Autism Neo-Spectrum – At Birth
Steinman G and Mankuta D
Published on: 2019-03-28
Now absent are early clues to foretell the eventual appearance of autism in a developing child. The innovative neo-spectrum protocol detailed here seeks to achieve two goals:
Identify by laboratory procedures at birth the probability of autism occurring in each neonate and with what anticipated severity.
Replace the sometimes confusing identifying names for the various known forms of autism by a general definition with itemized specific findings.
To help resolve questionable treatment protocols, the Diagnostic and Statistical Manual of Mental Disorders, volume 5 (DSM-5) was compiled and released in May, 2013 as an update and reorganization of the previous DSM-IV . In spite of its attempts to resolve controversy, misconceptions, and debate among health professionals, multiple criticisms remain. Part of the confusion persists because many of the protocols for diagnosis of these mental and psychological maladies now rely on subjective analyses of patient histories and demeanor rather than objective laboratory parameters such as biomarkers commonly utilized in other fields of medicine, if and when available.
For example, serious attention was given to refine the definition of “autistic psychopathy” as named by Hans Asperger in 1944 . In DSM-IV-TR, the application of the name “Asperger’s Syndrome” relied upon impeded socialization and communication abilities but with the absence of any language delay. According to DSM-5, autism spectrum disorder (ASD) incorporated under one heading the four conditions: Autistic Disorder, Asperger’s Syndrome, Childhood Disintegrative Disorder, and Pervasive Developmental Disorder - not otherwise specified PDD-NOS and Autistic Disorder are by far the most common of the Pervasive Developmental Disorders in this group . Each disorder group incorporated or excluded abnormalities in social interaction, communication, language, behavior repertoires, and interests. The WHO ICD-10 definition of ASD was similar but not identical to that of DSM-IV. However, confusion remained since each class is in fact a complex combination of low, medium, or high functionality as well, depending on levels of behavioral or pharmacological support needed [3,4].
Some families have experienced the birth of more than one child who ultimately displayed the characteristics of ASD . Three autistic siblings in a number of families have been reported several times . One such family had six children all diagnosed with some form of autism, ranging from high-functioning Aspergers to more severe forms of the syndrome . This would suggest that issues in addition to particular inherent genomic abnormalities specifically combine to determine the biodynamic variations of each occurrence. Autism is a highly variable neurodevelopmental condition . To elucidate the etiology of this spectrum, new stratagems have been derived. Many endorsed complex hypotheses favoring polygenetic causation. Each utilized some combination of impaired social interaction, communication impediments, limited interests, and repetitive behavior . Severity became a primary distinguishing property as well .
Influence of Etiology
Recent studies concluded that an analogous mechanism is involved in the generation of all forms of autism. In particular, the central role played in this condition by insulin-like growth factor (IGF) deficiency has been championed [10-12]. Until now, the diagnosis of autism had to await the appearance of atypical social characteristics many months or years after birth to make a definite determination [13,14]. In contradistinction, the underlyingPubtexto Publishers | www.pubtexto.com 2 Int J Neurobiol
neuropathologic processes (brain dysconnectivity) leading to the outward behavioral manifestations apparently proceed silently during the early months of neonatal life.
Hence, it has been proposed that appropriate biochemical determinations made at birth might define not only the possibility of the ultimate appearance of this ailment in some form, but also the severity could be predicted by the results of appropriate perinatal tests . If severity is a key defining parameter of each case of autism, the degree of departure of such laboratory results from normal at birth may well classify the ultimate position of each affected child on the neo-spectrum. This would replace the application of the diagnostic eponyms with divergent meanings to different investigators only months or years later.
- Recent reports have proposed perinatal forecasting of the eventual appearance of autistic characteristics. Four hematologic variables are quantitated to define the magnitude of probable eventuality [11,15,16]. These parameters, which can be represented by numerical values, bear significance in neurodevelopmental processes. These include: IRS1-SNP (rs1801123), insulin-like growth factor-I (IGF), serotonin, and anti-myelin basic protein (anti-MBP). Quantifying each of these variables on a scale of 0-10 based on laboratory results (with normal = 0), the proposed range for each parameter would be as follows:
IRS1-SNP : 0,5,10 (5 = trace; 10 = present)
IGF-1 deficiency : 0-10
Serotonin elevation : 0-10
Anti-MBP elevation : 0-10
Total possible range : 0-40
The highest potential neo-spectrum score would be 40, relating to a putative severe case, with abnormal neurologic characteristics beginning to appear near the end of the first or second year of untreated postpartum life. By contrast, in the absence of the IRS1-SNP polymorphism and the other three variables being within normal limits, an overall score of 0 would be given. This would predict that the child would probably not have an apparent future risk of neo-spectrum neurologic deficits. The anticipated severity of an untreated positive case could only be estimated from the lab results during the overtly symptomless early neonatal period.
It is recommended to perform all four tests. This becomes especially important in special situations where adjustments and corrections may be necessary for proper interpretation of results:
- Umbilical cord IGF-1 can be proportional to the ponderal index of the baby [17,18];
- Girls generally have higher IGF levels than boys, especially during the first four years of life ;
- Very small babies have a higher incidence later of autism ;
- Levels of IGF-1 in newborn are inversely proportional to parental age .
- Mothers who take selective serotonin reuptake inhibitors such as citalopram or fluoxetine during pregnancy may cause their newborn’s cord 5-HIAA level to be lower than expected .
- Some otherwise healthy individual’s exhibit elevated autoantibodies to MBP for unknown reasons .
In light of this proposed approach, it is first necessary to confirm this hypothesis by laboratory-based investigation using real umbilical cord samples, followed by neurologic examination of each child a couple of years later. If and when the validity of this method is statistically corroborated, it will:
- Reduce the dependence of clinicians on subjective impressions when evaluating the children of concern;
- Eliminate the sometimes confusing eponym nomenclature for designating the diagnosis in particular uncontrolled cases once symptoms appear; and
- Promote the application of replacement therapy such as IGF or its derivatives during the first year or so of postpartum life.
As a hypothetical example, suppose a 7-pound baby boy, with Apgar scores of 9 and 10, is born without displaying obvious neurologic deficits to a primigravida at term after an uncomplicated pregnancy. The neo-spectrum score for the cord blood sample is:
IRS1-SNP = 10
IGF1 = 8
Serotonin = 6
Anti-MBP = 7
Total = 31
Assuming the predictive value of this analytical method has been convincingly substantiated on many prior known cases, the neonatologist concludes that this baby is a candidate to display a moderately severe case of autism 1-3 years later if untreated now. An appropriate approach to preventive therapy would be to encourage the mother to breast-feed her neonate exclusively and to accept IGF treatment of the baby for at least one year . Three years later, the child displayed none of the stigmata of autism.
The quantity of IGF-I and its effect on neonatal brain development have been studied in early postpartum transgenic mice . The enhanced level of IGF has been correlated with the proliferation of neuron progenitors, appearance of viable oligodendrocytes, neuronal survival, axonal outgrowth, total brain myelin, amount of axon myelination, maturation of dendrites, and total synaptogenesis in particular areas of the brain. The increase in the number of synapses exceeds that of neurons. On the other hand, neonatal deficiency in IGF correlates with reduced myelination of neurons [26-28].
The concept that local hyper connectivity and long-range hypo connectivity in the human brain may well be the fundamental problem in autism was entertained around the beginning of this century (). The application of functional MRI (fMRI) was instrumental in arriving at this conclusion. Neuropathologic studies had previously identified abnormalities in neuronal migration in postmortem examinations . Local hyperconnectivities in autistic brains examined by fMRI have been observed between the thalamusand prefrontal cortex, temporal lobe, and sensorimotor cortex, as well as between frontal and parietal lobes [29-33].
The analytical methodology proposed here would employ testing umbilical cord blood for the quartet of parameters noted above at the time of birth. The degree of departure from the normal limits of the total would give an insight into the spectral severity of an autistic disorder that could be anticipated in the months and years to come. On the other hand, an abnormal perinatal hematologic finding with a clandestine neo-spectrum ailment would support the use of an agent such as IGF to reduce or completely exclude the eventual appearance of a pervasive developmental autistic disorder. At least three treatment methods have been reported, such as IGF supplementation via breast-feeding for a full year, which could attenuate or eliminate the otherwise adverse outcome [10,24].
Currently, little can be done to diminish the undesirable behaviors of patients with this disease once manifest. The key to ameliorate any such cases today is through psychotherapy and pharmaceuticals to moderate adverse conduct as much as possible. Hence, the exact name of the condition affecting each patient is less important than considering each as part of the overall Autism Disorder group and reducing the severity of his/her objectionable actions downward in the neo-spectrum scale.
Measuring blood IGF levels in subjects over 4 years of age has less predictive value than at birth. The concentration of IGF in the cerebrospinal fluid of youngsters destined to develop or already exhibiting autism is lower than in unaffected individuals up to the age of 4 years . Subsequently, the IGF level rises, corresponding to the appearance of enlarged head circumferences in some older autistic patients . The IGF hematologic maximum is typically reached in early puberty of nearly all children, corresponding to the “growth spurt”, with a gradual fall throughout life thereafter .
In this scheme, the IRS1 intermediate receptor transmits chemical signals from the IGF membrane receptor to PI3K/Akt via tyrosine/serine phosphorylation . In cases where the activity of the IRS1 protein is diminished by SNP polymorphism, the PI3K/Akt activity is similarly reduced for a given amount of IGF at the receptor site [10,37-39]. By the principles governing reaction rates, the transfer of chemical signals through this chain can be augmented by raising the concentration of IGF. One end result would be enhanced activity of oligodendrocytes acting to myelinate new axons in infants.
The author wishes to express his appreciation for the perspicacious critique of this manuscript by Roberta Zuckerman and the expert assistance provided by Aviva Adler, librarian of Touro College Israel, in locating relevant literature references.
Conflict of Interest
The author currently has no conflict of interest in this matter.
ASD - Autism Spectrum Disorder
DSM - Diagnostic & Statistical Manual
FMRI - Functional Magnetic Resonance Imaging
HIAA - Hydroxyindoleacetic Acid
ICD - International Classification of Diseases
IGF - Insulin-Like Growth Factor-1
IRS - Insulin Receptor Substance-1
MBP - Myelin Basic Protein
NOS - Not Otherwise Specified
PDD - Pervasive Developmental Disorder
SNP - Single-Nucleotide Polymorphism
WHO - World Health Organization
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