Regression in Autism (2):

Exploring Biological and Environmental Causes

Regression in autism, often seen within the first two years of life, represents a distinct subtype of autism that has sparked considerable scientific interest. While the exact causes of regression are still not fully understood, current research points to a combination of genetic, environmental, metabolic, immune, and neurological factors.

Genetic and Perinatal Factors

Regression in autism has been linked to both genetic predispositions and early-life medical factors. For example, Kaba & Arıcı Canlı (2024) found associations between regression and factors like a family history of psychiatric disorders, cesarean delivery, and febrile seizures. Additionally, Goin-Kochel et al. (2017) showed that certain genetic mutations, especially in postsynaptic density proteins, are more common in children with regressive autism, suggesting that genetic makeup can influence the likelihood of regression.

A recent study by Dale et al. (2025) also supports the role of chromatin-related gene mutations in children who experienced regression, particularly after infection or vaccination. Some of these children had immune dysfunction, which suggests a link between genetic vulnerability, immune response, and regression. These cases also demonstrated the role of chromatin dysregulation in autistic regression and abrupt-onset neuropsychiatric syndromes, potentially related to brain and immune gene dysregulation.

Neuroanatomical and Brain Structure Abnormalities

MRI studies have long pointed to abnormalities in the cerebellum as a consistent finding in autism. Courchesne et al. (1994, 1995, 1996) reported that these abnormalities begin early in development, possibly before birth, and may contribute to later regression. Potential causes of cerebellar damage include genetic mutations, prenatal oxygen deprivation, infections, and toxic exposures.

Other brain imaging studies, e.g., Zhang et al. (2018), identified changes in the arcuate fasciculus (AF) – a white matter tract linked to language: Compared with typically developing children, a significant reduction of fractional anisotropy along with an increase in tract volume and number of voxels was observed in ASD children with language regression.  These changes in the AF suggest that microstructural anomalies of the AF white matter may be associated with language deficits in ASD children exhibiting language regression starting from an early age – thus, supporting a neurobiological basis for this form of regression.

Mitochondrial Dysfunction and Metabolic Factors

Mitochondria, the energy-producing parts of cells, play a key role in brain function and development. A growing body of research connects mitochondrial dysfunction to regressive autism. For example, Frye et al. (2021) found that prenatal exposure to air pollution (PM2.5) affected mitochondrial function differently in children with neurodevelopmental regression compared to those without it.

Singh et al. (2020) and Gevezova et al. (2024) further supported this, showing that children with regression have distinct metabolic profiles, including altered mitochondrial activity and inflammatory responses. Thus, Singh et al. (2020)’s research suggests that individuals with ASD and developmental regression may represent a unique metabolic endophenotype with distinct abnormalities in respiratory function that may put their mitochondria in a state of vulnerability. This may allow physiological stress to trigger mitochondrial decompensation as is seen clinically as regression.

Gevezova’s study (2024) provides new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD, and a unique metabolic profile in regressive ASD group: children with regressive autism had higher maximal mitochondrial respiration and proton leak, while those without regression showed more pronounced immune-related inflammation.

Rangel-Huerta et al. (2019) also revealed subtle biochemical differences between autistic children with regression and without regression – especially in amino acid, lipid, and nicotinamide metabolism—between children with and without regression. These biochemical shifts suggest a unique metabolic fingerprint in regressive autism.

Immune Dysfunction and Autoimmunity

A large body of evidence suggests that immune system abnormalities may trigger or worsen regression in autism. Scott et al. (2017) found that 30% of children with regressive autism experienced febrile illness* in the six months before symptom onset, compared to none in the non-regressive group. Besides, these children had a higher rate of familial autoimmune diseases, such as type 1 diabetes and autoimmune thyroid disease, suggesting a hereditary immune vulnerability.

The role of autoimmune encephalitis, especially anti-NMDA receptor encephalitis, has also been explored. Studies by Hacohen et al. (2016) and Scott et al. (2014) reported that such conditions can cause significant behavioural and cognitive regression in children.

Further evidence of an immune link comes from Tamouza et al. (2020), who found that a specific HLA haplotype (HLA-DPA101-DPB104) was less common in children with regressive autism, possibly offering some protection against immune-related regression.

Infections and Inflammatory Triggers

Various infections have been linked to regressive autism. For instance, exposure to rubella or cytomegalovirus (CMV) during pregnancy has long been associated with autism. More recent studies also highlight postnatal infections as potential triggers.

Akcakaya et al. (2015) and Marques et al. (2014) described cases of enterovirus infections (which can cause meningitis or encephalitis) leading to "massive regression." These cases often occurred outside the typical age window for autism onset, suggesting that infections can trigger regression even in older children.

Environmental and Toxic Exposures

Environmental toxins, particularly air pollution and heavy metals, may also play a role in regression. Studies by Frye et al. (2021, 2022) linked prenatal exposure to pollutants like PM2.5 to mitochondrial disruption and an increased risk of regression.

Metal imbalances—such as low prenatal copper and zinc and high exposure to lead or manganese—were associated with disrupted energy metabolism in children with regressive autism. These findings point to a bioenergetic vulnerability triggered by toxic exposures (Frye et al. 2020).

Epilepsy and Seizures

Some studies have suggested a link between epilepsy or seizure disorders and regression in autism (e.g., Deonna et al. 1993). Seizures could potentially disrupt brain networks critical for language and social behaviour. However, this connection remains controversial. For instance, Thompson et al. (2019) found no clear difference in epilepsy rates between regressive and non-regressive autism, though they acknowledged that there are a number of different presentations of epilepsy outside of the classical signs of seizure. The researchers concluded that those displaying the regressive autism phenotype required a “careful neuropediatric work-up to investigate possible neurological disorders” that may be causative of such regression.

Other Biological Markers

Emerging biomarkers may help identify children at risk for regression. Li et al. (2022) discovered that children with regressive autism had elevated levels of sAPPα, a protein fragment linked to brain development, compared to non-regressive and typically developing peers. The authors concluded that increased plasma levels of sAPPtotal and sAPPα may be valuable biomarkers for the early identification of ASD regression.

Similarly, Gomez-Fernandez et al. (2018) found different levels of inflammatory cytokines, adhesion molecules, and growth factors in children with and without regression, suggesting varying underlying biological mechanisms.

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Autistic regression is a complex and multifactorial condition. While genetics play a strong foundational role, evidence increasingly points to a synergistic relationship between immune activation, mitochondrial dysfunction, metabolic imbalances, environmental toxins, and infections. These factors may act independently or together, depending on a child’s genetic susceptibility.

Understanding the unique biological pathways behind regression can pave the way for earlier identification, targeted therapies, and better support for children and families affected by this distinct form of autism.

The symptoms are similar, but the etiology and developmental trajectories of neonatal and regressive forms of autism are different. If these are investigated separately, instead of being part of the same disorder (ASD), faster progress can be made (Barbeau 2017).

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* A febrile illness is any illness that causes a fever (elevated body temperature – 38°C /100.4°F or higher). The term is often used to describe illnesses where fever is a prominent symptom, especially when the cause isn't immediately obvious.