Autism Spectrum Disorder (ASD) is a complex, multifactorial condition with wide-ranging symptoms and severities. Much like dental malocclusion, which has nutritional roots in vitamin D and A deficiency, autism resists simple explanations [1].

Recently the HHS has announced it will be investigating what causes autism.

While genetics, environment, and toxic exposures are frequently discussed, nutritional status is often overlooked as a fundamental contributor to neurodevelopmental outcomes.

This article explores what causes autism, through the evidence that vitamin A deficiency—especially in its active form, retinol—is the most likely candidate for a cause of autism.

Vitamin A in Brain Development: A Critical Role

Research shows that children with developmental delays, particularly those with ASD, often have low vitamin A levels, which may affect brain function and behavior [2, 3]. The cause appears especially strong in autism, where children often exhibit higher-than-normal serotonin levels, a brain chemical regulating mood and behavior [4]. Studies suggest this may be linked to vitamin A deficiency, which influences serotonin processing [5].

One study found that vitamin A was the most common nutrient deficiency in autistic children—more so than vitamins B9, B12, or D—and low levels were linked to lower scores on the Childhood Autism Rating Scale (CARS) [2]. Vitamin A supplementation reduced high serotonin levels and improved autism symptoms in many children [5].

Vitamin A is also critical for children with ADHD, supporting brain development, motivation, sensory processing, and behavior [3, 6]. Children with autism and ADHD may have higher vitamin and mineral needs than typically developing children [6, 7].

Vitamin A and Brain Development Fundamentals

Vitamin A, particularly retinoic acid, is essential for early brain development, regulating gene expression, neural patterning, neuronal and glial cell differentiation, cortical layering, synaptic growth, and neurotransmitter system development [8].

Disruptions in retinoic acid signaling can lead to major structural and functional abnormalities, including imbalanced brain growth, impaired connectivity, and disrupted neurotransmission [8]. Given these mechanisms, vitamin A’s role in brain development should be a primary consideration in conditions like autism.

Long-Term Impact of Vitamin A Deficiency

Even marginal or subclinical vitamin A deficiency during pregnancy or infancy can result in long-term impairments in cognition, emotion regulation, sensory processing, and behavior—domains heavily affected in ASD [9].

This suggests a plausible link between early-life vitamin A deficiency and neurodevelopmental challenges.

An Overlooked Risk: Toxicity Fears Hiding Subclinical Deficiency

Concerns over vitamin A toxicity, particularly during pregnancy, have led to a focus on avoiding excess while neglecting deficiency risks, especially mild or marginal deficiencies that may disrupt brain development without obvious clinical signs [10].

This is concerning in populations with limited intake of preformed vitamin A (e.g., liver, eggs, dairy) or poor beta-carotene-to-retinol conversion due to BCMO1 gene variants or epigenetic suppression [11].

The Spectrum and Symptoms of Vitamin A Deficiency

Vitamin A deficiency, like autism, presents as a spectrum with varying severity:

• Mild to Moderate Symptoms: Night blindness, dry eyes, dry or rough skin, frequent infections, poor growth, fatigue, low mood, and subtle delays in learning or behavior.

• Severe Symptoms: Full vision loss (xerophthalmia), poor wound healing, chronic respiratory infections, gut dysbiosis, impaired brain development, and higher risk of complications during fetal development and pregnancy [10].

These symptoms often go unnoticed until severe or are misdiagnosed without examining vitamin A status. The deficiency’s varied presentation, influenced by age, genetics, sleep, immune health, diet, stress, and socioeconomic status, mirrors the heterogeneity of autism [10].

Reduction of Vitamin A in the Diet

For over half a century, public health campaigns discouraging saturated fat and cholesterol have reduced consumption of vitamin A-rich foods like liver, red meat, egg yolks, and full-fat dairy [12]. While beta-carotene is recommended, its conversion to retinol is inefficient and highly variable, likely inadequate for brain development [12].

The World Health Organization estimates that nearly 19 million pregnant women worldwide are affected by vitamin A deficiency [13]. Fortification efforts using beta-carotene in poor vehicles (e.g., cereals, vegetable oils) fail to address the need for fat-soluble retinol [14].

Re-evaluating Prenatal Vitamin A Guidelines

Current Recommended Dietary Intakes (RDIs) for vitamin A aim to prevent acute deficiency and toxicity but may lead to underconsumption, especially among pregnant women [15]. Retinol supplementation is often discouraged due to toxicity concerns, with the WHO recommending it only where deficiency is a known public health issue [15].

This overlooks subclinical deficiencies and vitamin A’s essential role in fetal brain development, necessitating a re-evaluation of toxicity thresholds and adequate intake levels [15].

Genetic Or Environmental Causes of Autism?

The Male Brain: A Clue in the Biology

Autism is diagnosed more frequently in males (4:1 ratio), consistent across countries and cultures, including Australia, the US, Canada, Japan and Sweden suggesting a biological basis [16]. The male brain’s greater dependency on retinoic acid signaling, influenced by testosterone, makes it more vulnerable to vitamin A deficiency, particularly in synaptic plasticity and hormonal regulation [17].

Females may have more robust compensatory mechanisms or lower developmental requirements for vitamin A [17].

The Link Between Serotonin, Autism, and Vitamin A

• Serotonin as a Biomarker: Elevated blood serotonin (hyperserotonemia) is seen in 25–30% of individuals with ASD, making it a consistent biomarker [18].

• Gut-Brain Axis and SERTs: Over 90% of serotonin is produced in the gut, regulated by serotonin transporters (SERTs). In ASD, SERT mutations or overexpression can reduce brain serotonin availability while increasing blood levels, contributing to neurological and digestive symptoms [19].

• Vitamin A’s Role: Vitamin A deficiency increases SERT activity, disrupting serotonin homeostasis in the brain and gut [20].

• Supplementation Benefits: Restoring vitamin A levels corrects SERT expression, stabilizes serotonin, and reduces ASD-like behaviors in animal models, improving social interaction and decreasing repetitive behaviors [20].

Genetics vs. Environment: How Vitamin A Shapes Genes

Many autism-related genes are influenced by epigenetic mechanisms, such as histone changes, DNA methylation, non-coding RNAs, and chromatin remodeling, modulated by retinoic acid binding to over 500 genes [21].

Striking similarities exist between genetic presentations of autism and vitamin A deficiency, suggesting a misinterpretation of inherited (genome) versus environmentally cued (epigenome) factors [21].

Beta-Carotene Metabolism and Autism

The BCMO1 gene converts beta-carotene to retinal, but variants can reduce enzyme activity by nearly 60% [22]. Epigenetic factors, including DNA methylation, histone modifications, and microRNAs, further modulate BCMO1 expression, influenced by diet, inflammation, and stress [22].

Children with ASD often show impaired carotene-to-retinol conversion, lower retinol levels, and disrupted retinoid signaling, indicating that even a carotenoid-rich diet may be insufficient [22].

Retinol-Binding Protein: The Delivery System

Retinol-Binding Protein (RBP) transports retinol to tissues, but inflammation, liver dysfunction, or genetic anomalies can impair its function, reducing retinol delivery to the brain [23].

Lower RBP levels are observed in ASD, and high-bioavailability retinol supplementation may bypass this bottleneck, improving sleep, attention, and social engagement [23, 24].

Genetic Changes in Vitamin A Deficiency: Fat Metabolism and Peroxisomes

Vitamin A deficiency and autism share disruptions in fat metabolism and peroxisome function making it a lead contender as a cause for autism.

• Fat Metabolism: Vitamin A regulates enzymes (FADS1, FADS2, ELOVL5) that produce brain-critical fatty acids like DHA. Both conditions show lower DHA levels and reduced FADS1/FADS2 activity [25, 26].

• Peroxisomes: Vitamin A supports peroxisome function via PPARs. Both conditions exhibit reduced peroxisome function, genetic variations in PEX genes, and oxidative stress [27, 28].

Clinical Symptoms of Vitamin A Deficiency and Causes of Autism

1. Vision Loss and Eye Problems

Vitamin A deficiency causes night blindness, xerophthalmia, and impaired visual processing, leading to autism-like behaviors (e.g., lack of eye contact, sensory avoidance) [10]. Case reports show children with severe deficiency misdiagnosed with developmental delays, with rapid improvement after supplementation [29, 30].

WHO recommends 200,000 IU of vitamin A for children over 12 months, restoring visual function and improving behavior [31].

2. Speech and Language Delays

Vitamin A deficiency can cause delayed speech, loss of words, poor articulation, and weak oral motor skills, mimicking autism [29]. Supplementation (200,000 IU) and a vitamin A-rich diet can reverse delays, with pilot studies showing improved speech in ASD children with low vitamin A levels [30, 32].

3. Middle Ear Infections

Prenatal vitamin A deficiency impairs inner ear development, increasing ear infection risk, with autistic children showing a higher incidence (5.8% vs. 3%) [33]. Supplementation (200,000 IU every six months) reduces infections and hearing loss [34].

4. Skin, Lung, and Immune Dysfunction

Both conditions share eczema, respiratory infections, and immune dysfunction due to vitamin A’s role in maintaining skin, lung, and immune barriers [35]. Supplementation improves skin health and reduces respiratory issues in ASD [35, 36].

5. Gut and Digestive Issues

Vitamin A deficiency and autism involve leaky gut, digestive problems, dysbiosis, and inflammation [37]. Supplementation enhances gut barrier function, reducing symptoms like constipation and diarrhea in ASD [37].

6. Sleep and Airway Dysfunction

Vitamin A deficiency exacerbates airway inflammation and skeletal airway growth issues, contributing to sleep apnea and poor sleep quality, common in ASD [38]. Supplementation reduces inflammation and improves sleep [38].

7. Seizures and Epilepsy

Vitamin A deficiency increases seizure risk by disrupting neuronal excitability and synaptic plasticity, a concern in ASD [39]. Supplementation may stabilize signaling and reduce seizure frequency [40].

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