Author: Gianpiero Pescarmona
Date: 11/09/2009



Autism is a brain development disorder characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old

The Diseases DatabaseAutism




Provisional diagnosis was made at 3.5 years in 1985 but 3.0 years by 1995 for childhood and atypical autism. For Asperger's syndrome, provisional diagnosis was made at 6.0 years in 1985 but 4.9 years by 1995.
(Prevalence of autism and parentally reported triggers in a north east London population. Archives of Diseases in Childhood 2003)




Symptoms affect mainly the behavior, but there are no clear evidences that they don't depend on metabolic disorders, that could be treated (iron, essential aminoacids deficiency e.g.).

PRR7_HUMAN (high P and H similar to AUTS2)




Describing the brain in autism in five dimensions--magnetic resonance imaging-assisted diagnosis of autism spectrum disorder using a multiparameter classification approach. 2010
It is really useful this approach? It has been tested on adult patients and on a specific sub-group of autism.
It is possible to have a reliable control group at the age of 2?
The results should be compared with the results in Alzheimer Disease (Davatzikos C, Fan Y, Wu X, Shen D, Resnick SM (2008) Detection of prodromal Alzheimer’s disease via pattern classification of magnetic resonance
imaging. Neurobiol Aging 29:514 –523, Klo¨ppel S, Stonnington CM, Chu C, Draganski B, Scahill RI, Rohrer JD, Fox NC, Jack CR Jr, Ashburner J, Frackowiak RS (2008) Automatic classification of MR scans in Alzheimer’s disease. Brain 131:681– 689.)

Laboratory tests


As Autism is a disorder of the highest brain functions (more or less the same that are lost in Alzheimer Disease) the risk factors should include all factors affecting brain ATP synthesis and respiratory rate (nutrients and oxygen supply, hormones, neurotransmitters etc)

This factors may be

  • genetic
    • Papers Autism MTHFR
    • Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet. 2009 Aug;19(4):171-6.
      Mohammad NS, Jain JM, Chintakindi KP, Singh RP, Naik U, Akella RR.
      OBJECTIVE: To investigate whether genetic polymorphisms are the underlying causes for aberrations in folate pathway that was reported in autistic children. BASIC METHODS: A total of 138 children diagnosed as autistic based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria and Autism Behavior Checklist scoring and 138 age and sex matched children who are nonautistic were tested for five genetic polymorphisms, that is, cytosolic serine hydroxyl methyl transferase (SHMT1 C1420T), methylene tetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C), methionine synthase reductase (MTRR A66G), methionine synthase (MS A2756G) using PCR-restriction fragment length polymorphism methods. Fisher's exact test and logistic regression analysis were used for statistical analyses. RESULTS: MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. The frequencies of MTRR 66A allele (12.7 vs. 21.0%) and SHMT 1420T allele (27.9 vs. 45.3%) were lower in autistic group compared with nonautistic group with odds ratios 0.55 (95% CI: 0.35-0.86) and 0.44 (95% CI: 0.31-0.62), respectively, indicating reduced risk. MTHFR 1298C-allele frequency was similar in both the groups (53.3 vs. 53.6%) and hence individually not associated with any risk. However, this allele was found to act additively in the presence of MTHFR 677T allele as evidenced by 8.11-fold (95% CI: 2.84-22.92) risk associated with MTHFR 677CT+TT/1298AC+CC genotypes cumulatively. CONCLUSION: MTHFR C677T is a risk factor, whereas MTRR A66G and SHMT C1420T polymorphisms reduce risk for autism. MTHFR A1298C acts additively in increasing the risk for autism.
  • MicroRNA regulation of gene expression in autism
    • Mechanistic biomarkers for autism treatment 2009
      Research by Valerie Hu and colleagues, recently published in Genome Medicine, suggests that microRNAs (miRNAs) have a role in the gene expression changes which can underlie autistic spectrum disorders.
      Autism spectrum disorders are neurodevelopmental in origin and often include behavioral and language abnormalities.
      In their article “Investigation of post-transcriptional gene regulatory networks associated with autism spectrum disorders by microRNA expression profiling of lymphoblastoid cell lines”, Hu and colleagues suggest that expression changes in 43 miRNAs are seen in patients with this condition. These miRNAs may regulate genes which have previously been linked to roles in autism and other comorbid disorders.
      A recent article from the same group, published in The FASEB Journal, suggests that differential methylation may also have a role in autism, providing further evidence for an epigenetic origin of autistic spectrum disorders. With evidence growing for a genetic overlap between autism and other conditions such as schizophrenia and bipolar disorder, it will be interesting to consider whether the same factors are at work in other neurological and neurodevelopmental conditions

effect on PRL ?

  • Genes controlling affiliative behavior as candidate genes for autism. 2008
  • Neurobehavioral syndrome induced by H2-receptor blocker withdrawal: possible role of prolactin.1997 Cimetidine and ranitine are histamine H2-receptor blockers widely used for the treatment of gastric hypersecretion and duodenal pathologies. They are known to induce hyperprolactinemia in humans. Forty-six patients treated with cimetidine or ranitidine who were exhibiting a neurobehavioral syndrome after withdrawal of the drugs were selected. This syndrome was associated with a drop in plasma prolactin levels. The symptoms of this syndrome were greatly improved by restoration of treatment with the same drugs and reappeared when the treatment was again suspended. This syndrome was inhibited in 36 patients by administration of domperidone (30 mg/day), a drug inducing hyperprolactinemia without crossing the blood-brain barrier, as compared with 10 control patients treated with placebo. These results suggest that the drop in prolactin levels occurring when cimetidine and ranitidine are suspended may contribute to the development of this syndrome. Also, the withdrawal of H2-receptor blockers could be included among the possible causes of some neurotic syndromes.
  • [The H2-antagonist therapy withdrawal syndrome: the possible role of hyperprolactinemia] 1990 Patients previously treated with H2-receptor blocking agents (cimetidine or ranitidine) exhibited a complex neurobehavioral and gastroenteric syndrome, including anxiety, insomnia, anorexia, growing thin, irritability, tachycardia, diarrhoea, nausea, vomiting, abdominal pain, headache, vertigo. These symptoms were dramatically reduced by administration of cimetidine or ranitidine, and reappeared with a new suspension of the therapy. The withdrawal syndrome from H2-receptor antagonists was reversed by treatment with domperidone (10 mg three times per day), a potent hyperprolactinaemic drug which does not cross the blood brain barrier. These results suggest that the drop in prolactin levels that occurs when cimetidine or ranitidine are suspended may contribute to the development of the withdrawal syndrome.

or a proper combination of them.

Genetic Risk Factors

Neurexin and Neuroligin







Papers Autism Neurosteroids

Altered synthesis of neurosteroids at the 5-alpha-reductase step.
A related Clinical Report



anatomical (due its structure)

vascular (due to the local circulation)

physiopathological (due to tissue function and activity)



Guide Lines

Regione Piemonte

Disturbi dello Spettro Autistico
Sempre piu' frequentemente noi, pediatri di famiglia, ci dobbiamo confrontare con le patologie croniche, affrontando problemi che richiedono ulteriori approfondimenti rispetto alla nostra formazione
tradizionale. Ne sono un esempio i Disturbi dello Spettro Autistico che incontriamo anche piu' volte nella nostra vita professionale.
L' approccio ad un bambino autistico ci pone molteplici difficolta' : prima di tutto bisogna avere la capacita' di sospettare precocemente tale disturbo per un invio tempestivo allo specialista, il rapporto con
il bambino autistico e con la sua famiglia non e' facile ad instaurarsi inoltre e' necessario collaborare con altri professionisti per la presa in carico dei pazienti. L' obiettivo e' di realizzare la presa in carico
precoce, entro i DUE anni, importante non per guarire la malattia ma per contenere i danni e migliorarne l'evoluzione

Vagus nerve stimulation

Vagus nerve stimulation therapy in patients with autism spectrum disorder and intractable epilepsy: results from the vagus nerve stimulation therapy patient outcome registry. 2010

Autism and Diet

The review of most frequently occurring medical disorders related to aetiology of autism and the methods of treatment. 2010

[Substitutive and dietetic approaches in childhood autistic disorder: interests and limits] Encephale. 2008 Oct;34(5):496-503. Epub 2008 Mar 4. Hjiej H, Doyen C, Couprie C, Kaye K, Contejean Y.

  • INTRODUCTION: Autism is a developmental disorder that requires specialized therapeutic approaches. Influenced by various theoretical hypotheses, therapeutic programs are typically structured on a psychodynamic, biological or educative basis. Presently, educational strategies are recommended in the treatment of autism, without excluding other approaches when they are necessary. Some authors recommend dietetic or complementary approaches to the treatment of autism, which often stimulates great interest in the parents but also provokes controversy for professionals. Nevertheless, professionals must be informed about this approach because parents are actively in demand of it. LITERATURE FINDINGS: First of all, enzymatic disorders and metabolic errors are those most frequently evoked in the literature. The well-known phenylalanine hydroxylase deficit responsible for phenylketonuria has been described as being associated with autism. In this case, adapted diet prevents mental retardation and autistic symptoms. Some enzymatic errors are also corrected by supplementation with uridine or ribose for example, but these supplementations are the responsibility of specialized medical teams in the domain of neurology and cannot be applied by parents alone. Secondly, increased opoid activity due to an excess of peptides is also supposed to be at the origin of some autistic symptoms. Gluten-free or casein-free diets have thus been tested in controlled studies, with contradictory results. With such diets, some studies show symptom regression but others report negative side effects, essentially protein malnutrition. Methodological bias, small sample sizes, the use of various diagnostic criteria or heterogeneity of evaluation interfere with data analysis and interpretation, which prompted professionals to be cautious with such diets. The third hypothesis emphasized in the literature is the amino acid domain. Some autistic children lack some amino acids such as glutamic or aspartic acids for example and this deficiency would create autistic symptoms. However, for some authors, these deficits are attributed to nutritional deficits caused by the food selectivity of children. A fourth hypothesis concerning metabolic implication in autism is the suspicion that a food allergy phenomenon could interfere with development, and it has been observed that Ig levels are higher in autistic children than in control children. Autistic children with a positive reaction to food Ig would have a more favourable outcome with diet excluding some kinds of food; but most of those diets are drastic and ethically debatable. Fifth, glucidic catabolism could be deleterious with an excess of ketonic products that will initiate comitial seizures. Few studies with ketogenic diet have been conducted but, as it has been described with epileptic subjects, those diets would diminish autistic symptoms. Not enough studies have been conducted that would allow one to draw any firm conclusions. The sixth hypothesis is linked with vitamin deficiencies that are a notably important area of research in the treatment of autism. Vitamin B12 or B6 deficiencies have been studied in several articles, and many of them were controlled studies. French teams also emphasize an interest in supplementation with B12 or B6. The two last hypotheses concern auto-immune patterns and the toxic effects of heavy metals like mercury. There is a paucity of methodologically satisfying studies that support these two hypotheses and diet recommendations. Following these assumptions, some dietetic approaches have been recommended, even though the methodological aspects of supporting studies are poor. The most famous diet is the gluten-free and/or casein-free diet. Only two controlled studies attracted our attention. Even if for some autistic children such a diet was positive, for others, gluten-free or casein-free diets were poorly tolerated and, for some authors, not without considerable side effects, the more prejudicial of which was the Kwashiorkor risk. Ketogenic diets have been studied in one non controlled study, but even if positive results have been noted by the authors, the ketogenic diet is very restricting and the long term effects have not been evaluated. Vitamin supplementation is the one and only diet domain where there have been many repeated and placebo-controlled studies. Side effects are rare and mild even if high doses of vitamin B6 are advocated in these studies. In total, as evoked by Rimland, 11 controlled placebo-blind studies have been conducted and 50% of autistic children with this supplementation had improved autistic signs. However, these results still remain debated. Finally, more rarely, enzymatic abnormalities need specific diets which have some positive consequences, but such diets could not be applied by parents alone and are the responsibility of specialized teams. For discussion purposes we can emphasize that, in spite of the amount of studies concerning the effects of specialized diets, few are methodologically satisfying. We can not ignore that some side effects are possible with such approaches and parents need to be informed of them. Some are even potentially serious, such as diets with metal chelators. In spite of those results, vitamin supplementation seems to be the only one that some specialized teams in autism could apply, always with parent agreement. In conclusion, within this scientific field, studies on eating habits of autistic children should be conducted because of their food selectivity or avoidance.

Transcriptomic analysis of autistic brain reveals convergent molecular pathology, 2011

Analysis of estrogen receptor β gene methylation in autistic males in a Chinese Han population. 2017

  • Autism spectrum disorder (ASD) is a neurodevelopment disorder with abnormalities of social interaction, communication and repetitive behaviors. The higher prevalence of ASD in men implies a potential relationship between sex hormones and ASD etiology. The ESR2 gene encodes estrogen receptor beta (ESR2) and plays an important role during brain development. A relationship between ESR2 and ASD has been suggested by studies on single nucleotide polymorphisms and mRNA and protein expression levels in ASD patients. Here, we explored the possible epigenetic regulation of the ESR2 gene in autism. We collected genomic DNA from the peripheral blood of Chinese Han males with autism and age-matched normal males and measured DNA methylation of CpG islands in the ESR2 gene, which consisted of 41 CpG sites among the proximal promoter region and an untranslated exon, by bisulfite sequencing. We also investigated a relationship between DNA methylation and phenotypic features of autism, as assessed by the Children Autism Rating Scale. We found little overall difference in the DNA methylation of the ESR2 5'-flanking region in individuals with autism compared with normal individuals. However, detailed analyses revealed that eight specific CpG sites were hypermethylated in autistic individuals and that four specific CpG sites were positively associated with the severity of autistic symptoms. Our study indicates that the epigenetic dysregulation of ESR2 may govern the development of autism.
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