C AV E AT: I a m a p a r e n t o f a n A S D c h i l d a n d I h a v e n o m e d i c a l t r a i n i n g . I h a v e s u m m a r i z e d D r. F r y e ’s p a p e r ( a v a i l a b l e a t w w w. n a j m s . n e t / v 5 i 3 p 1 4 1 w / ) t o t h e b e s t o f m y a b i l i t y i n t h e h o p e t h a t i t m a y h e l p b u s y p a r e n t s a c c e s s t h i s i m p o r t a n t m a t e r i a l . T h e r e m a y b e e r r o r s o f u n d e r s t a n d i n g h e r e . I f y o u h a v e c o m m e n t s o r c o r r e c t i o n s , e - m a i l –p a r e n t s . g r o u p . M A P S . f o r. a u t i s m @ g m a i l . c o m

A LAYMAN’S SUMMARY OF “Biomarkers of Abnormal Energy Metabolism In Children

with ASD”, Richard Frye, MD PhD, NAJMS July 2012

FIRST, A WORD ABOUT THIS FILE

NOTES: You are seeing this file because you are a member of the Facebook Group “MAPS for

Autism – Parents Group” or because this file was re-posted by one of the members on another group.

MAPS is an organization whose mission is to provide biomedical physicians with training and long-term support, to ensure the quality and consistency of care for children with autism and related chronic conditions. For more info on MAPS Phsyicians, see www.medmaps.org

MAPS for Autism – Parents Group is a parents-only group for parents who see MAPS physicians or are interested in the treatments. This is an informal parents-only group that is NOT endorsed by the MAPS organization in any way, shape or form.

If you are interested in joining this group, search Facebook for the group name and ask to join; if you have any problems with this, e-mail the Group Admin at maps.for.autism.parents.group@gmail.com

AS A PARENT, WHY SHOULD YOU CARE ABOUT THIS STUDY?

The following is my opinion as a parent

Prior studies in ASD kids looked at some biomarkers to figure out, “Do ASD kids have mitochondrial disease”?

This study goes further.

It looks at a variety of biomarkers in ASD kids.

It also links abnormalities in biomarkers to physiologic abnormalities in autism.

WHAT IS THE PURPOSE OF THIS STUDY?

Before I answer that, I’ll first share some info about the research on mito dysfunction in ASD kids -

According to a recent study by Frye & Rossignol, about 5% of ASD kids have classic markers for mitochondrial disease

These children have clinical symptoms different from the general ASD population. This sub-group of kids is called the autism/mitochondrial disease (ASD/MD) group

According to various other studies, about 30-80% of ASD kids have impaired mitochondrial function

Now, 5% - 80% is quite a range! Why such a wide variance? This is because the studies all used different biomarkers to study mitochondrial function in ASD kids

So back to the question … what is the purpose of this study?

This study tries to address some of the limitations of earlier studies.

It looks at a large number of biomarkers in a large sample of ASD kids (133 kids.)

It looks to answer the questions – how many ASD kids actually have impaired mitochondrial function? What does this mean in terms of other markers of mitochondrial function?

WHAT BIOMARKERS WERE LOOKED AT?

The study specifically looked at these biomarkers in a morning blood sample with overnight fasting: Plasma lactate Plasma alanine Alanine/Lysine ratio Creatine Kinase AST level (a measure of liver function) Plasma acylcarnitines

If there was an abnormal value, the testing was repeated.

DIAGNOSES AND DEVELOPMENTAL ISSUES IN THE KIDS IN THE STUDY

Each child in the study had one of the following clinical diagnoses -

Classic autistic disorder (AD) with no motor delay

PDD-NOS with no motor delay

AD with motor delay

PDD-NOS with motor delay

Isolated speech delay

ADHD (with hyperactivity)

ADHD (without hyperactivity)

The study also looked at clinical characteristics like whether the child had epilepsy or a developmental regression.

STUDY FINDINGS

STUDY FINDINGS

Over 30% of the children in the sample of 133 were found to have metabolic abnormalities. Here is a summary. There are lots more tables of results, look at the Frye paper for more data.

Biomarker % of kids with

abnormalities

Lactate 16.9%

Alanine 1.7%

Alanine/Lysine Ratio 15.9%

Acylcarnitines 23.8%

AST 10.1%

CK 6.8%

THE STUDY FOUND FOUR DISTINCT SUB-GROUPS

Of the children with metabolic abnormalities, there were four distinct sub-groups -

Sub-group 1 – Abnormally elevated lactate

Sub-group 2 – Abnormally elevated AST

Sub-group 3 – Abnormally elevated alanine/lysine ratio

Sub-group 4 – Abnormal elevations in multiple acylcarnitines

The sub-groups had some over-lap i.e. some kids could be in more than one group at once. But there wasn’t a whole lot of overlap. Let’s take a look at these subgroups

TWO SUB-GROUPS MAY HAVE MITOCHONDRIAL DYSFUNCTION

TWO SUB-GROUPS MAY HAVE OTHER ISSUES, NOT MITO

Sub-group 1 – Abnormally elevated lactate This sub-group may indeed have

mitochondrial dysfunction There is no genetic abnormality common to

all children in the group

Sub-group 3 – Abnormally elevated alanine-to -

lysine ratio

ASD children with abnormally elevated alanine/lysine ratio may indeed have mitochondrial dysfunction associated with a Complex I deficiency.

This is not due to a genetic abnormality common to all children in the group.

Sub-group 2 – Abnormally elevated AST ASD children with elevated AST values

may have oxidative stress rather than mitochondrial dysfunction.

Sub-group 4 – Abnormal elevations in

multiple acylcarnitines ASD children with this pattern of elevated

acyl carntines may not have mitochondrial dysfunction.

Data from an animal model suggests that these metabolic abnormalities may be associated with propionic acid created by a bacteria species called clostridia.

THE STUDY FOUND FOUR DISTINCT SUBGROUPS

MORE DETAILS ON METABOLIC ABNORMALITIES IN EACH SUB-

GROUP

SUB-GROUP 1 – ELEVATED LACTATE

Children with abnormally elevated lactate had - Elevated urine 2-methyl-3-hydroxybutyric acid which may be due to an

inefficient citric acid cycle Higher values for ammonia than controls A higher rate of motor delays

CONCLUSION: This sub-group of ASD children may indeed have mitochondrial dysfunction.

FIGURE: Metabolic biomarkers which demonstrate significant differences between a subgroup with consistently elevated lactic acid and a control group of ASD children without metabolic abnormalities.

SUB-GROUP 2 – ABNORMALLY ELEVATED AST VALUES

AST is a marker for liver function Compared to ASD controls, those with

highly elevated AST also had lower urine 5-oxoproline (also known as pyroglutamate)

Pyroglutamate is a metabolite of the gamma-glutamyl cycle which is involved in glutathione utilization and recovery

Low urine 5-oxoproline may mean glutathione depletion, which reduces the liver’s ability to protect itself against oxidative stress and neutralize toxins

This could cause liver dysfunction resulting in increased AST

CONCLUSION: ASD children with elevated AST values may have oxidative stress rather than mitochondrial disease.

FIGURE: Metabolic biomarkers which demonstrate significant differences between a subgroup of children with consistently elevated AST and a control group of ASD children without metabolic abnormalities.

SUB-GROUP 3 – ABNORMALLY ELEVATED ALANINE/LYSINE RATIO

Compared to controls, ASD children with elevated alanine/lysine ratio also had abnormally elevated alanine and urine pyruvate

Lactate was not abnormally elevated like Sub Group 1, but it was still higher than controls

These children had a higher rate of epilepsy

There were no genetic abnormalities found that were common to all children in the group

These metabolic abnormalities may be associated with a mito Complex I deficiency

CONCLUSION: ASD children with abnormally elevated alanine/lysine ratio may indeed have mitochondrial dysfunction, which is not due to a genetic abnormality common to all children in the group; this may be associated with a Complex I deficiency.

FIGURE: Metabolic biomarkers which demonstrate significant differences between a subgroup of children with consistently elevated alanine-to-lysine ratio and a control group of children without metabolic abnormalities.

SUB-GROUP 4 – CONSISTENT ELEVATIONS IN ACYLCARNITINES

ASD children with consistent abnormalities in acylcarnitines were found to have -

Higher C5OH, C12, C14, C14:OH and C16 acylcarnitines – i.e. carnitines associated with short & long chain but not medium-chain fatty acids; this pattern of acylcarnitine elevations is not consistent with any known fatty oxidation disorder

Higher urine 3-OH-3-methylglutaric acid, which suggests citric acid cycle abnormalities

This pattern is consistent with abnormalities seen in a rodent model when rodents were injected with propionic acid

This sub-group of children has a high rate of regression

Propionic acid can be produced by Clostridia , a bacterial species seen in kids with regressive ASD

CONCLUSION: ASD children with this pattern of elevated acylcarntines may not have mitochondrial dysfunction. Data from an animal model suggests that these metabolic abnormalities may be

associated with propionic acid created by a bacteria species called clostridia.

FIGURE: Metabolic biomarkers which demonstrate significant differences between a subgroup of children with consistent elevations in multiple acyl-carnitines and a control group of children without metabolic abnormalities.