On 2015 May 28, Peter Good commented:

Cochran et al. measured brain glutamate, glutamine, GABA, and other metabolites by MRS in the anterior cingulate cortex of ASD adolescents to test whether autistic behavior arises from imbalance of excitatory vs. inhibitory neurotransmitters. They found normal concentrations of excitatory transmitter glutamate, but significantly high non-transmitter glutamine and significantly low inhibitory GABA. They concluded high brain glutamine and/or low GABA might explain imbalance of excitatory vs. inhibitory transmission – i.e. autistic behavior.

True, low brain GABA could be responsible – but implicating high brain glutamine in autistic behavior is risky at best, and potentially dangerous. Not only do ASD children consistently have low plasma glutamine, high brain glutamine appears to protect against ASD. This is most obvious in children with high brain glutamine from inborn urea cycle disorders (UCD) or propionic acidemia (PA) [Good 2014]. In UCD, failure of the liver urea cycle to detoxify blood ammonia at first pass allows high levels into the brain, which astrocytes detoxify by combining with glutamate to form glutamine. Krivitzky et al.: “Children in this cohort [UCD] show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders.”[Krivitzky L, 2009] Saul Brusilow (MD) never mentioned autism or autistic behavior in any paper on UCD or hepatic encephalopathy (HE) [personal communication 2013]. Gropman et al., however, noted patients with partial deficiencies of urea cycle enzymes and late-onset presentations may show signs of autism [Gropman AL, 2007]. Cochran et al. also found the osmolyte myoinositol normal in ASD brains; when astrocyte glutamine is high in urea cycle disorders or HE, myoinositol is consistently low. Gabis et al., however, found myoinositol high in ASD astrocytes [Gabis L, 2008].

Propionic acidemia is another inborn metabolic disorder where high blood ammonia becomes high brain glutamine. Al Owain et al.: “In the consensus conference about diagnosis and management of PA hosted in Washington, D.C. in January 2011, there was no reported association among the neurological sequelae of the disease between PA and autism.”[Al-Owain M, 2013] Other physicians who treat PA and UCD children also report they rarely show autistic behavior. Sabine Scholl-Bürgi (MD): “In our PA patient group none has an ASD.”[personal communication 2014]. Professor of pediatrics (MD): “I see lots of kids with PA and UCD but few (perhaps none) have ASD.”[personal communication 2013]

Moreover, plasma concentrations of glutamine and GABA in ASD children are consistently opposite brain concentrations detected by Cochran et al. Plasma glutamine is consistently low [e.g. Moreno-Fuenmayor H, 1996; Aldred S, 2003; Shimmura C, 2011] and plasma GABA high [Cohen 2000; Dhossche D, 2002]. Ghanizadeh concluded: “The low level of plasma glutamine . . . is suggested as a screening test for detecting autism in children especially those with normal IQ. The decreased level has been reported before in all children with autism.”[Ghanizadeh A, 2013] Dhossche et al. thought high plasma GABA explained mood disorders and stupor. Burrus concluded a reaction between ammonia and propionic acid could produce a molecule structurally very similar to GABA [Burrus CJ, 2012].

Glutamine is normally the most abundant amino acid in blood [Souba WW, 1991], a primary brain osmolyte, alternative fuel for brain neurons and astrocytes (especially during hypoglycemia) [Stelmashook EV, 2011], and primary fuel in rapidly replicating cells (e.g. blood vessel endothelial cells, intestinal enterocytes, liver cells, and lymphocytes) [Souba WW, 1987; Souba WW, 1991; Deutz NE, 2008]. Glutamine released from skeletal muscles for anabolic responses to infection may explain the dramatic ability of fever to relieve autistic behavior [Good P, 2013]. A new clue to this phenomenon was recently published at <www.autismstudies.net>.

Autism Research Institute practitioners commonly give ASD patients oral glutamine to heal their intestines, from 250mg–8g/day, with few side effects (some hyperactivity) [Good P, 2013] – although one neurologist reported seizures. Only two practitioners, however, reported improved behavior from glutamine. Franco Verzella (MD) in Bologna, Italy gives ASD children 5–7g/day of oral glutamine after cleansing their intestines of pathogens like bacteria and Candida: “Multifactorial and multisystemic is the condition, so that the improvement has different aspects in different children. Most common: sedation, less stereotypes, better sleep, more concentration.”[personal communication 2013]

Cochran and colleagues need to think twice about reducing brain glutamine in ASD children – whose plasma and brain glutamine are more likely TOO LOW than too high. Pangborn (2013) recommended the free amino acid taurine as a natural way to increase conversion of ammonia + glutamate to glutamine.

Peter Good Autism Studies La Pine OR www.autismstudies.net autismstudies1@gmail.com

Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord 2003;33:93–97.

Al-Owain M, Kaya N, Al-Shamrani H, et al. Autism spectrum disorder in a child with propionic acidemia. JIMD Rep 2013;7:63–66.

Burrus CJ. A biochemical rationale for the interaction between gastrointestinal yeast and autism. Med Hypotheses 2012;79:784–785.

Cohen BI. Infantile autism and the liver: a possible connection. Autism 2000;4:441–442.

Deutz NEP. The 2007 ESPEN Sir David Cuthbertson Lecture: amino acids between and within organs. The glutamate-glutamine-citrulline-arginine pathway. Clin Nutr 2008;27(3):321–327.

Dhossche D, Applegate H, Abraham A, et al. Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monit 2002;8:PR1–PR6.

Gabis L, Wei Huang, Azizian A, et al. 1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders. J Child Neurol 2008;23(7):766–774.

Ghanizadeh A. Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers 2013;35:281–286.

Good P. Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel? Med Hypotheses 2013;80:1–12.

Good P. Why do children with propionic acidemia or urea cycle disorders rarely show autistic behavior? Autism–Open Access 2014;4:3.

Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30:865–879.

Krivitzky L, Babikian T, Lee HS, et al. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009;66:96–101.

Moreno-Fuenmayor H, Borjas L, Arrieta A, et al. Plasma excitatory amino acids in autism. Invest Clin 1996;37:113–128.

Pangborn JB. Nutritional Supplement Use for Autism Spectrum Disorder. San Diego: Autism Research Institute; 2013.

Shimmura C, Suda S, Tsuchiya KJ, et al. Alteration of plasma glutamate and glutamine levels in children with high functioning autism. PLoS One 2011;6:e25340–e25346.

Souba WW. Interorgan ammonia metabolism in health and disease: a surgeon’s view. J Parenter Enteral Nutr 1987;11:569–579.

Souba WW. Glutamine: a key substrate for the splanchnic bed. Ann Rev Nutr 1991;11:285–308.

Stelmashook EV, Isaev NK, Lozier ER, et al. Role of glutamine in neuronal survival and death during brain ischemia and hypoglycemia. Int J Neurosci 2011;121:415–422.

On 2015 May 28, Peter Good commented:

Cochran et al. measured brain glutamate, glutamine, GABA, and other metabolites by MRS in the anterior cingulate cortex of ASD adolescents to test whether autistic behavior arises from imbalance of excitatory vs. inhibitory neurotransmitters. They found normal concentrations of excitatory transmitter glutamate, but significantly high non-transmitter glutamine and significantly low inhibitory GABA. They concluded high brain glutamine and/or low GABA might explain imbalance of excitatory vs. inhibitory transmission – i.e. autistic behavior.

True, low brain GABA could be responsible – but implicating high brain glutamine in autistic behavior is risky at best, and potentially dangerous. Not only do ASD children consistently have low plasma glutamine, high brain glutamine appears to protect against ASD. This is most obvious in children with high brain glutamine from inborn urea cycle disorders (UCD) or propionic acidemia (PA) [Good 2014]. In UCD, failure of the liver urea cycle to detoxify blood ammonia at first pass allows high levels into the brain, which astrocytes detoxify by combining with glutamate to form glutamine. Krivitzky et al.: “Children in this cohort [UCD] show other behavioral/emotional strengths, including a minimal percentage with previous diagnoses of Autism spectrum disorders, mood disorders, and other psychiatric disorders.”[Krivitzky L, 2009] Saul Brusilow (MD) never mentioned autism or autistic behavior in any paper on UCD or hepatic encephalopathy (HE) [personal communication 2013]. Gropman et al., however, noted patients with partial deficiencies of urea cycle enzymes and late-onset presentations may show signs of autism [Gropman AL, 2007]. Cochran et al. also found the osmolyte myoinositol normal in ASD brains; when astrocyte glutamine is high in urea cycle disorders or HE, myoinositol is consistently low. Gabis et al., however, found myoinositol high in ASD astrocytes [Gabis L, 2008].

Propionic acidemia is another inborn metabolic disorder where high blood ammonia becomes high brain glutamine. Al Owain et al.: “In the consensus conference about diagnosis and management of PA hosted in Washington, D.C. in January 2011, there was no reported association among the neurological sequelae of the disease between PA and autism.”[Al-Owain M, 2013] Other physicians who treat PA and UCD children also report they rarely show autistic behavior. Sabine Scholl-Bürgi (MD): “In our PA patient group none has an ASD.”[personal communication 2014]. Professor of pediatrics (MD): “I see lots of kids with PA and UCD but few (perhaps none) have ASD.”[personal communication 2013]

Moreover, plasma concentrations of glutamine and GABA in ASD children are consistently opposite brain concentrations detected by Cochran et al. Plasma glutamine is consistently low [e.g. Moreno-Fuenmayor H, 1996; Aldred S, 2003; Shimmura C, 2011] and plasma GABA high [Cohen 2000; Dhossche D, 2002]. Ghanizadeh concluded: “The low level of plasma glutamine . . . is suggested as a screening test for detecting autism in children especially those with normal IQ. The decreased level has been reported before in all children with autism.”[Ghanizadeh A, 2013] Dhossche et al. thought high plasma GABA explained mood disorders and stupor. Burrus concluded a reaction between ammonia and propionic acid could produce a molecule structurally very similar to GABA [Burrus CJ, 2012].

Glutamine is normally the most abundant amino acid in blood [Souba WW, 1991], a primary brain osmolyte, alternative fuel for brain neurons and astrocytes (especially during hypoglycemia) [Stelmashook EV, 2011], and primary fuel in rapidly replicating cells (e.g. blood vessel endothelial cells, intestinal enterocytes, liver cells, and lymphocytes) [Souba WW, 1987; Souba WW, 1991; Deutz NE, 2008]. Glutamine released from skeletal muscles for anabolic responses to infection may explain the dramatic ability of fever to relieve autistic behavior [Good P, 2013]. A new clue to this phenomenon was recently published at <www.autismstudies.net>.

Autism Research Institute practitioners commonly give ASD patients oral glutamine to heal their intestines, from 250mg–8g/day, with few side effects (some hyperactivity) [Good P, 2013] – although one neurologist reported seizures. Only two practitioners, however, reported improved behavior from glutamine. Franco Verzella (MD) in Bologna, Italy gives ASD children 5–7g/day of oral glutamine after cleansing their intestines of pathogens like bacteria and Candida: “Multifactorial and multisystemic is the condition, so that the improvement has different aspects in different children. Most common: sedation, less stereotypes, better sleep, more concentration.”[personal communication 2013]

Cochran and colleagues need to think twice about reducing brain glutamine in ASD children – whose plasma and brain glutamine are more likely TOO LOW than too high. Pangborn (2013) recommended the free amino acid taurine as a natural way to increase conversion of ammonia + glutamate to glutamine.

Peter Good Autism Studies La Pine OR www.autismstudies.net autismstudies1@gmail.com

Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord 2003;33:93–97.

Al-Owain M, Kaya N, Al-Shamrani H, et al. Autism spectrum disorder in a child with propionic acidemia. JIMD Rep 2013;7:63–66.

Burrus CJ. A biochemical rationale for the interaction between gastrointestinal yeast and autism. Med Hypotheses 2012;79:784–785.

Cohen BI. Infantile autism and the liver: a possible connection. Autism 2000;4:441–442.

Deutz NEP. The 2007 ESPEN Sir David Cuthbertson Lecture: amino acids between and within organs. The glutamate-glutamine-citrulline-arginine pathway. Clin Nutr 2008;27(3):321–327.

Dhossche D, Applegate H, Abraham A, et al. Elevated plasma gamma-aminobutyric acid (GABA) levels in autistic youngsters: stimulus for a GABA hypothesis of autism. Med Sci Monit 2002;8:PR1–PR6.

Gabis L, Wei Huang, Azizian A, et al. 1H-magnetic resonance spectroscopy markers of cognitive and language ability in clinical subtypes of autism spectrum disorders. J Child Neurol 2008;23(7):766–774.

Ghanizadeh A. Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers 2013;35:281–286.

Good P. Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel? Med Hypotheses 2013;80:1–12.

Good P. Why do children with propionic acidemia or urea cycle disorders rarely show autistic behavior? Autism–Open Access 2014;4:3.

Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30:865–879.

Krivitzky L, Babikian T, Lee HS, et al. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr Res 2009;66:96–101.

Moreno-Fuenmayor H, Borjas L, Arrieta A, et al. Plasma excitatory amino acids in autism. Invest Clin 1996;37:113–128.

Pangborn JB. Nutritional Supplement Use for Autism Spectrum Disorder. San Diego: Autism Research Institute; 2013.

Shimmura C, Suda S, Tsuchiya KJ, et al. Alteration of plasma glutamate and glutamine levels in children with high functioning autism. PLoS One 2011;6:e25340–e25346.

Souba WW. Interorgan ammonia metabolism in health and disease: a surgeon’s view. J Parenter Enteral Nutr 1987;11:569–579.

Souba WW. Glutamine: a key substrate for the splanchnic bed. Ann Rev Nutr 1991;11:285–308.

Stelmashook EV, Isaev NK, Lozier ER, et al. Role of glutamine in neuronal survival and death during brain ischemia and hypoglycemia. Int J Neurosci 2011;121:415–422.