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 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 to the best of my ability in the hope that it helps busy parents access the material. There may be errors of understanding here. If you have comments or corrections, e-mail healingsiggy@gmail.Com
AS A PARENT, WHY SHOULD YOU CARE ABOUT THIS STUDY? Before we go any further, let me say (in my opinion) why an ASD parent should care about this study To date, most studies on mitochondrial dysfunction in ASD kids have mainly looked at a small number of biomarkers to answer the question “do the kids have mitochondrial disease”? This study goes further. It looks at a broad variety of biomarkers in ASD kids and also looks to suggest what abnormalities in these biomarkers mean in terms of physiologic abnormalities in autism In some cases, it means the ASD children may have ASD/MD but that is only one finding. There are other possibilities discussed, which are worth knowing about.
HOW FREQUENT IS MITOCHONDRIAL DISEASE IN ASD KIDS? About 5% of ASD kids have “classic” mitochondrial disease, according to a Rossignol/Frye study These children have clinical symptoms different from the general ASD population We call this the autism/mitochondrial disease (ASD/MD) group According to various other studies, about 30-80% of ASD kids don’t have classic mitochondrial disease but do have impaired mitochondrial function 30-80% is quite a range, why such a wide variance? Because the studies all used different biomarkers to study mitochondrial function in ASD kids
WHAT WAS THE PURPOSE OF THIS STUDY? This study seeks to address the limitations of earlier studies This study looked at a broad range of biomarkers in a large sample (133) of ASD kids The purpose is to characterize what biomarkers are elevated Also determine how the selected biomarkers correlated to 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 whether thechild had epilepsy or a developmental regression.
STUDY FINDINGSOver 30% of the children in the sample of 133 were found tohave metabolic abnormalities. Of the children with metabolicabnormalities, there were four distinct sub-groups - Sub-group 1 – Consistently elevated lactate Sub-group 2 – Consistently elevated AST Sub-group 3 – Consistently elevated alanine/lysine ratio Sub-group 4 – Consistent elevations in multiple acylcarnitines
SUB-GROUP 1 – ELEVATED LACTATEChildren with elevated lactate had - A higher rate of motor delays Higher values for ammonia than controls Elevated urine 2-methyl-3-hydroxybutyric acid which may be due to an ineffecient citric acid cycleCONCLUSION:This sub-group of ASD children may indeed havemitochondrial disease.
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 5-oxoproline (also known as pyroglutamate) Pyroglutamate is a metabolite of the gamma-glutamyl cycle which is involved in glutathione utilization and recovery Low 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 ASTCONCLUSION:ASD children with elevated AST values may haveoxidative stress rather than mitochondrial disease.
SUB-GROUP 3 – ABNORMALLY ELEVATED ALANINE/LYSINE RATIOCompared to controls, ASD children with elevatedalanine/lysine ratio had - Elevated alanine Elevated lactate Elevated urine pyruvate Higher rate of epilepsyCONCLUSION:ASD children with abnormally elevated alanine/lysine ratiomay indeed have mitochondrial disease, which is not due toany particular genetic abnormality; this may be associatedwith a Complex I deficiency.
SUB-GROUP 4 – CONSISTENT ELEVATIONS IN ACYLCARNITINESCompared to controls, ASD children with consistentabnormalities in acylcarnitines were found to have - Higher C5OH, C12, C14, C14:OH and C16 acylcarnitines – i.e. carnitines associated with short and long chain fatty acids but not medium-chain fatty acids are elevated Higher urine 3-OH-3-methylglutaric acid, which suggests citric acid cycl abnormalities This pattern of acylcarnitine elevations is not consistent with any known fatty oxidation disorder
SUB-GROUP 4 – CONSISTENT ELEVATIONS IN ACYLCARNITINES (continued) 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 children with regressive ASDCONCLUSION:ASD children with elevated acylcarntines may not havemitochondrial disease. Data from an animal model suggests thatthese abnormalities may be associated with propionic acid createdby a bacteria species called clostridia.
WHAT ABNORMALITIES DID THE STUDY FIND?Biomarker % of kids with abnormalitiesLactate 16.9%Alanine 1.7%Alanine/Lysine Ratio 15.9%Acylcarnitines 23.8%AST 10.1%CK 6.8%
HOW DID THE ABNORMALITIES CORRELATE TO DIAGNOSIS ?Abnormal AD or PDD- Isolated AD PDD- OtherBiomarker NOS with Speech NOS diagnoses motor delay delayLactate 44% --- 12% 44% ---AST --- --- 25% 63% 13%Alanine-to- 25% 13% 25% 38% ---Lysine ratioAcylcarnitines --- 17% 33% 15% ---ASD Controls 33% --- 67% --- ---(no biomarkerabnormalities)
HOW DID THE ABNORMALITIES CORRELATE TO EPILEPSY & REGRESSION? Biomarker Regression Epilepsy Lactate 22% 33% Alanine/Lysine 25% 75% Ratio Acylcarnitines 67% 17% AST 38% 13% ASD Controls - 55% 33% no abnormal biomarkers