Maternal neuronal antibodies associated with autism and a language disorder.

Neurodevelopmental disorders could be caused by maternal antibodies or other serum factors. We detected serum antibodies binding to rodent Purkinje cells and other neurons in a mother of three children: the first normal, the second with autism, and the third with a severe specific language disorder. We injected the serum (0.5-1.0 ml/day) into pregnant mice during gestation and found altered exploration and motor coordination and changes in cerebellar magnetic resonance spectroscopy in the mouse offspring, comparing with offspring of mice injected with sera from mothers of healthy children. This evidence supports a role for maternal antibodies in some forms of neurodevelopmental disorder.

Impaired processing of brief, rapidly presented auditory cues in infants with a family history of autoimmune disorder.

Studies have shown that individuals with language disorders, such as developmental dyslexia and specific language impairment, exhibit impairments in the processing of brief, successive, or rapidly changing auditory information. It is also the case that a higher rate of autoimmune disorders have been identified in those with language-based learning disorders and, conversely, that individuals with autoimmune disorders show a higher incidence of language-related disorders. The rapid auditory processing (RAP) deficits described for older individuals with language impairments may also be used as a behavioral marker to identify infants at higher risk for language delays. Thus, we were interested in examining RAP abilities in a subset of infants with a positive family history of autoimmune disorders. Eleven infants from our ongoing prospective longitudinal studies were identified based on parental response to a question about the presence of a family history of autoimmune disease and compared to 11 matched controls. The RAP threshold of each infant was assessed at 6 and 9 months of age using a conditioned head-turn procedure (using tone pairs with brief interstimulus intervals) and an auditory-visual habituation-recognition memory task using computer-generated consonant-vowel syllables (/ba/ vs. /da/). A visual habituation-recognition memory task that did not require processing of brief temporal cues was also administered. Group differences emerged on the infant RAP tasks, and on language outcome measures at 12 and 16 months of age. Infants from families with a history of autoimmune disorder had significantly higher (i.e., poorer) RAP thresholds and lower language scores than did control infants, whereas visual discrimination scores did not differ between family history infants and controls. Moreover, when brief auditory cues were necessary for the discrimination of /ba/ vs. /da/, infants with a family history of autoimmune disorder performed significantly more poorly than did controls. These findings lend support to the hypothesis that a similar mechanism, perhaps a neural-immune interaction, may underlie the observed co-occurrence of autoimmune disorders and learning impairments.

Maternal antibody-mediated dyslexia? Evidence for a pathogenic serum factor in a mother of two dyslexic children shown by transfer to mice using behavioural studies and magnetic resonance spectroscopy.

The causes of dyslexia are unknown, but previous studies have suggested an immunological basis in some cases. We hypothesised that maternal antibodies, which cross the placenta and bind to fetal antigens, could be responsible, particularly when the dyslexia recurs in consecutive pregnancies. We injected serum samples from five mothers of two or more children with dyslexia into pregnant mice, and tested the offspring for behavioural abnormalities and cerebellar metabolites by magnetic resonance spectroscopy (MRS). Mice exposed in utero to serum factors from one woman with two dyslexic children, who had also had three spontaneous fetal losses, showed deficits in motor tests which correlated with cerebellar choline (Cho) and creatine (Cr) levels. These preliminary results are consistent with a role for maternal serum factors, probably antibodies, in causing some of the features of dyslexia, and possibly in other neurodevelopmental disorders.

A twin and family study of the association between immune system dysfunction and dyslexia using blood serum immunoassay and survey data.

We conducted a study of the association between developmental reading disability (DRD) and immune disorders (ID) using both survey and immunoassay data in two separate samples of families. One sample was made up of twins and their parents and was ascertained through a population-based sampling scheme. The other sample was a set of extended pedigrees selected for apparent autosomal dominant transmission of DRD. We failed to find an association between DRD and ID in either sample, regardless of the method used to assess immune system function. Even though our twin sample provided evidence that both DRD and immune conditions were significantly heritable, there was no evidence for a genetic correlation between ID and DRD nor was there any clear indication that a special subgroup of individuals may be comorbid for these conditions because of genetic reasons. How these negative findings can be reconciled with the developmental hypothesis of Geschwind, Behan, Galaburda, and colleagues, and how they may relate to the gene locus influencing DRD that has been recently located in the HLA region of the short arm of chromosome 6 is discussed.

Urine patterns, peptide levels and IgA/IgG antibodies to food proteins in children with dyslexia.

There is an association between psychiatric disorders and dyslexia. In some psychiatric disorders abnormal urinary peptide patterns and peptide levels, and elevated levels of IgA antibodies to food proteins have been detected. These abnormalities are probably due to insufficient breakdown of the proteins gluten and casein. The aim of this study was to discover whether such abnormalities could be found in urine samples and serum of children with dyslexia. After screening 291 pupils in the fourth grade, 15 dyslexics and 15 controls were pairwise matched by gender, age, and cognitive level. Word decoding, spelling, and short-term memory tests were carried out, and information on handedness, immune and other disorders was obtained. Analyses of 24-h urine samples and of serum were performed. The reading abilities significantly differentiated the groups, and significant differences were found in frequency of left-handedness, immune disorders and other disorders. Three dyslexic children had elevated IgA antibodies. Two of these had positive endomycium tests, and coeliac disease was confirmed by biopsy. One had antibodies to proteins in milk. Our findings may suggest weak urinary peptide abnormalities in the dyslexic children, and they show significant differences in levels of IgA of antibodies to food proteins.

Immune disorders and handedness in dyslexic boys and their relatives.

Thirty dyslexic and 30 control boys aged 7-11 years were compared for frequency of immune disorders and handedness as well as for family history of immune disorders and learning disabilities (dyslexia and stuttering). They were also compared for neurological status and for history of speech and language difficulties. There were no significant differences between the two groups in the frequency of immune disorders and in handedness. The results showed significantly more dyslexic boys with soft neurological signs and signs of speech and language disorders. The frequency of dyslexia was significantly higher in the relatives of the dyslexic boys. Also significantly more mothers of the dyslexic boys reported difficulties during pregnancy and complications at delivery. The results are discussed in terms of Geschwind's hypothesis and neuromaturational delay as possible determinants of developmental dyslexia.

Are families of children with reading difficulties at risk for immune disorders and nonrighthandedness?

This study used questionnaire data to examine immune disorders and nonrighthandedness in the families of children enrolled in a learning disabilities school and children attending regular classrooms in public schools. Groups were organized according to their performance on a standardized test of reading comprehension to avoid overlap. In total, 468 questionnaires were returned, from which we were able to derive a final sample of carefully matched subjects: 55 subjects undergoing remediation for reading problems and 55 age- and sex-matched control subjects. The results indicated that children with reading problems and their families more frequently suffered from some immune and autoimmune disorders, particularly those involving the gastrointestinal tract and the thyroid gland. In addition, symptoms of attention deficit hyperactivity disorder were associated with Crohn's disease and migraine headache in the families. There was no evidence of an elevated prevalence of nonrighthandedness in the children with reading problems and their families.

Reading disability, immune disorders and non-right-handedness: twin and family studies of their relations.

Geschwind and colleagues discussed associations among learning disorders, immune disorders and non-right-handedness. In this study, we examined the associations between reading disability (RD) and both immune disorders (ID) and non-right-handedness (NRH) in family and twin samples (total N = 1731 cases) identified through an RD proband. We also conducted co-segregation analyses to ascertain the degree to which NRH, ID and RD were biologically related. There was little evidence for an overall association between RD and NRH. There was not convergent evidence across all four samples for an association between RD and ID, although we did find an association between RD and ID in two of four samples. Nor was there strong support for a subtype where RD and NRH, or RD and ID, co-segregate in families. These data suggest that the associations postulated by Geschwind and colleagues are not robust in RD samples, although we cannot completely rule out the possibility of an RD plus ID subtype.

Immune and autoimmune diseases in dyslexic children.

One hundred and five dyslexic and 105 control children were compared for frequency of immune diseases, autoimmune diseases, and non-right-handedness in the light of the Geschwind-Behan (1982) "testosterone hypothesis". The results showed significantly more immune- and autoimmune-diseases int he dyslexic group. There were no differences between the groups in the frequency of non-right-handedness. There were no interactions with gender, although there were more non-right-handed boys than girls in the total sample. Mothers of children who were dyslexic experienced significantly more negative life-events during pregnancy, they also experienced the pregnancy as more difficult, and they had more spontaneous abortions. In conclusion, the results support some aspects of the "testosterone hypothesis", but they also point to a more complex pattern of interaction between the factors that still remain unanswered.

[Biological foundations of dyslexia. A review]. / Fundamentos biológicos de la dislexia: Una revisión.

This is a review that summarizes the work done in our laboratory during the last three years. We have studied four dyslexic brains. They all bear a symmetric anatomical pattern in a structure closely related to the language areas (planum temporale), which is more commonly asymmetric in normal brains. In addition, their microscopic examination shows numerous ectopias and dysplasias in the cerebral cortex. The high incidence of immune disease in dyslexics and their families suggests a more general developmental problem in developmental dyslexia. The hypothesis is raised that fetal effects of testosterone are involved in regulating neurological as well as immunological development, whereby abnormally high testosterone activity would produce a twofold deficit. Finally, strains of immune-defective mice have been found that bear the same cortical abnormalities as seen in the dyslexic brains previously studied. The immune-defective mouse may prove to be an excellent model for the study of the neuropathological basis of developmental dyslexia.