The autism spectrum disorders are mysterious as they are devastating, frustrating parents, physicians, and researchers looking for a cause and a cure. However, a recent paper from Greece published in Frontiers of Human Neuroscience gives us some amazing clues that could open future treatment options for families.

Part of the problem in diagnosing and treating autism is that there is no one single cause. The symptoms are similar enough to fit into a broad diagnostic category, but it is clear that a number of different issues, some known, some unknown, could be causing the symptoms. Genetic factors, metabolic issues, and environmental exposures could all be at fault, and/or a combination of those, making any specific target elusive. In Greece, the researchers took on that challenge by testing a cohort of 187 children ages 4-14 diagnosed with autism on the island of Crete. By using a relatively isolated island population, the scientists thought they might be more likely to find genetic “inborn errors of metabolism” that could be common to several of the children.

“Metabolism” is our body’s blindingly complex way of taking all the food, vitamins, and minerals we eat and using them and reusing them to make everything we need to keep all of our body functions humming along. Thousands upon thousands of chemical reactions occur in our body at any given time, in every organ and in every cell. Some of us have enzymes and cells that work very efficiently, some of us are born with defective enzymes that cause devastating neurological problems even obvious at birth, others have more minor inefficiencies that could cause medical problems later in life. With so many different enzymes, any number of  rare problems could occur along the same metabolic pathway, ending up causing symptoms of autism.

Some inborn errors of metabolism have no treatment or cure, but others can be compensated for by changing the diet or using high doses of certain vitamins. Researchers did a detailed family history of all 187 children, checking for others in the family with similar symptoms, or if close relatives had married and had children, increasing the chances of having a genetic disease. Detailed blood and urine exams were done, along with testing for seizure or unusual brain activity, and glucose metabolism testing by checking out how efficiently glucose was processed. Urine amino and organic acids were measured, which can sometime give clues to certain metabolic diseases. In certain patients, muscle biopsies were done to look for mitochondrial disorders (problems with the cells’ power plants that supply energy; mitochondria are particularly numerous in the muscle, for obvious reasons.) 

Here in Massachusetts, a large number of inborn errors of metabolism are tested for at birth in every baby, unless the parent ops out. It is done with a heel stick spot of blood. Many (perhaps most?) parents have no idea of the number of disorders in the test and think of the newborn screen as “that test for PKU.” Phenylketonuria aka PKU is a well-known inborn error of metabolism. PKU can cause severe mental retardation, but if one starts certain dietary restrictions from birth, the brain damage can be avoided. Imagine if many cases of autism could be prevented or helped in the same sort of way. While many European countries do mandatory expanded newborn screening tests as done in the United States and Canada, some countries test only for PKU and congenital hypothyroidism (1).

In the autism cohort on Crete, five of the children were diagnosed with known inborn errors of metabolism (one of them even had PKU). Twelve (or 7% of the patients) had metabolites in the urine and blood that suggested defects in a metabolic pathway involving the vitamin biotin. The researchers decided to treat these twelve with biotin for six months, at which point over half the affected children showed improvement. One 3&1/2 year old boy had complete remission of his severe autism spectrum symptoms with biotin treatment, and was followed over the next five years. Any time his biotin was discontinued, his autism symptoms returned.

16 of 187 were found to have elevations of beta-hydroxybutyrate on glucose metabolism testing, suggesting problems with the metabolism of carbohydrates. Six of these children were successfully put on a ketogenic diet, which would switch the primary fuel used to fat and ketones rather than glucose. (See this article for a discussion of a study of ketogenic diet in autism, and this article for a general view of ketogenic diets and how they affect energy metabolism in the brain.) One of the six children had significant improvement, and the other five had more subtle improvements. The other ten screened children’s families were not able to stick to the diet.

Other findings in the cohort showed that thirteen had close relatives with similar syndromes, and twenty-six had evidence of dietary intolerance. Five of the twenty-six had abnormal glucose testing and worsened symptoms on high-carbohydrate diets. In three patients who showed abnormally low levels of beta-hydroxybutyrate after a 12 hour fast, suggesting inefficient fat metabolism, a dietary history revealed that the families had steered the child to a low fat diet, and that fat consumption increased autism symptoms (hyperactivity and stereotyped behaviors). 15/187 patients had no biochemical abnormalities found, but had food intolerance by history, and key symptoms seemed to be exacerbated by high protein consumption.

One other large autism cohort study of 274 children in France had been attempted to find inborn errors of metabolism (Shiff et all, 2011 in PLOSone). This paper is open access and can be downloaded here. The researchers discovered only two children with abnormalities in metabolism, no greater than in the general population, suggesting that the rigorous metabolic screening was likely not cost-effective for general clinical use in autistic children. The authors of the Greek study wondered if the differences in the two cohorts reflected the isolated island population of Crete, where genetic inborn errors of metabolism might be far more likely.

Certainly the biomarkers found in the Greek study (uncovering specific issues with biotin and glucose metabolism, leading to actionable therapeutic interventions that were, in a few cases, remarkably successful) warrant further investigation in other populations. And as technology improves and prices drop, rigorous and detailed metabolic testing may become more accessible outside the research setting.  The standard newborn screen of fifty-four conditions in Massachusetts can be done for $68.74 per child, using a technology called tandem mass spectrometry (2), but most of the children in the Greek study had no known inborn error of metabolism, just metabolic abnormalities suggestive of unknown disorders.

Just the fact that relatively simple targeted interventions could be so effective in a few children is exciting news. It also shows that no one shoe fits all…for some children, the answer was a high fat diet, in others, a low fat or low protein one. In others, certain vitamin supplementation. The study highlights why interventions studied in a group of kids diagnosed with autism without more careful understanding of exactly what is going on in the brain will be likely to help a few, perhaps harm some others, and end up a wash as a clinical trial. A more intelligent and subtle targeted approach is needed if we are to gain some traction against these disorders.

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Copyright Emily Deans, MD

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