC homozygous
GG and GST M1null genotypes had a 2.67-fold increase in risk. In contrast,
a decrease in MTRR homozygous GG genotype among autistic children was
suggestive of a protective effect.(20)
relatively small number of cases and controls in the present study, it
encourages one to note that several susceptibility
alleles that perturb a common metabolic pathway were increased among
the autistic children. This supports the possibility that some forms
of autism could be a manifestation of a genetic predisposition to abnormal
methionine/glutathione metabolism and oxidative stress. Further, the
abnormal metabolic profile observed in a significant proportion of autistic
children suggests the provocative possibility that some autistic behaviors
could be a neurologic manifestation of a genetically based systemic
An area on
chromosome 16p near the telomere was the next most significant, with
an MLS of 1.97 in the UK families, and 1.51 in all families.(30)
are involved in the production of heme which is a necessary ingredient
of the P450 enzymes which are critical for detoxification of chemicals
and toxins including pesticides. Heme is also necessary to remove beta-amyloid
plaques from the brain.(31) In a recent study, children with severe
autism secreted 2-3 times more beta-amyloid precursor protein than children
without autism.(32) Certain metals, particularly toxic metals such
as mercury, lead, and arsenic, will inhibit different enzymes of the heme porphyrin pathway and will thus cause different and specific porphyrin
patterns (or “profiles”) in the urine, the analysis of which can
help us determine which metal is involved, and to what degree.(33)
prospective study of 115 children with autism demonstrated porphyrinuria
when compared to 119 control children.(34) In this study, 53% of the
autistic children had elevated urinary porphyrin levels. This study
enrolled 115 children with autism, 63 with PDD-NOS, and 88 children
with other neurological disorders such as Asperger disorder, attention
deficit, hyperactivity, epilepsy, and cerebral palsy. When compared
to the control group, children with autism had a mean increase of 2.6-fold
(p <0.001) in coproporphyrin (which I refer to as “copro”).
This elevation persisted when normalized to urinary levels of creatinine.
The elevation in coproporphyrin also correlated with the severity of
study on 37 autistic patients confirmed that the severity of autism
was directly correlated to the degree of porphyrinuria. Non-chelated
autistic children had more porphyrins present in the urine compared
to children with PDD, Asperger syndrome, or control children.
is likely a multifactorial disorder with diverse etiologies, evidence
is accumulating that a combination of genetic predisposition, an environmental
insult, and resulting alterations in immunity lead to the development
of autoimmunity in many of the children who have a period of normal
development and then develop autistic symptoms.
have reported significant changes in various immune responses in children
with autism. These changes demonstrate dysregulation of the immune system
(deficiency in some components of the immune system and excesses in
others). In addition, certain genes in the major histocompatibility
complex (that regulates immune responses) appear to be involved in autism.
Based upon immunological abnormalities, various treatment modalities
have been applied to children with autism. In this brief review, these
immunological changes and various biological therapies are analyzed
adaptive immune responses in children with developmental regression
and autism spectrum disorders (ASD, N=71), developmentally normal siblings
(N=23), and controls (N=17) were determined. With lipopolysaccharide
(LPS), a stimulant for innate immunity, peripheral blood mononuclear
cells (PBMCs) from 59/71 (83.1%) ASD patients produced >2 SD above
the control mean (CM) values of TNF-alpha, IL-1beta,and/or IL-6 produced
by control PBMCs. ASD PBMCs produced higher levels of proinflammatory/counter-regulatory
cytokines without stimuli than controls. With
of phytohemagglutinin (PHA), tetanus, IL-12p70, and IL-18, PBMCs from47.9%
to 60% of ASD patients produced >2 SD above the CM values of TNF-alpha
depending on stimulants. Results indicate excessive innate immune responses
in a number of ASD children that may be most evident in TNF-alpha production.(36)
approaches and yields:
instruments have been developed to quickly gather information about
a child’s social and communicative development within medical settings.
Among them are the Checklist of Autism in Toddlers (CHAT) (37), the
modified checklist for Autism in Toddlers (M-CHAT), (38), the screening
tool for autism in Two-Year-Olds (STAT) (39), and the Social Communication
Questionnaire (SCQ) (40).Two other tests that should be used to assess
any child with a developmental delay are a formal audiologic hearing
evaluation and a lead screening. Children with an autistic disorder
usually have elevated blood lead levels.(41)
estimates for autism are now are reported to be on the order of 10-60
per 10,000 individuals, if all forms of ASD’s are considered. In fact
the Centre for Disease Control and Prevention has recently estimated
the prevalence of ASD’S in the United States at approximately 5.6
per 1000 (1 of 155 to 1 of 160) children (42,43) This wide range of
prevalence points to a need for earlier and more accurate screening
for the symptoms of ASD.
occurrence of autism and autistic-like findings simultaneously with
certain genetic diseases (44) has led to the intensification of studies
of the cause of autism. Whiteley and Shattock (45) discussed the opioid-excess
theory in autism spectrum disorders. This theory suggests that autism
is the result of metabolic disorder whereby peptides with opioid activity
derived from dietary sources, in particular foods that contain gluten
and casein, pass through an abnormally permeable intestinal membrane
and enter the central nervous system.
old girl presented with only psychiatric findings rather than any physical
or neurologic pathologic findings, and the diagnosis was reached when
physical findings emerged.(46) She had multi-axial diagnoses. First,
her condition was diagnosed as pervasive developmental disorder not
otherwise specified (axis I disorder). She also received a diagnosis
of borderline intelligence functioning (axis II disorder) and metabolic
disorder placed in the order of general medical conditions (axis III
disorder), according to the criteria of the Diagnostic and Statistical
manual of mental disorders, fourth edition (DSM-IV).(47) This fact underlines
the importance of keeping in mind the “metabolic disorder” that
causes psychiatric findings such as behavioral problems, hyperactivity
and autistic-like findings during infancy and early childhood and is
accompanied by mild or severe mental retardation and cognitive impairment.
Central nervous system functions are oversensitive to the metabolic
changes that emerge during fetal or early postnatal life. Spade et al
(48) described a 4-year old boy who had normal development but bizarre
behavior, such as laughing and crying for no reason. Normal results
were obtained in this case from general physical and neurologic examinations.
This case was diagnosed as OTC when the patient was aged 8 years because
of the absence of physical findings.(48) Behavioral problems and autistic-like
findings similarly emerge with mental retardation in some other metabolic
disorders caused by innate metabolic damage. Another metabolic disease
is Phenylketonuria, which is similarly often accompanied by autistic
The metabolic profile of children diagnosed with autistic disorder with
regressive onset was found to be severely abnormal. The autistic children
were found to have significant decreases in methionine levels and in
the ratio of plasma S- adenosylmethionine (SAM) to S-adenosylhomocysteine
(SAM/SAH ratio), an index of methylation capacity. Total glutathione
levels (GSH, the major intracellular antioxidant) were decreased and
oxidized glutathione disulfide (GSSG) was increased, resulting in a
threefold reduction in the redox ratio of reduced (active) GSH to oxidized
(inactive) glutathione (GSH/GSSG).(20)
the abnormal metabolic phenotype in autistic childrenas a guide for
the selection of functional candidate genes, common SNPs in genes encoding
methylenetetrahydrofolate (MTHFR 677C>T, MTHFR 1298A>C), methioninesynthase
reductase (MTRR 66A>G), transcobalamin II (TCN2 776C>G), catechol-O
methyltransferase (COMT472G>A), glutathione-S-transferase (GST M1
null, GST T1 null), reduced
folate carrier (RFC 80A>G), glutamate carboxypeptidase(GCPII1561C>T)
were evaluated. These are among several high frequency low penetrance
polymorphisms that have been previously shown to modulate metabolite
levels in the methionine transmethylation and transsulfuration pathways.(49-52) Significant increases in odds ratios, allele frequencies
and genotype distributions among autistic children were found for RFC-1
80A>G, TCN2 776C>G, and COMT 472G>A genes. An increase in the
frequencies of MTHFR 677CT and GST M1 null genotypes among autistic
cases achieved borderline significance. A decrease in the MTRR homozygous
GG genotype and G allele frequency also achieved borderline significance
Preferred biomarkers and Lab Tests:
A list that
may be intended to target core issues in autism may include the following:
- Immune blood markers:
- Autoantibodies to
endovasculature (54) performed at Washington University in St. Louis
predicts immune involvement in speech.
- Neopterin/ Biopterin:(55) Neopterin predicts the degree of cell mediated immune activation
and Biopterin is a measure of attempts to down-regulate immune activation.
In this urine is preferred over blood.
- ASO and Anti-DNase
B: These if significantly elevated indicate recent strep infection.
- Vaccine titers:
Can be used to show immunocompetency and may reflect a response to IVIG.
- Immunoglobulin subsets
IgG (1-4), IgM, IgA and IgE: They are most helpful in sickly or autoimmune
children where they can predict response to IVIG therapy.
- Immune Urine markers:
- Oxidative stress
- Reduced Glutathione:
It is the opposite of Glutathione so it is inversely related. The higher
the number the better.
- GSSG, which is oxidized
- Levels of major
antioxidant proteins in the serum i.e., transferrin (iron-binding protein)
and ceruloplasmin (copper-binding protein) are significantly reduced
in autistic children as compared to their developmentally normal non-autistic
- Blood ammonia and
lactate: Reflect mitochondrial function and as such reflect the state
of mitochondrial function in the presence of likely oxidative stress.(59)
- Oxidative stress
- 8 Hydroxyguanine
(8-OHG): Is a marker for RNA oxidation in the mitochondria and cytoplasm
of cells and easy to obtain for intracellular oxidative stress (60).
- Isoprostane looks
at fatty acid oxidation and reflects cell membrane stress (61)
- Heavy Metal Markers
- Packed erythrocyte
levels of toxic metals (mercury, lead, and arsenic in particular) reflect
ongoing exposure or rapid turnover from tissue. Lead in particular is
trapped in bone and can be released during growth spurts without renewed
- Heavy Metal Markers
- Urinary Fractionated
porphyrins are an ideal way to assess the metals that are left behind.
It can tell if mercury is present but is a little hard to distinguish
how much is mercury versus lead.
- Decreased methylation
capacity and limited transsulfation- blood:
- Plasma Cysteine
or cystine (the double form of cysteine) and plasma Methionine are frequently
deficient in Autism. Decrease in either or both of these may help to
determine Methyl B12 responder status. Cysteine is the sulfur containing
amino acid that will act as the rate limiting step in production of
glutathione- the key intracellular defence against oxidative stress.
Methionine is the main donor of methyl via an intermediate S-adenosylmethionine
(SAM or SAMe)
- Intestinal permeability
: Abnormal absorbtion of lactulose and mannitol can be used to determine
altered permeability in the gastrointestinal tract.(62)
Can be measured in the urine and if high, support reduction in oral oxalates
and perhaps reduce Vitamin C intake.
Urine Mucopolysaccharides and Organic acids: Trifiletti and Packard
(63) emphasized that any organic condition that produces cortical dysfunction
could present with psychiatric symptoms. At present it is not possible
to associate a specific metabolic disease, but it is known that the
genetic basis and consequently the fundamental biochemical defect are
important in the pathogenesis.
- Serum lactate,
amino acids, ammonia, and Acyl Carnitines profile.
Urine Uric acid:
- If elevated, Hypoxanthine
Guanine Phosphoribosyl Transferase (HGPRT) and Phosphoribosylpyrophosphate
(PRPP) synthetase testing.
- If low, Purine/
Pyrimidine panel (Uracil excretion, Xanthine, Hypoxanthine).
are many concerns about labeling a young child with an ASD, the earlier
the diagnosis of ASD is made, the earlier needed interventions can begin.
Proven biomarkers are essential for diagnosis. Given the fact that ASD
is a multifactorial disease, choices of a biomarker are limited, since
one cannot perform an array of investigations on every child, which
in most cases may amount to over-investigating. Accumulated evidence
indicates a few markers and an approach to the diagnosis. Fragile X
syndrome has been suggested to be ruled in all cases of suspected ASD.
Other investigations, mentioned in the article are relevant at this
point of time, but a more aggressive approach in the research of autism
will definitely lead to a better package of biomarkers for suspected
ASD. This, we hope will pave way for prenatal diagnosis too.
the last 15 years indicates that intensive early intervention in optimal
educational settings for at least 2 years during the preschool year’s
results in improved outcomes in most young children with ASD.(1) Autism
treatment, particularly in the areas of language and social skills,
is extremely important and should be started early on to help increase
the chances of developing language and social skills. In recent years,
experts have made remarkable strides in better understanding autism,
including developing more effective methods of diagnosis in treatment.
In the department of metabolic diseases and research, Narayana Hrudayalaya
we are continuing to investigate this complex disorder in the hopes
of not only improving diagnoses and interventions, but also discovering
autism’s causes and possible means of prevention.
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