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Monday, July 24, 2017

Brain Carnitine Deficiency Causes Nonsyndromic Autism with an Extreme Male Bias: A Hypothesis

From Wiley Online Library

By Arthur L. Beaudet
July 13, 2017


Could 10–20% of autism be prevented?

We hypothesize that nonsyndromic or “essential” autism involves extreme male bias in infants who are genetically normal, but they develop deficiency of carnitine and perhaps other nutrients in the brain causing autism that may be amenable to early reversal and prevention.

That brain carnitine deficiency might cause autism is suggested by reports of severe carnitine deficiency in autism and by evidence that TMLHE deficiency − a defect in carnitine biosynthesis − is a risk factor for autism.

A gene on the X chromosome (SLC6A14) likely escapes random X-inactivation (a mixed epigenetic and genetic regulation) and could limit carnitine transport across the blood-brain barrier in boys compared to girls.

A mixed, common gene variant-environment hypothesis is proposed with diet, minor illnesses, microbiome, and drugs as possible risk modifiers. The hypothesis can be tested using animal models and by a trial of carnitine supplementation in siblings of probands.

Perhaps the lack of any Recommended Dietary Allowance for carnitine in infants should be reviewed.

Introduction and Hypothesis

Understanding the biochemical basis of a rare genetic disorder sometimes sheds light on the processes underlying a more common disease. The discovery of a not so rare inborn error of carnitine biosynthesis (deficiency of the X-linked TMLHE gene) may prove to be such a case.

This deficiency, discovered in males with non-dysmorphic autism [1], prevents the synthesis of carnitine from trimethyllysine. Although 1 in 350 males (estimated ∼460,000 males in USA) have TMLHE deficiency, only about 3% of these males develop autism, with most of the remainder becoming healthy adults; furthermore, less than 1% of autistic males have TMLHE deficiency.

Nevertheless, we believe there are compelling reasons to think that brain deficiency of carnitine and perhaps other micronutrients such as essential polyunsaturated fatty acids (PUFA) can cause autism with an extreme male bias, and that 10–20% of cases of autism could be prevented by changes in infant nutrition.

Video Abstract

Arthur Beaudet discusses the importance of diet, genes, epigenetics, drugs, microbiome, and minor illnesses (especially gastrointestinal) in the hypothesis. Carnitine is absorbed from the intestine to the blood for distribution to liver, kidney, skeletal and cardiac muscle, and across the bloodbrain barrier. Carnitine can be synthesized in liver, kidney, and brain. Read the full article here:

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