Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel?

Abstract

First reported formally in 1980, the frequent ability of infectious fever to relieve autistic behavior, often dramatically (and rarely aggravate), has long tantalized parents, practitioners, and researchers – yet its physiology and biochemistry have never been investigated, to judge from the literature. Fever is a complex interplay of immune, metabolic, and stress responses, yet its benefit in autistic disorders (ASD) may derive largely from a single response – release of the amino acid glutamine from skeletal muscles as provisional fuel. This proposal is based on evidence of low blood and brain glutamine in ASD children and adults, notable lack of autistic behavior in children with high brain glutamine from urea cycle disorders, and other events that elicit dramatic improvements – fasting, panic, pain, and the corticosteroid prednisone – that release or synthesize glutamine. Glutamine released from muscles is metabolized by the intestines like ingested glutamine. If glutamine released by fever rarely aggravates autistic behavior, why would supplemental glutamine?

Introduction

[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 [1].

High concentrations of ammonia in the blood of children with autistic disorders (ASD) were first detected in the 1980s [2]. Filipek et al. found plasma ammonia high in a majority of 100 autistic children [3]. Wakefield et al. proposed that bacteria in their diseased intestines generate more ammonia than their impaired liver can clear, which reaches the brain: “Following passive diffusion across the [intestinal] mucosa, failure by the diseased liver to effect what should, under normal circumstances, be a high first-pass clearance, leads to excessive ammonia levels in the brain.” [4] Bradstreet et al. noted that high blood ammonia is more toxic to children than adults [5]. Wang et al. recently reported high levels of fecal ammonia in ASD children [6].

Most ammonia is generated by bacteria digesting proteins in the large intestine, and decomposing the amino acid glutamine in the small intestine [7]. The liver uses the amino acid arginine to detoxify blood ammonia to urea, excreted in urine [8]. The brain lacks enzymes for this urea cycle, and is the organ most affected when the liver cannot clear blood ammonia rapidly (hepatic encephalopathy). Ammonia that reaches the brain is trapped by astrocytes combining it with the excitatory transmitter glutamate to form glutamine, with no transmitter activity but much osmotic activity. Brusilow et al. concluded that the primary pathology of ammonia in the brain is reversible astrocyte swelling from glutamine and its water [9]. Astrocytes also detoxify ammonia with α-ketoglutarate. Pangborn: “Ammonia grabs alpha-ketoglutarate, especially in the brain … where that’s the natural ammonia detox route. Ammonia plus alpha-ketoglutarate becomes glutamate.” [2] α-Ketoglutarate is also a key intermediate in the citric acid cycle that generates adenosine triphosphate (ATP) [10], thus depletion by ammonia reduces brain energy.

Albrecht and Jones concluded that acute ammonia toxicity releases glutamate at brain synapses, inducing excitation; chronic ammonia accumulation downregulates glutamate receptors and releases gamma aminobutyric acid (GABA), inducing inhibition [11]. Chronic ammonia accumulation also shifts brain metabolism and blood flow from cortical to subcortical structures [12]. Hindfelt noted that an early manifestation of hepatic encephalopathy is a “frontal lobe syndrome” – loss of cortical ‘executive’ functions [13]. Brain metabolism slows in early stages of hyperammonemia [14].

Children with inborn urea cycle disorders (UCD) cannot detoxify enough ammonia in the liver, inducing plasma ammonia concentrations 5× greater than in liver failure [15], high brain glutamine, astrocyte swelling and intracranial pressure, and impaired cognition. Yet children with UCD rarely show autistic behavior [1], [16], [17]. One explanation might be that they detoxify more free brain ammonia than ASD children, but Felipo and Butterworth noted that glutamine synthetase, the astrocyte enzyme that neutralizes ammonia to glutamine, normally functions at near-maximum capacity [12] – implying UCD children have high brain glutamine and ammonia. If high brain ammonia doesn’t provoke autistic behavior in UCD children, why would it do so in ASD children? One obvious explanation is that ASD children are not ‘protected’ by high brain glutamine.