Summary biomarkers of energy metabolism in asd children
A LAYMAN’S SUMMARY OF“Biomarkers of Abnormal Energy Metabolism In Children with ASD”, Richard Frye, MD PhD, NAJMS July 2012 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 / ) to t h e best of my ability in the hope that it may help busy parents access this important material. There may be errors of understanding here. If you have comments or corrections, e-mail – 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
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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 kidsSo 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 amorning blood sample with overnight fasting: Plasma lactate Plasma alanine Alanine/Lysine ratio Creatine Kinase AST level (a measure of liver function) Plasma acylcarnitinesIf there was an abnormal value, the testing wasrepeated.
DIAGNOSES AND DEVELOPMENTAL ISSUES IN THE KIDS IN THE STUDYEach 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 whetherthe child had epilepsy or a developmental regression.
STUDY FINDINGSOver 30% of the children in the sample of 133 were found to have metabolicabnormalities. Here is a summary. There are lots more tables of results, look atthe 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-GROUPSOf the children with metabolic abnormalities, there were fourdistinct 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 acylcarnitinesThe sub-groups had some over-lap i.e. some kids could be inmore than one group at once. But there wasn’t a whole lotof overlap. Let’s take a look at these subgroups
THE STUDY FOUND FOUR DISTINCT SUBGROUPSTWO SUB-GROUPS MAY HAVE TWO SUB-GROUPS MAY HAVEMITOCHONDRIAL DYSFUNCTION OTHER ISSUES, NOT MITOSub-group 1 – Abnormally elevated lactate Sub-group 2 – Abnormally elevated AST This sub-group may indeed have ASD children with elevated AST values mitochondrial dysfunction may have oxidative stress rather than There is no genetic abnormality common to mitochondrial dysfunction. all children in the groupSub-group 3 – Abnormally elevated alanine-to - lysine ratio Sub-group 4 – Abnormal elevations in ASD children with abnormally elevated multiple acylcarnitines alanine/lysine ratio may indeed have ASD children with this pattern of elevated mitochondrial dysfunction associated acyl carntines may not have with a Complex I deficiency. mitochondrial dysfunction. This is not due to a genetic abnormality Data from an animal model suggests that common to all children in the group. these metabolic abnormalities may be associated with propionic acid created by a bacteria species called clostridia.
MORE DETAILS ON METABOLICABNORMALITIES IN EACH SUB- GROUP
SUB-GROUP 1 – ELEVATED LACTATE 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.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 delaysCONCLUSION: This sub-group of ASD children may indeed havemitochondrial dysfunction.
SUB-GROUP 2 – ABNORMALLY ELEVATED AST VALUES AST is a marker for liver function FIGURE: Metabolic biomarkers which demonstrate significant differences between a subgroup of children with consistently Compared to ASD controls, those with elevated AST and a control group of ASD children without highly elevated AST also had lower urine metabolic abnormalities. 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.
SUB-GROUP 3 – ABNORMALLY ELEVATED ALANINE/LYSINE RATIO Compared to controls, ASD children FIGURE: Metabolic biomarkers which demonstrate significant with elevated alanine/lysine ratio also differences between a subgroup of children with consistently had abnormally elevated alanine and elevated alanine-to-lysine ratio and a control group of children without metabolic abnormalities. 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.
SUB-GROUP 4 – CONSISTENT ELEVATIONS IN ACYLCARNITINESASD children with consistent abnormalities inacylcarnitines were found to have - FIGURE: Metabolic biomarkers which demonstrate significant Higher C5OH, C12, C14, C14:OH and C16 differences between a subgroup of children with consistent acylcarnitines – i.e. carnitines associated with elevations in multiple acyl-carnitines and a control group of children without metabolic abnormalities. 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.