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Rett's Disorder

Pervasive Developmental Disorders include Autism, Rett's Disorder, Childhood Disintegrative Disorder, and Asperger's Disorder.  They are severe and pervasive impairments in several areas of development: social interaction, communications, stereotyped and repetitive behavior, and restricted interests and activities.  Anxiety is quite common as are ADHD type behaviors.  Symptoms usually appear in the first year of life and all except Asperger's are usually accompanied by mental retardation.  There is a high prevalence of clumsiness in Asperger's syndrome (J Child Psychol Psychiatry. 2002 Jul;43(5):655-68).  One sad phenomenon is that many psychological tests, e.g. for autism, which were developed at public institutions like the University of Michigan with public funding, are only available to treatment professionals for significant sums of money.

Studies report that autism is a strongly inherited or genetic disorder with inheritance as high as 90% (Biol Psychiatry 2006 Sep 21).  Genetic research is early in development, but makes is clear that autism is not one disease, but many different genetic diseases with somewhat similar presentations.  There are very likely other organic causes of brain damage that cause the disorder.  No one has found a "cure" or even suggested that a "cure" can ever be found.

Among environmental factors, alcohol during pregnancy and lack of breastfeeding coupled with the use of infant formula not supplemented by DHA omega-3 fatty acid are linked to increased risk of autism.  

I am worried that the diagnosis of Asperger's disorder is being overused and resulting in many children being given powerful psychotropic medications without a clear research foundation or even a reliable diagnosis.  At least some children may be bright or even very bright academically and just not that interested in interacting with other children.  In earlier times, this would have been considered a phase and a personality type, now it is considered a major childhood disease.  It makes a lot of money for neurological psychologists, but the research foundation for much of what is being done appears to be seriously lacking.  

Even Michelangelo, the famous Italian painter, is now being called a "high functioning autistic" (J Med Biogr. 2004 May;12(2):115-20) as is the legendary teenage leader King Charles XII of Sweden (Lakartidningen. 2002 Nov 28;99(48):4874-8).  And Ramanujan, one of India's greatest mathematicians is claimed to have suffered from Asperger's (J Med Biogr. 2002 Aug;10(3):167-9) and on and on.  Two-thirds of the winners of the United Kingdom's Math Olympiad met the diagnostic criterion of Asperger's symdrome and 100% came at least close (J Autism Dev Disord. 2001 Feb;31(1):5-17).

Autism Up 300% in California: A UC Davis study by Robert Byrd found a huge increase in the diagnosis of severe autism between 1987 and 1998 and says there has been a further increase since then. Milder Asberger’s Disease was not included in study. NYT 10/17/02.  Ed: The increase in diagnosis is almost certainly to tap into governmental monies designated to treat children with autism and are totally unrelated to any increase in the disease.

Autism Up 1000% Due to Change in Diagnosis and Increased Awareness: The definition of autism changed in 1994 to include milder forms of the disorder, such as Asperger’s syndrome, in which children lack social skills but are often highly verbal. Data gathered in random study in Atlanta in 1996. Now 3.4 children per 1000 get this diagnosis. JAMA 2003;289:49-55. 

Almost 1% of Children Now Called Autistic: Studies published before 1985 showed prevalence rates of 4 to 5 per 10,000 children for the broader autism spectrum, and about 2 per 10,000 for classic autism. Since 1985 there have been higher rates of autism reported from several countries. The UK a prevalence rate of 16.8 per 10,000 children for autistic disorder was reported, and 62.6 per 10,000 for the entire autistic spectrum disorders. Sweden reported a prevalence of 36 per 10,000 for Asperger and 35 per 10,000 for social impairment, or a total prevalence of 71 per 10,000 for suspected and possible cases. From the US, 40 per 10,000 in three to ten year old children for autistic disorder and 67 per 10,000 children for the entire autism spectrum was reported. It was less common in Israel: 10 per 10,000. Trends in autism. Merrick J, Kandel I, Morad M. Jerusalem, Israel. Int J Adolesc Med Health. 2004 Jan-Mar;16(1):75-8.


Alcoholic Mothers More Common in Autism: In an analysis of 167 pedigrees with an autistic child, 39% had alcoholism in patterns consistent with transmission of a genetic trait. Children from high alcoholism families were more likely to have the onset of their autistic behavior occur with a loss of language (52.5% vs. 35.8%, p = 0.04). This occurred primarily in families where the mother was alcoholic (80% vs. 40%, p = 0.05), suggesting an association between maternal alcoholism and regressive onset autism. Children from high alcoholism families were less likely to be macrocephalic (14.7% vs. 40.6%, p = 0.0006). Children from high alcohol and low alcohol families did not differ in dysmorphology status, IQ, sex ratio or sib recurrence risk. Autism families with a high incidence of alcoholism. Miles JH, Takahashi TN, et al. University of Missouri. J Autism Dev Disord. 2003 Aug;33(4):403-15.

Antibodies Against Brain Tissue More Common: There is evidence for systemic and neuroimmune mechanisms in children with autism. Although genetic factors are important, atypical prenatal maternal immune responses may also be linked to the pathogenesis of autism. Testing 11 mothers and their autistic children, maternal controls, and several groups of control children, to prenatal, postnatal, and adult rat brain proteins, by immunoblotting, similar patterns of reactivity to prenatal (gestational day 18), but not postnatal (day 8) or adult rat brain proteins were identified in autistic children, their mothers, and children with other neurodevelopmental disorders, and differed from mothers of normal children, normal siblings of children with autism and normal child controls. Specific patterns of antibody reactivity were present in sera from the autism mothers, from 2 to 18 years after the birth of their affected children and were unrelated to birth order. Immunoblotting using specific antigens for myelin basic protein (MBP) and glial acidic fibrillary protein (GFAP) suggests that these proteins were not targets of the maternal antibodies. The identification of specific serum antibodies in mothers of children with autism that recognize prenatally expressed brain antigens suggests that these autoantibodies could cross the placenta and alter fetal brain development. Maternal antibrain antibodies in autism. Zimmerman, et al. Johns Hopkins. Brain Behav Immun 2006 Oct 5.

Birth Weight Low in Autism: VLBW Children High ADHD and Psychiatric Symptoms: In a population follow-up study of 56 very low birthweight (VLBW: birthweight </=1500 g), 60 term small for gestational age (SGA: birthweight <10th centile), and 83 normal term children at 14 years of age, the 46% of VLBW adolescents had psychiatric symptoms vs. 13% for controls or 470% more likely [OR 5.7] and psychiatric disorders 25% vs. 7% (OR 4.3), especially anxiety disorders. Attention problems were present in 25% of the VLBW adolescents with 7% diagnosed ADHD. Four had Asperger's disorder. Psychiatric symptoms and disorders in adolescents with low birthweight. Child Care Health Dev. 2005 Jan;31(1):121

Birth Factors and Parental Mental Illness are Risk Factors: In a study of 698 Danish children with autism and 25 controls each, the risk of autism was associated with breech presentation (risk ratio (RR) = 1.63), low Apgar score at 5 minutes (RR = 1.89), gestational age at birth <35 weeks (RR = 2.45), and parental psychiatric history (schizophrenia-like psychosis: RR = 3.44; affective disorder: RR = 2.91). Analyses showed no statistically significant association between risk of autism and weight for gestational age, parity, number of antenatal visits, parental age, or socioeconomic status. Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status. Larsson HJ, Eaton WW, et al. University of Aarhus, Denmark. Am J Epidemiol. 2005 May 15;161(10):916-25.

Birth Interventions Not Related to Autism: In a population-based, matched case-control study of infantile autism, the risk of infantile autism was increased for mothers aged >35 years, with foreign citizenship, and mothers who used medicine during pregnancy. A higher risk of infantile autism was seen among children with low birth weight and with congenital malformations. Birth interventions, pathological cardiotocography, green amnion fluid and acidosis during delivery were not associated with increased risk for infantile autism. Perinatal risk factors and infantile autism. Maimburg RD, et al. University of Aarhus, Denmark. . Acta Psychiatr Scand 2006 Oct;114(4):257-64.

Breastfeeding: Lack of Breastfeeding More Common: In a study of 145 autistic and 224 normal children, a significantly higher proportion of autistic children (24.8%) compared to control children (7.5%) were weaned by the end of the first week of life. Tanoue Y, Oda S. Weaning time of children with infantile autism. J Autism Dev Disord. 1989;19:425–434. One study found decreased DHA in the composition of plasma total phospholipids which resulted in significantly lower levels of total omega-3 polyunsaturated fatty acids for autistic compared to mentally retarded subjects [Vancassel S, et al. Plasma fatty acid levels in autistic children. Prostaglandins Leukot Essent Fatty Acids. 2001]. Another study found a significant decrease in the ARA composition of red blood cell polar lipids for children with regressive autism compared to control children [Bell JG, et al. Essential fatty acids and phospholipase A2 in autistic spectrum disorders. Prostaglandins Leukot Essent Fatty Acids. 2004;71:201–204.].

Breastfeeding: DHA Infant Formula and Breastfeeding Linked to Less Autism: In a case-control study using data from the parental Autism Internet Research Survey of 861 children with Autistic Disorder and 123 control children, absence of breastfeeding when compared to breastfeeding for more than six months was significantly associated with an increase in the odds of having autistic disorder when all cases were considered (OR 2.48) and after limiting cases to children with regression in development (OR 1.95). Use of infant formula without docosahexaenoic acid and arachidonic acid supplementation versus exclusive breastfeeding was associated with a significant increase in the odds of autistic disorder when all cases were considered (OR 4.41) and after limiting cases to children with regression in development (OR 12.96). Breastfeeding, infant formula supplementation, and Autistic Disorder: the results of a parent survey. Schultz ST, et al. University of California, San Diego. . Int Breastfeed J 2006 Sep 15;1:16. 

Carnitine: Deficiency May Play a Causative Role: In a study of 100 children with autism, free and total carnitine (p < 0.001), and pyruvate (p = 0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001). The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children. Relative carnitine deficiency in autism. Filipek PA, et al. University of California, Irvine. J Autism Dev Disord. 2004 Dec;34(6):615-23

Epidermal Growth Factor Much Lower in Study: In measuring 17 male subjects with high-functioning autism and 18 age-matched healthy controls, the serum levels of EGF in the subjects with high-functioning autism (72.4 pg/mL) were significantly lower (p < .001) than those of normal control subjects (322.3 pg/mL). Decreased Serum Levels of Epidermal Growth Factor in Adult Subjects with High-Functioning Autism. Suzuki K, et al. Biol Psychiatry 2006 Nov 20.

Genes: Duplications and Deletions Frequent: Duplications or deletions of portions of the genome may cause many - if not most - cases of autism. Such errors can alter the number of copies of particular genes in the regions affected. These copy-number variations are 10 times as common in autistic children as in other children. A team led by Jonathan Sebat of Cold Spring Harbor Laboratory on Long Island, New York, examined 118 families that have one autistic child and 99 families with children who are not autistic. Ten per cent of the autistic children, but only 1 per cent of the other children, had copy-number variants in their genomes that didn't appear in their parents (Science, 3/2007). The copy-number variants tend to affect different genes in each autistic child. This suggests that autism is not caused by a single genetic defect. 

Melatonin: Nocturnal Production Low: In a study of 49 children and adolescents with autistic disorder and 88 normal children, nocturnal production of melatonin was reduced in autism. Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder (.75 vs. 1.80 microg/hr, p =.0001), and was significantly negatively correlated with severity of autistic impairments in verbal communication and play (p < .05). Tordjman S, Anderson GM, et al. Universite de Rennes, France. Biol Psychiatry. 2005 Jan 15;57(2):134-8. 

Melatonin: Nocturnal Production Low: In a study of 14 children suffering from classical infantile autism and 20 age-matched healthy children, no autistic patient showed a normal MLT circadian rhythm. Autistic children showed significantly lower mean concentrations of MLT, mainly during the dark phase of the day. Evidence of pineal endocrine hypofunction in autistic children. Kulman G, et al. Milan, Italy. Neuro Endocrinol Lett 2000;21(1):31-34.

Mercury: No Proven Connection to Autism: In a meta-analysis of the accuracy of hair mercury, hair mercury levels correlated with mercury level in blood, with 24 h urine and with cord blood, the correlation for hair mercury level with 24 h urine level and blood level was not high enough to replace them in clinical decision-making of individual patient. Epidemiological evidence has shown that low-level mercury poisoning is not a cause of autism. The risk of neurodevelopmental disabilities from low-level exposure to methylmercury from the regular consumption of fish is still controversial even after combining results from different epidemiological studies worldwide. There is a lack of data in the literature about the effect of chelation therapy in children with neurodevelopmental disabilities. There is no evidence to support the association between mercury poisoning and autism. Low-level chronic mercury exposure in children and adolescents: Meta-analysis. Ng DK,et al. Kowloon, Hong Kong. Pediatr Int 2007 Feb;49(1):80-7.

Mercury Very Low in Autism Hair: 94 autistic children vs 45 other. Baby hair mercury of children later diagnosed as autistic was 0.47 parts per million, compared with 3.63 ppm in the others. The more severe the autism, the lower the mercury levels. The mean levels of children with mild, moderate and severe autism were 0.79, 0.46 and 0.21 ppm respectively. Most of this mercury came from the mothers. The main sources of exposure, according to the team, were mercury amalgam fillings, Rho D immunoglobulin injections containing thimerosal given to Rhesus negative mothers, and heavy consumption of fish (defined as more than five fish meals a month). In the control group, hair mercury rose in line with the mothers' exposure. But the baby hair of autistic children had consistently low mercury levels, even when the mothers' exposure was high, the team found. Holmes, 9/03 International Journal of Toxicology

Oxidative Stress and Impaired Methylation Found More Common in Study: Plasma concentrations of methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), adenosine, homocysteine, cystathionine, cysteine, and oxidized and reduced glutathione were measured in 20 children with autism and in 33 control children. On the basis of the abnormal metabolic profile, a targeted nutritional intervention trial with folinic acid, betaine, and methylcobalamin was initiated in a subset of the autistic children. Children with autism had significantly lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of SAH, adenosine, and oxidized glutathione. The intervention trial was effective in normalizing the metabolic imbalance in the autistic children. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. James SJ, et al. University of Arkansas. .  Am J Clin Nutr 2004 Dec;80(6):1611-7.

Paternal Age Higher is Autistic Children: Using a smaller subset of data on 132 271 young Israelis on both paternal and maternal age for the primary analysis and the larger subset of 318 506 with data on paternal but not maternal age for sensitivity analyses, there were 110 cases of ASD (8.3 cases per 10 000 persons), mainly autism, in the smaller subset with complete parental age data. There was a significant monotonic association between advancing paternal age and risk of ASD. Offspring of men 40 years or older were 5.75 times (P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Reichenberg A, et al. Mount Sinai School of Medicine, New York, NY 10029, USA. . Arch Gen Psychiatry 2006 Sep;63(9):1026-32. Ed: This is still a very small risk factor, but childbirth by older mothers and hence older fathers has increased in recent decades.

Rett Syndrome MECP2 Gene Causes Some Schizophrenia and Autism: The gene MECP2 is mutated in Rett Syndrome girls, a cause in mental retardation in 1/10,000 births. Earlier research suggested that the MeCP2 protein was responsible for making sure that genes the cell has marked with a molecular tag, called a methyl group, are silenced. The MeCP2 protein latches on to these methyl groups and prevents them from being translated into protein.  Cases of both classic autism and schizophrenia are caused by mutations in this gene. Neuron 7/18/02

Serotonin Elevated in Many Autistic: Hyperserotonemia is the most consistent serotonin-related finding in autism. Measurement of platelet serotonin level in 53 autistic adults and 45 healthy controls found the autistic group (75.7 ng/muL) was significantly higher than the control sample (59.2 ng/muL) due to a presence of hyperserotonemic subjects which comprised 32% of the patients. Hyperserotonemia in Adults with Autistic Disorder. Hranilovic D, et al. University of Zagreb, Croatia. J Autism Dev Dis 2006 Dec 13.

Vaccination Not Related to Autism: A huge study of over 2,000,000 children found no relationship to increased autism and either thimerosal or non-thimerosal vaccines. Association between thimerosal-containing vaccine and autism. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. JAMA. 2003 Oct 1;290(13):1763-6

Vaccination: No Link Vaccines and Autism: There was no significant link between childhood vaccines containing the mercury-based preservative thimerosal and neurological problems such as autism and attention-deficit disorder in a U.S. study of more than 140,000 children. Frank DeStefano, a CDC researcher, Pediatrics 11/03

Vaccination: No Link Vaccines and Autism: In a very large national study of children and young adults diagnosed with a pervasive developmental disorder with 1294 cases and 4469 controls, only 78% of cases vs. 82% of controls had had MMR vaccination before the age of diagnosis.  Thus, individuals receiving MMR vaccinations were 14% less likely to develop PDD, a non-significant difference, but in the opposite direction from which some activists had been claiming. Researchers concluded that MMR vaccination is not associated with an increased risk of pervasive developmental disorders.

Valproic Acid In Utero Increases Risk of ASD: Valproic acid exposure in utero has been associated with an increased risk of both neural tube defects and autism spectrum disorders. Retinoic acid produces similar terata and is known to act in part by increasing the expression of Hoxa1. This study reports similar i

Vasopressin Antagonist Apelin Reduced in Autistic: Dysregulation of the vasopressin (AVP) system has been implicated in the pathogenesis of autistic spectrum disorder (ASD). Apelin is a recently discovered neuropeptide that could counteract AVP actions and whose receptors are colocalized with vasopressin in hypothalamic magnocellular neurons. In a study of 18 autistic and 21 control children, reduced levels of apelin (p < 0.001) and elevated concentrations of AVP (p = 0.02) were found in ASD patients. An inverse correlation between apelin and AVP levels was found within the ASD group (r = -0.61; p = 0.007), but not in healthy participants.


These are just a few of many available studies.  Much research is going on, but many of the findings have not been replicated by other researchers.  It appears very likely that there are numerous genetic diseases that result in problems falling somewhere in the autistic spectrum.  Improved genetic tools will someday in the not distant future being given exact answers for genetic cases.  That day has not arrived.  Since the research has no current practical application and is confusing and hard to understand, I will only post a few.

Cerebellar Abnormalities and ASD Linked to Homeobox Transcription Factor Gene SNPs: Mouse mutants of the homeobox transcription factor Engrailed2 (En2) and autistic individuals display similar cerebellar abnormalities including hypoplasia and a decrease in the number of Purkinje cells. Human EN2 maps to 7q36, a chromosomal region linked to autism spectrum disorder (ASD). In 138 triads of autistic individuals and their parents, two intronic SNPs (rs1861972 and rs1861973) demonstrated significant association with autism (rs1861972, P=0.0018; rs1861973, P=0.0003; haplotype, P=0.000005). Flanking exonic SNPs (rs3735653 and rs2361689) did not. This analysis was then extended to include 167 small nuclear ASD pedigrees and significant association was again only observed. Association of the homeobox transcription factor, ENGRAILED 2, 3, with autism spectrum disorder. Gharani N, Benayed R, et al. Rutgers University. Mol Psychiatry. 2004 May;9(5):474-84.

GABRB3 Gene for Insistence on Sameness Autism: Families whose children scored high in the IS (insistence on sameness) category had a strong link to the GABRB3 gene on chromosome 15q. (Gamma amino butyric receptor B3). 2/7/03, Duke, March 2003, Amer J Human Genetics  

Neurexin 1beta Gene May Be Involved: Neuroligins are postsynaptic membrane cell-adhesion molecules which bind to beta-neurexins, a family of proteins that act as neuronal cell surface receptors. The coding regions and associated splice junctions of three beta-neurexin genes were scanned with detection of virtually all mutations-SSCP in 72 European-American patients with autism. In addition, segments of the neurexin 1beta gene were sequenced in 131 additional European-American and 61 Afro-American patients with autism. Two putative missense structural variants were identified in the neurexin 1beta gene in four European-American patients with autism and not in 535 healthy European-American controls (P=0.0056). Initial family data suggest that incomplete penetrance may occur. No structural variant was found in the neurexin 2beta gene and the neurexin 3beta gene.

SHANK3 Synaptic Scaffolding Gene Involved in a Few Cases: SHANK3 regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. A mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Thomas E. Radecki, M.D., J.D.