The case for autism being biochemically similar to schizophrenia and Alzheimer’s disease


Aconitase activity was significantly decreased in cerebellums of individuals who had autism. Glutathione levels were decreased in individuals with autism. Glutathione peroxidase activity is decreased in individuals with autism. Homocysteine levels are increased in children with autism. Vitamin D levels are decreased in individuals with autism. Individuals with autism have reduced bone mineral density. Taurine levels are low in a subset of individuals with autism. There are low levels of biotin in patients with autism. Iron deficiency is very common in autism.

See my papers Treatment-resistant schizophrenia: focus on the transsulfuration pathway. and A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway as to how similar biochemical abnormalities are also present in schizophrenia and Alzheimer’s disease. Other posts on this blog are also relevant to biochemical abnormalities found in schizophrenia.

Autism, schizophrenia and Alzheimer’s disease are epigenetic illnesses. Despite various biochemical commonalities between autism, schizophrenia and Alzheimer’s disease there are epigenenetic differences with these epigenetic differences channeling the illnesses in divergent directions. However, with autism, schizophrenia and Alzheimer’s disease being fundamentally similar treatments for autism, schizophrenia and Alzheimer’s disease could be very similar. As there are now no biological treatments for autism treatments currently used in autism and which are partially effective can not now be clearly hooked up to a treatment for schizophrenia.

Social skills interventions is individuals with autism aged 6-21 have shown limited and equivocal effectiveness. Biological treatments for autism are needed.

Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.

Iron defciency and negative sypmtoms in schizophrenia

Latent Iron Deficiency as a Marker of Negative Symptoms in Patients with First-Episode Schizophrenia Spectrum Disorder

by Sung-Wan Kim 1,2,*, Robert Stewart 3,4, Woo-Young Park 2, Min Jhon 1,2, Ju-Yeon Lee 1,2, Seon-Young Kim 1, Jae-Min Kim 1, Paul Amminger 5, Young-Chul Chung 6 and Jin-Sang Yoon 1,*


Iron deficiency may alter dopaminergic transmission in the brain. This study investigated whether iron metabolism is associated with negative symptoms in patients with first-episode psychosis. The study enrolled 121 patients with first-episode schizophrenia spectrum disorder, whose duration of treatment was 2 months or less. Negative symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and Clinician-Rated Dimensions of Psychosis Symptom Severity (Dimensional) scale of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Prominent negative symptoms were defined as moderate or severe negative symptoms on the Dimensional scale of the DSM-5. Iron deficiency was defined as a serum ferritin ≤ 20 ng/mL. Patients with iron deficiency were significantly more likely to have prominent negative symptoms (45.2 vs. 22.2%; p = 0.014) and a higher PANSS negative symptoms score (p = 0.046) than those with normal ferritin levels. Patients with prominent negative symptoms had significantly lower ferritin levels (p = 0.025). The significance of these results remained after controlling for the duration of illness and other confounding variables. Our finding of an independent association between iron deficiency and negative symptoms in patients at the very early stage of illness implies that iron dysregulation has an effect on negative symptoms in patients with schizophrenia. The possibility of therapeutic intervention with iron should be further investigated.

I have been argunig in this blog that there are high IRP1 levels in schizophrenia due to difficulties in iron-sulfur cluster formation whereby cytosolic aconitase switches to IRP1. As ferritin mRNA has an iron response element in the 5′ untranslated region high levels of IRP1 will decrease ferritin levels.

Iron positively regulates other enzymes in the citric acid cycle besides aconitase

Besides aconitase iron positively affects three other citric acid cycle enzymes, the enzymes being citrate synthase, isocitric dehydrogenase synthase and and succinate dehydrogenase.

Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation

Horst Oexle, Erich Gnaiger and Gunter Weiss Biochimica et Biophysica Acta (BBA) – Bioenergetics


Iron modulates the expression of the critical citric acid cycle enzyme aconitase via a translational mechanism involving iron regulatory proteins. Thus, the present study was undertaken to investigate the consequences of iron perturbation on citric acid cycle activity, oxidative phosphorylation and mitochondrial respiration in the human cell line K-562. In agreement with previous data iron increases the activity of mitochondrial aconitase while it is reduced upon addition of the iron chelator desferrioxamine (DFO). Interestingly, iron also positively affects three other citric acid cycle enzymes, namely citrate synthase, isocitric dehydrogenase, and succinate dehydrogenase, while DFO decreases the activity of these enzymes. Consequently, iron supplementation results in increased formation of reducing equivalents (NADH) by the citric acid cycle, and thus in increased mitochondrial oxygen consumption and ATP formation via oxidative phosphorylation as shown herein. This in turn leads to downregulation of glucose utilization. In contrast, all these metabolic pathways are reduced upon iron depletion, and thus glycolysis and lactate formation are significantly increased in order to compensate for the decrease in ATP production via oxidative phosphorylation in the presence of DFO. Our results point to a complex interaction between iron homeostasis, oxygen supply and cellular energy metabolism in human cells.

Inhibition of TCA cycle at the aconitase step could be associated with obesity

J. Theor Biol 2003 Nov 7;225(1):33-44
Wlodek D. and Gonzalez M.


Obesity has reached epidemic proportions and has become one of the major health problems in developed countries. Current theories consider obesity a result of overeating and sedentary life style and most efforts to treat or prevent weight gain concentrate on exercise and food intake. This approach does not improve the situation as may be seen from the steep increase in the prevalence of obesity. This encouraged us to reanalyse existing information and look for biochemical basis of obesity. Our approach was to ignore current theories and concentrate on experimental data which are described in scientific journals and are available from several databases. We developed and applied a Knowledge Discovery in Databases procedure to analyse metabolic data. We began with the contradictory information: in obesity, more calories are consumed than used up, suggesting that obese people should have excess energy. On the other side, obese people experience fatigue and decreased physical endurance that indicates diminished energy supply in the body. The result of our work is a chain of metabolic events leading to obesity. The crucial event is the inhibition of the TCA cycle at the step of aconitase. It disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation. Further steps in obesity development are the consequences of diminished energy supply: inhibition of beta-oxidation, leptin resistance, increase in appetite and food intake and a decrease in physical activity. Thus, our theory shows that obesity does not have to be caused by overeating and sedentary life-style but may be the result of the “obese” change in metabolism which is forcing people to overeat and save energy to sustain metabolic functions of cells. This “obese” change is caused by environmental factors that activate chronic low-grade inflammatory process in the body linking obesity with the environment of developed countries.