The putative etiology and prevention of autism.

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic faults in particular. However, such studies were able to reveal a plausible etiology for this malady in only a small percentage of instances. Key bio-molecular characteristics of this syndrome have been uncovered when the potential roles of the glia were studied in depth. Findings related to biochemical deficiencies appearing early in the newborn, such as depressed IGF-1 (insulin-like growth factor #1) in neurogenesis/myelination, are becoming emphasized in many laboratories. Progress leading to timely diagnoses and subsequent prevention of central nervous system dysconnectivity now seems plausible. The tendency for an infant to develop autism may currently be determinable and preventable before irreversible psychosocial disturbances become established. These discussions about glial function will be inter-spersed with comments about their apparent relevance to autism. The concluding portion of this presentation will be a detailed review and summation of this diagnosis and prevention proposition.

COVID-19 and autism.

The current pandemic of Covid-19 has created a paradigm for possibly gaining greater insight in two conditions:Studies since the beginning of this century have supported the view that IGF-1 deficiency in the neonate defines the basis of autism. As a result, it appears that interleukin-6 in corona virus-based infections causes reduced defenses because of suppressed IGF-1, especially in older patients. This may also portend an increase of autism in the offspring of gravidas currently affected severely by Covid-19.

The role of oligopeptides in preventing autism.

Previous reports in this series point to insufficient insulin-like growth factor-1 (IGF1) in the newborn as the key to brain dysconnectivity characteristic of autism. Such a deficiency should be detectable in the baby's blood at or soon after birth. Breast-feeding exclusively for the first year of postpartum life or supplementation with oral agents to raise the serum IGF1 level, such a cyclo-glycylproline, could be helpful for this purpose.

Molecular biology of autism's etiology - An alternative mechanism.

Autism is a neuropathologic condition believed to be the consequence of cerebral dysconnectivity. Hypomyelination of axons in brain nerve pathways parallels behavioral abnormalities characteristic of autism. The present discussion will examine the functional association of insulin-like growth factor-1 (IGF1) to neo-neuron myelination, especially in autistic children. These structural defects apparently correlate with a reduced level of circulating IGF. In addition, the potential connection of single nucleotide polymorphism to the etiology of autism is considered. Pharmaceutical and nutritional supplements that may enhance IGF1 to reduce the incidence of autism are proposed.

Prenatal identification of autism propensity.

The innovative method described involves antepartum testing to determine if the fetus has the potential of later developing autism. A technique is detailed which allows examining the maternal blood for SNPs (single-nucleotide polymorphisms) known to be associated with IGF1/IRS1 cellular pathway malfunction potentially leading to brain dysconnectivity in neonates. Results can then be corroborated with umbilical cord sampling at birth by the Autism Index test. [The discussion presented here is the follow-up to the recent prior report: Steinman, G. IGF - Autism prevention/amelioration, Medical Hypotheses 2019;122:45-47].

IGF - Autism prevention/amelioration.

Autism continues to be a significant cause of psychosocial pathology in affected children and adults. Until recently, the predominant research thrust to uncover the cause of this condition has been the search for a major nuclear mutation. Although a small percentage of cases do demonstrate such a DNA fault, recent effort has come to emphasize problems in the biochemistry of its sufferers. In particular, insulin-like growth factor-1 (IGF) has become the center of concern in many laboratories. A deficiency in this growth factor, leading to insufficient neuron myelination and defective synapse function, appears to result in brain dysconnectivity during the first year of postpartum life, and cause social malfunction in childhood years and beyond. At least three approaches have been reported by which this deficiency can be corrected in neonates before irreversible damage has been caused. The overall purpose of this report is to bring together related observations and to evolve a coherent, plausible explanation of the cause and prevention of autism.

Hot Button Protocol and Operational Issues Between Sponsors and Sites in Clinical Pharmacology Studies: A Moderated Forum Session.

This paper summarizes a discussion that took place at the 52nd Annual DIA Meeting in Philadelphia, PA, on June 30, 2016, titled "Hot-Button Protocol and Operational Issues between Sponsors and Sites in Clinical Pharmacology Studies." The symposium was a moderated panel of phase 1 clinical research experts representing the sponsor, and investigational sites. Conference attendees of similar experience joined in the discussion after commentary by each panelist. The learning objectives of the symposium were (1) to recognize issues that can provoke sponsor/site conflict or diminish conduct efficiency when they arise in the course of preparing to conduct or execution of phase 1 clinical studies, (2) to discuss how to handle such issues with counterparts when they arise and describe ways to negotiate and formulate a successful resolution. Sponsors and sites both have challenges in executing clinical trials on time and within budget. Both need to set and maintain realistic expectations and communicate with honesty, transparency, and timeliness. Achieving this goal will advance the more important take-away message, that developing new drugs requires sound execution of clinical trials.

Plausible etiology of brain dysconnectivity in autism - Review and prospectus.

This report summarizes recent findings related to the neuropathology of autism. Combining the relevant observations assessed here, a comprehensive, coherent hypothesis explaining the etiology of juvenile autism may be deduced. This proposed mechanism describes a process initiated by insulin-like growth factor deficiency, resulting in brain dysconnectivity as central to the behavioral manifestations of this disease.

Breastfeeding as a possible deterrent to autism--a clinical perspective.

The emergence of autism in young children appears to result from dysmyelination of brain neurons, related to inadequate supply of insulin-like growth factor (IGF) in the newborn. This report is intended to bring together relevant observations from prior research to develop a new, innovative hypothesis to elucidate the mechanism underlying autism development. The deficiency of IGF in affected infants may be due to a combination of genetic and environmental factors yet to be determined. If this hypothesis is correct, breastfeeding in particular could increase IGF levels, thereby compensating for an inborn deficiency of the growth factor.

Predicting autism at birth.

The amounts of at least three biochemical factors are more often abnormal in autistic people than neurologically normal ones. They include insulin-like growth factor, anti-myelin basic protein, and serotonin. This may explain why processes initiated in utero which hinder normal neurogenesis, especially myelination, continue after delivery. Quantitation of these parameters may make possible the calculation of an autism index, anticipating at birth which children will ultimately develop overt autism.

Insulin-like growth factor and the etiology of autism.

The basic hypothesis for this study is that reduced peripartum level of insulin-like growth factor-1 (IGF) due to genetic, epigenetic, or environmental factors is a sentinel biomarker of increased probability of later development of autism. The central objective of the resultant proposed study described here is examining if a correlation exists between the serum level of IGF in the fetus/newborn and the probability of autism developing later in the child. Mechanisms possibly causing such a decrease are considered. This would define a prospective biomarker for and possible etiology of this disorder. Insulin-like growth factor-1 directly affects the rate at which oligodendrocytes promote myelination in the central nervous system, especially in the brain. Factors which reduce the production or availability of IGF could retard normal nerve programming in the fetus or neonate. Thus, it would be desirable to arrest the pathologic processes of autism in the early neonatal stage before irreversible nerve damage occurs.

Twin Town in South Brazil: a Nazi's experiment or a genetic founder effect?

Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the "Twins' Town" due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the "Nazi's experiment" and of the "founder effect" hypotheses. We surveyed a total of 6,262 baptism records from 1959-2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the "Nazi's experiment hypothesis", there is no spurt in twinning between the years (1964-1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927-1958 and 1959-2008 (P = 0.638). On the other hand, the "founder effect hypothesis" is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the "Nazi's experiment hypothesis" and strongly suggest that the "founder effect hypothesis" is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified.

Difficulties in controlling and preventing preterm labor in multiple gestations: a clinical perspective.

Prevention of preterm labor or arrest of ongoing premature labor in a twin gestation is more difficult to achieve than in singleton pregnancies. This clinical perspective is intended to review currently applied methods and to propose a more effective means to resolve this problem. A number of tocolytic methods have been employed in multifetal gestations, but none is routinely effective once true labor has commenced. Whereas a fall of serum progesterone levels precedes the onset of labor in animals, such is not the case in humans. It is proposed here that the level of serum progesterone does not define the relevance of this hormone to the maintenance of myometrial quiescence in humans. Rather, it would appear to be the progesterone supplied by the placenta directly to the myometrium that delays the onset of labor. The ratio of placental surface area to myometrial surface (P/M) as the gestation progresses more accurately reflects the capability to delay labor, especially in twin pregnancies. Hence, the application of therapeutic progesterone in closer proximity to the placenta/myometrial interface (e.g., via the vagina) should be more effective than by injection in preventing preterm labor as the P/M ratio decreases in a multifetal gestation.

Why the twinning rate is higher in Africa than elsewhere: an analysis of selected factors.

OBJECTIVE: To examine the rate of spontaneous twinning in selected countries in order to evaluate the impact of environmental stress and related socioeconomic factors on balancing reproductive activity and longevity. STUDY DESIGN: Four countries with similar ancestry were considered, 2 in Africa and 2 in the Caribbean. Data on gross domestic product per capita, as a measure of indigenous conditions, access to proper diet, health care, sanitation and shelter were compared with the relative rate of twinning. RESULTS: The data show an inverse relationship between wealth and environmental conditions, and the incidence of multiple gestations. CONCLUSION: Through goods and services, improved living conditions reduce environmental stress and its adverse effect on the balance of biologic reproduction vs. longevity. In addition, breast-feeding, as a social expression and an economic easement, correlates with the chance of conceiving twins in a subsequent pregnancy. It would thus appear that the twinning rate can be taken as a barometer of the population's biologic attempt to perpetuate its gene pool expeditiously when an existential threat occurs.

Mechanisms of twinning: X. The male factor.

OBJECTIVE: To evaluate the possibility of male-line inheritance of dizygotic twinning potential. STUDY DESIGN: Women with multiple births who had previously volunteered to participate in studies in this series were asked about the frequency of males genetically related to the index mother's husband who had also fathered multiples. Only spontaneous gestations were considered. RESULTS: If male involvement in twin pregnancies were entirely random, <1% would have had male relatives who had also fathered multifetal gestations. However, 30% were found to have such relatives in the families evaluated here. CONCLUSION: These results suggest that the capability to father multiples (twins or higher) spontaneously is, in many cases, an inherited trait along the male line--i.e., the male factor in twinning. Producing multiples requires not only women able to doubly ovulate but also men capable of supplying active sperm that could fertilize >1 egg in a given cycle.

Mechanisms of twinning: VIII. Maternal height, insulinlike growth factor and twinning rate.

OBJECTIVE: To evaluate the relationship of maternal height to the rate of twinning and the possible connection of these parameters to the coexistent level of insulinlike growth factor (IGF). STUDY DESIGN: Since spontaneous multiple gestations in humans are relatively uncommon in general, it is reasonable to consider distin guishing physical attributes such as height, that may have some functional relationship to this phenomenon. In a prior study, hereditary and dietary factors affecting the level of IGF were found to correlate with the rate of twinning. In that height is known to parallel the serum level of IGF, a survey of women who had previously conceived spontaneously and had given birth to twins or triplets was undertaken. Their heights were compared with the mean value for the general female population, RESULTS: Mothers of 129 sets of spontaneous multiples displayed a mean height of 164.8 cm as compared to 161.8 cm for the general population of women (p < 0.005). CONCLUSION: These data confirm those from previous studies and corroborate the proposed relationship between maternal height and the rate of twinning. Thus, the results reported here further support the IGF model of twinning.

Mechanisms of twinning: VII. Effect of diet and heredity on the human twinning rate.

OBJECTIVE: To evaluate the possible biochemical effect of diet and heredity on the rates of monozygotic and dizygotic twinning. STUDY DESIGN: In that insulin-like growth factor (IGF) has been found to be elevated in cows selected for their demonstrated increased twinning rate, the effect of agents that influence the level of IGF in women was examined. This was correlated with their prior history of singleton versus twin birthing. In particular, the effect of diets consisting of or excluding animal products that have elevated IGF content (e.g., milk) was considered. RESULTS: Vegan women, who exclude dairy products from their diets, have a twinning rate which is one-fifth that of vegetarians and omnivores. CONCLUSION: The results reported here support the proposed IGF model of dizygotic twinning. Genotypes favoring elevated IGF and diets including dairy products, especially in areas where growth hormone is given to cattle, appear to enhance the chances of multiple pregnancies due to ovarian stimulation.

Mechanisms of twinning. VI. Genetics and the etiology of monozygotic twinning in in vitro fertilization.

OBJECTIVE: To examine the possible role of inheritance in monozygotic twinning. STUDY DESIGN: Via public announcement in national media, volunteers were requested who had given birth to monozygotic (MZ) twins or triplets and who also had relatives with twins. From the data received, common factors in such sets were sought. Zygosity was confirmed with various combinations of placental pathology, sex, blood type, DNA analysis, fingerprints and physical appearance. RESULTS: Among the 109 responses, 78 mothers of MZ multifetal pregnancies with twin relatives were identified. Of special interest were 13 cases of triplets that resulted from transfer of 2 viable embryos during in vitro fertilization (IVF). Each of these cohorts had twin relatives. They were compared to 33 cases of spontaneous MZ triplets, also with twin relatives. The familial clustering phenomenon appeared to be a function of maternal age, whereas the effect of zygosity or lineage (paternal versus maternal) of the related twins was nonspecific. CONCLUSION: The findings are consistent with the suggested influence of genetics and familial clustering on the MZ twinning rate, especially in IVF procedures. The risk of unintended dizygotic triplet pregnancies could be reduced by limiting transfer to 1 embryo in cases of older women with a family history of multiple gestation. Roles of calcium and insulinlike growth factor in this phenomenon appear plausible.