acid deficiency underlies rare form of autism

acid deficiency underlies rare form of autism<br /><br />This might represent the first treatable form of autism, says Joseph Gleeson, a child neurologist at the University of California, San Diego, who led the study. That is both heartening to families with autism, and also I think revealing of the underlying mechanisms of autism.<br /><br />He emphasizes, however, that the mutations are likely to account for only a very small proportion of autism cases. We dont anticipate this is going to have implications for patients in general with autism, says Gleeson. And there is as yet no proof that dietary supplements will help the six children, whose mutations the researchers identified by sequencing the exome the part of the genome that codes for proteins.<br /><br />In the familyThe children came from three families with Middle Eastern ancestry; in each case the parents were first cousins. Studying such families makes the hunt for the rare recessive mutations underlying some forms of autism simpler than it would be among the general population, Gleeson says, because the odds are higher that children will be born with two copies of the recessive mutation.<br /><br />In each family, Gleesons team identified mutations that inactivate the enzyme BCKD kinase, which normally prevents the body from breaking down branched chain amino acids called leucine, isoleucine and valine after a meal. Humans cannot synthesize these amino acids and must obtain them from food.<br /><br />We predicted that patients would burn through these amino acids, says Gleeson. The prediction was correct: after eating, the children had low blood levels of the branched chain amino acids. Mice lacking the gene that codes for BCKD kinase also had low levels of the amino acids in their blood and tissue.<br /><br />Transport problemsHow this deficiency causes autism is still a mystery. Branched chain amino acids enter the brain through specialized transporters in the fortress of brain protecting cells known as the blood brain barrier. The transporter proteins also shuttle other large amino acids into the brain, and when levels of the branched chain amino acids are low, more of these other large molecules get through. Gleesons team found high levels of these larger amino acids in the brains of mice lacking the BCKD kinase gene.<br /><br />Gleeson proposes that symptoms of autism are caused by low levels of branched chain amino acids, high levels of these other amino acids or a combination of the two. The amino acids that were present at elevated levels in the brains of mutant mice provide the raw materials for two neurotransmitter chemicals, and the synapses where these chemicals are released are implicated in autism.<br /><br />In mice, at least, the chemical imbalance can be treated. The mutant mice had neurological problems typical of mouse versions of autism, including tremors and epileptic seizures. But those symptoms disappeared in less than a week after the mice were put on diets enriched in branched chain amino acids.<br /><br />Gleesons team has tried supplementing the diets of the children with this form autism, using muscle building supplements that contain branched chain amino acids. The researchers found that the supplements restore the childrens blood levels of amino acids to normal. As for their autism symptoms, Gleeson says, the patients did not get any worse and their parents say they got better, but its anecdotal.<br /><br />Blood testThe team hopes to conduct a properly controlled clinical trial looking at whether dietary supplements ease the childrens symptoms. To that end, Gleeson wants to identify further patients with mutations in the gene for BCKD kinase. They are likely to be very scarce, he says, but metabolic screening and genome sequencing should identify some. Theyre hiding out there, he adds.<br /><br />Matthew Anderson, a physician scientist at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, says that the study will encourage other researchers to explore metabolic pathways as causes of autism. A number of uncommon metabolic disorders, such as phenylketonuria in which the body cant break down the amino acid phenylalanine can be linked to autism spectrum disorder if left untreated2. Many more such connections may be lurking in clinics.<br /><br />If 5 or 10% are caused by metabolic disorders and theres a simple imbalance that one can correct with nutrition, thats something that human genetics will identify over the next five to ten years, says Daniel Geschwind, a neurogeneticist at the University of California, Los Angeles. Thats exciting.<br /><br />2012 09 07 04:09 PM<br /><br />Autism and many similar conditions can be seen as a continuum of condition comments on Mottron, Nature, 2 Nov 2011. Explanations for the condition would appear to of greater relevance than clinical descriptions, which tend to be imprecise and can be seen as aspects of normal behaviour. The advantage of explanations over theory is they can be tested. The possible importance of diet is in a variety of conditions is a favourite. However, Callaway piece appears to have a rational although genetic explanations are always problematic since so many steps are involved in expression of a condition. As Gallaway says, the blood brain barrier presents a problem with orally administered solutions. However, many conditions such as anxiety and depression are treated with apparent success with pills. Precursors can get through the barrier. The neurotransmitter serotonin, as a catch all solution, is attractive specialty as it resonates with evolutionary changes in human diet. The serotonin system in the brain is thought to modulate other synaptic systems involved in behaviour. Autism and its accompanying behaviour might be account for by differences in synapse distribution and number. The evolutionary increase in the size of the in the human brain has been in part due to neoteny. The ancestral juvenile brain has been retained in the adult and accounts for a larger number of synapses than are found in other primates. In humans the process may have led to language, which is a means by which individuals manipulate one another for personal advantage. It requires an increase size of the associative areas. Increased neocortical size has also resulted in the brain becoming labile. Serotonin maintains the balance needed for a greater repertoire of behaviour. It is a modulator that appears to be necessary for hunting skills in early hominids. Bipedalism led to greater protein consumption and increase serotonin levels. It is associated with specified types of behaviour such as dominance. Lower levels lead to the reverse. The introduction of farming, depending on cereals, reduced the need for protein. The resulting lower serotonin levels produced greater tolerance. These assertions are backed by primate studies. The switch in diet accompanying farming may have led to sociality. The aftermath of this switch might, as others have suggested, accounts for learning difficulties: autisms being just one. Oscillations in behaviour might be perturbed by levels of protein consumption.