Do salt cravings in children with autistic disorders reveal low blood sodium depleting brain taurine and glutamine?
Introduction
High levels of ammonia in the blood of children with autistic disorders (ASD) were first detected in the early 1980s [2]. Cohen subsequently found high plasma ammonia in one autistic boy [3]; Filipek et al. detected significantly elevated plasma ammonia in a majority of 100 autistic children [4]. Wakefield et al. suggested their diseased intestines generate more ammonia than their impaired liver can clear, which reaches the brain, provoking a form of hepatic encephalopathy [5].
Most ammonia (NH3) is generated as a byproduct of bacteria digesting proteins in the large intestine, and degrading the amino acid glutamine in the small intestine [6]. The liver uses the amino acid arginine to detoxify ammonia to urea, excreted in urine [7]. Ammonia that reaches the brain is trapped by astrocytes combining ammonia and the amino acid transmitter glutamate to form glutamine, with no transmitter activity but much osmotic activity [8]. Excessive glutamine causes astrocytes to swell, inducing compensatory release of the amino acid taurine and other solutes and their water to restore normal cell volume [9]. Persons with high brain ammonia from liver disease (e.g. cirrhosis) or inborn urea cycle disorders (UCD) have high concentrations of glutamine in astrocytes [10], inducing swelling and intracranial pressure, e.g. hepatic encephalopathy [8].
Plasma ammonia concentrations in children with UCD are five times greater than plasma ammonia in liver failure [11], elevating brain glutamine and impairing cognition. Yet children with UCD are rarely diagnosed with autistic disorders or mood disorders [12], [13], [14]. This striking observation corroborates Wakefield’s speculation that glutamine is low in autistic brains [5] – based on low serum levels [15] and evidence that liver dysfunction impairs the astrocyte glutamate transporter. But if glutamine is low in autistic brains, why are astrocytes swollen [16]? Ammonia and other neurotoxins implicated in autistic disorders, e.g. organic mercury and arsenic, cause astrocytes to swell [17], [18]. A more productive explanation may be chronic hyponatremia (low blood sodium), which drives water into astrocytes, inducing compensatory release of taurine, glutamine, and their water [19]. Why would children with autistic disorders be chronically hyponatremic? One obvious explanation is recurring diarrhea [20]. Another is high concentrations of water-conserving arginine vasopressin (AVP) [21]. A third is depletion of taurine, the inhibitory neurotransmitter that suppresses vasopressin [22].
Section snippets
Hypothesis: is autistic behavior induced by low blood sodium, low brain taurine and glutamine?
[C]hildren in this cohort [urea cycle disorders] show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders. Krivitzky et al. 2009 [12].
Low concentrations of the amino acid glutamine detected in plasma and platelets of children with autistic disorders [23], [24], [25], [26], [27] are not thought to affect brain glutamine concentrations because glutamine does not cross the
Evaluating the hypothesis
[I]t is possible that changes in mood and appetite are among the first noticeable manifestations accompanying sodium deficiency. Morris et al. [56].
High arginine vasopressin in autistic disorders [21] has not been confirmed, although suspected from high androgens and effects of AVP on male behavior [39], [47]. Nor have swollen astrocytes [16] been confirmed, although they appear proliferated [38]. Swollen astrocytes compressing brain capillaries were proposed to explain low brain blood flow in
Implications and remedies
Two stubborn questions vex autism researchers and theorists [76]: (a) why is autistic behavior recognizable in many other disorders (non-specificity), and (b) why does autistic behavior look different in every child (heterogeneity)? Many disorders show autistic features: ADHD, obsessive–compulsive disorder, language impairments, epilepsies, digestive, allergic, and immune disorders, metabolic disorders, toxic and infectious diseases, and genetic syndromes [76].
Heterogeneity complicates the
Grant support
No grant support received for this article.
Conflict of interest statement
None to declare.
Acknowledgments
I am most grateful to James Harduvel of the Deschutes County Library in Bend, Oregon, for dedicated retrieval of the literature; Martha Herbert, who inspired this study; Jon Pangborn of ARI, for clues to the problem of ammonia; Eugene Kiyatkin of NIH, for literature and encouragement; William Ellis, for helping spread the word; and Helen Emily Couch, for everything else. Special thanks also to Jeff Bhavnanie of Flowchart.com.
My apologies to anyone offended by the word autistic to describe these
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