Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift

Abstract

The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called 'First 1000 Days') are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.

Keywords: Autism Spectrum Disorder (ASD); epigenetics; gut dysbiosis; immune activation; machine learning; metabolomics; mitochondrial impairment; oxidative stress; pathogenesis; prevention.

Figure 1

Interplay between the main determinants of Autism Spectrum Disorder. MD, Mitochondrial dysfunction; MIA, Maternal Immune Activation; ROS, Reactive Oxygen Species. In the new individual, matrilinear transfer of mitochondria and microbiota adds to the genetic information stored in the maternal and paternal germinal cells. Environmental factors as a whole may directly affect the epigenetic machinery, as it happens with heavy metals, or may influence the interconnected molecular pathways involved in the ‘bad trio’ (mitochondrial dysfunction (MT)/oxidative stress (ROS) plus maternal immune activation (MIA) plus dysbiosis). The ‘omniscient placenta’ [51] drives the metabolic and epigenetic regulation of fetal programming, hence influencing the ontogenesis and the crucial early stages of neurodevelopment. The epigenome—similarly to a software switching genes on and off [29]—is programmed in an adaptive and predictive sense by the intrauterine and cellular microenvironment, setting the limits of physiological adaptations to the postnatal environment and influencing the lifelong risk for diseases [43]. After birth, the same mechanisms involving environmental factors and the ‘bad trio’ are at play, and may continue to undermine human health lifelong. As for neurodevelopment, the maximum impact occurs in the first two years of life, which is the crucial time window for brain wiring.

Figure 2

Mother’s health is the premise for a successful intrauterine life. During pregnancy, the gynecologist ensures the best control of risk factors and the enhancement of protective factors, largely related to proper maternal nutrition and supplementation. After birth, the baby–mother dyad is supported by the neonatologist–gynecologist duo. The qualified support for the well-being of the mother is integrated by neonatal care, which includes the best conditions of neurosensory-motor integration aimed at the physiological postnatal neuronal wiring. With variable times and modalities—mostly depending on the outcome of the pregnancy and the characteristics of the newborn—the child’s care is subsequently entrusted to the pediatrician, who provides suggestions for a positive physical and neuro-psychomotor development. In case of clinical abnormalities, the pediatrician prompts diagnostic pathways and early interdisciplinary interventions based on clinical and laboratory findings. In the event of motor and/or socio-communicative abnormalities, the pediatrician consults the neuropsychiatrist, who shall consider whether to include standardized diagnostic tools for ASD in the clinical assessment. The diagnosis of ASD is followed by further diagnostic evaluations (neurophysiologist, geneticist), functional assessment, and timely psychoeducational evidence-based interventions. The neuropsychiatrist orchestrates the cooperation of numerous professionals (psychologist, educator, occupational therapist), monitors the results, and tailors the supports according to the evolving skills and needs. In parallel with the neuropsychiatrist, the pediatrician prompts a clinical assessment according to the expected comorbidities in ASD, involving in particular gastroenterologist, allergist-immunologist, and nutritionist. A close collaboration with the neuropsychiatrist allows the best integration of physical and neuropsychiatric aspects, involving at the same time professionals linked both to the pediatric and the neuropsychiatric sides. The transition towards adulthood requires a handover on both levels of intervention, from the pediatrician to the general practitioner for the biological features, and from the neuropsychiatrist to the psychiatrist for the psychiatric sphere. The connection between the two levels (body and mind) is maintained even in adulthood. It should be noted that the above described structured model acquires worth and meaning if it places in the center the person with ASD and his/her family, as the main stakeholders of a flexible model, able to adapt to the evolving needs and favoring the highest level of feasible well-being.