A review of the literature
Autism spectrum disorder (ASD), a disorder characterized by social, communication, and behavioral impairments, has increased dramatically in recent years. The conventional medical paradigm defines ASD as a neurological disorder. Conventional treatments rely on behavioral therapies and psychotropic medications but have limited success and tolerability. A new paradigm is emerging that views ASD as a multisystem disorder accompanied by metabolic and mitochondrial impairments. A clinical approach to assess and treat metabolic dysfunction in ASD is reviewed here.
The prevalence of ASD in the United States has increased dramatically over recent decades and recent years. The estimated prevalence of autism in 1975 was 1 in 5000 children; now it is 1 in 50 children.1 The change in prevalence has been most significant in recent years: between 2007 and 2012, the rate of ASD in school-aged children increased from 1.16% to 2.00%.1Boys are disproportionately affected by ASD, with an estimated 4:1 male to female ratio.2
ASD is characterized by social or communication deficits and restricted or repetitive behaviors. These 2 areas of dysfunction must be present to meet the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition.3 ASD can occur with or without language impairment and with or without intellectual impairment.4 The previously differentiated subtypes of developmental disorders (autism disorder, Asperger syndrome, and pervasive developmental disorder not otherwise specified) are now categorized as a single entity.
In light of the limited success of a purely neurological approach to autism spectrum disorder, a new paradigm is emerging: What was once viewed as a brain disorder is now viewed as a multisystem disorder associated with predictable patterns of physiological and biochemical dysfunction.
ASD has traditionally been viewed as a neurological disorder. Neuroimaging studies have identified anatomical differences in the brains of autistic patients that may correlate with behavioral symptoms, and current research continues to explore the anatomy of the autistic brain.5,6 There has been particular interest in changes in the amygdala, including its effect on the autonomic response.7 However, no single area of brain involvement has been identified typically, and no consistent neuropathology has been defined.8 Consistent with the view of ASD as a disorder of the brain, conventional medical treatments for ASD rely predominantly on behavioral therapies and psychotropic medications. There are 2 approved pharmaceutical medications for children with ASD: risperidone (Risperdal) and aripriprazole (Abilify).9 Other psychotropic medications, such as selective serotonin reuptake inhibitors or mood stabilizers are used for the behavioral symptoms associated with ASD. Unfortunately, these medications are often not tolerated well and offer only limited benefit.10
In light of the limited success of a purely neurological approach to ASD, a new paradigm is emerging: What was once viewed as a brain disorder is now viewed as a multisystem disorder associated with predictable patterns of physiological and biochemical dysfunction. These patterns include gastrointestinal (GI) disease, immune dysregulation, oxidative stress, metabolic impairment, and mitochondrial disease.11 Many children with ASD, for example, have intestinal pathologies, such as diarrhea, constipation, gastroesophageal reflux, or intestinal infections; others have immune system problems, such as allergies or autoimmunity.12 Metabolic dysfunctions in patients with ASD include impairments in methylation, transulfuration, and mitochondrial function.
Integrative healthcare practitioners are now routinely evaluating children with ASD for GI disorders, food allergies, heavy metal toxicities, and nutritional deficiencies. These evaluations are foundational to a multisystem approach to ASD, but an exhaustive discussion of these is beyond the scope of this review. Here it is our aim to describe 3 metabolic impairments associated with ASD: methylation, transulfuration, and mitochondrial function. We review the pathophysiological mechanisms, assessment, and treatment of these metabolic impairments. We hope that clinicians will gain a greater awareness of, a deeper understanding of, and a confidence to navigate these complex metabolic pathways in children with ASD.
Mechanisms of Metabolic Impairments
The majority of patients with ASD have defects in methylation or transulfuration pathways.13 The methylation cycle involves conversion of methionine to S-adenosyl methionine (SAMe), then S-adenosyl homocysteine, then homocysteine, and then back to methionine. SAMe is the primary methyl donor in the body. It provides methyl groups to produce substances that are critical for mitochondrial, neurological, and enzymatic functions. Homocysteine can also be converted into cysteine, which is the rate-limiting amino acid for transsulfuration. The process of transsulfuration is essential for the production of glutathione—the most important intracellular antioxidant in humans. Impaired methylation and transulfuration mean a decreased production of the body’s primary methyl donor (ie, SAMe) and primary antioxidant (ie, glutathione). This combination increases susceptibility to oxidative stress and impairs immune function, potentially contributing to higher rates of allergies, heavy metal toxicity, GI problems, and behavioral patterns associated with ASD.
Impaired methylation can also affect genetic expression, which may play a role in both the etiology and pathophysiology of ASD. SAMe not only contributes methyl groups to produce substances such as creatine, carnitine, coenzyme Q10, and neurotransmitters, but also methylates DNA. A case-control study of the autistic brain revealed significantly different patterns of DNA methylation in autistic brains compared to controls.14 Hypomethylation is correlated with increased genetic expression, suggesting that impaired methylation has an epigenetic effect (epigenetic changes affect genetic expression without changing the genetic code). Epigenetic changes are heritable, and impaired methylation is seen not only in children with ASD but also in their parents.15 Emerging evidence suggests that epigenetic change is 1 mechanism by which methylation defects may contribute to the pathophysiology of ASD.16
Transulfuration defects, by depleting glutathione, result in increased oxidative stress. Mitochondria are especially susceptible to oxidative damage. Mitochondria are cellular organelles that generate adenosine triphosphate, the energy carrier in human cells. They are also the only organelle with their own genome. Because mitochondria are concentrated at neuronal synapses, mitochondrial dysfunction can directly affect neurological function.17 A meta-analysis found that mitochondrial dysfunction was present in 5.0% of children with ASD compared to only 0.01% of the general population.18 In the majority of cases, the mitochondrial dysfunction resulted from environmental influences rather than genetics. This study suggests that, while mitochondrial dysfunction disproportionately affects children with ASD, it may not play a role in many cases. Moreover, when mitochondrial dysfunction does occur, it most likely results from underlying oxidative stress or other environmental factors.
We have shown that impaired methylation can contribute to impaired transulfuration, which can contribute to impaired mitochondrial function, but the underlying reasons for these impairments are multifactorial. The production of cysteine to drive transulfuration requires vitamin B6.19 The production of SAMe requires vitamin B12 and activated folate. Nutrient deficiencies or genetic polymorphisms affecting folate metabolism can disrupt these metabolic pathways. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, for example, block activation of folate and therefore impair methylation. In the next section, we discuss assessment tools, and in the section on treatments, we review studies that demonstrate changes in biomarkers and improvement in symptoms when methylation, transulfuration, and mitochondrial function are addressed.
Assessment of Metabolic Impairments
Analysis of a patient begins with a thorough history and physical exam. Indications of methylation defects in the mother include recurring fetal loss or babies born with midline defects such as cleft palate or tied tongue. An important clinical indication of faulty sulfation is an intolerance of foods that contain phenols. This is because it is a sulfation reaction, dependent on the enzyme phenol sulfotransferase, which processes phenols. Phenols are found in many foods, including artificial ingredients and salicylates. Clinical signs of mitochondrial dysfunction include low muscle tone, fatigability, constipation, regressive speech, sensitivity to environmental toxins, or regression after an illness, vaccine, or anesthesia.18
With the majority of ASD patients exhibiting impaired methylation or transulfuration, it is reasonable to utilize empiric therapy. But ideally, metabolic deficiencies should be documented through laboratory data. With laboratory data, interventions can be tailored to the patient. One approach is to do a broad-spectrum nutritional evaluation. Several functional labs have composite panels that detect functional nutritional deficiencies, methylation defects, toxic burden, and genomic polymorphisms.
If choosing only a few specific laboratory tests to detect methylation and transulfuration abnormalities, consider the following: urinary methylmalonic acid (MMA), formiminoglutamic acid (FiGlu), reduced glutathione, and MTHFR genetic analysis. Elevations in urinary MMA or MMA and FiGlu indicate vitamin B12 deficiency.20 Vitamin B12 is a cofactor for methionine synthase, an enzyme at the juncture between the folate cycle and the methylation cycle; when B12 is not available, methylation is impaired. An elevation in FiGlu indicates a deficiency in folate metabolism. A decrease in reduced glutathione indicates either low glutathione production or high oxidative stress.21 MTHFR polymorphisms block activation of folic acid and therefore create methylation and transulfuration problems.
There are no definitive laboratory tests to detect mitochondrial dysfunction. Any of the following results suggest mitochondrial dysfunction: elevated serum lactate and pyruvate, elevated ammonia, elevated creatinine kinase, or low free and total carnitine.18 Analysis of amino acids may reveal an elevated alanine to lysine ratio (>2). Analysis of organic acids will show elevated fatty acid metabolites.22
Treatment of Metabolic Impairments
Diet and Lifestyle
The foundation of treatment for metabolic dysfunction should begin with nutrition through whole foods. In practice, this can be challenging. Children with ASD tend to have limited diets, choosing foods with only certain colors, textures, or tastes. Bland white foods, which offer minimal nutrients, are often favorite foods for these patients. Whereas the ideal diet to support metabolic pathways will be rich in vitamin B12and antioxidants, this requires patients to eat organic eggs, meats, and highly colored fruits and vegetables. The best way to improve the diet in children with ASD is to work with a creative nutritionist who can help the family find ways to gradually include a broader variety of foods in the child’s diet.
Another lifestyle pattern to address is sleep. Sleep is commonly disrupted in children with ASD, yet it is a time when the body performs critical detoxification and metabolic processes.23 Sleep disturbance can be a sign of an undetected medical problem or source of pain: Consider apnea due to allergies or structural issues and digestive discomfort due to reflux or constipation. Epsom salt baths in the evening, a cool temperature in the bedroom, and no nightlights in the room can help balance pineal gland function and foster sleep. In some cases, it is necessary to use melatonin, 5-hydroxytryptophan, magnesium, or zinc to encourage restful sleep.24
Stress should also be addressed. The vast majority of children with ASD live in a sympathetic-dominant state.25,26 Activation of the sympathetic nervous system produces catecholamines, which rely on methylation for their metabolism.27 Stress is catabolic and depletes nutrients that are needed for proper methylation, transulfuration, and mitochondrial function. Parasympathetic activation, on the other hand, can reduce stress, control inflammation, and calm the brain.28,29 Therapies to increase parasympathetic tone can be very helpful for patients with ASD. Deep pressure from weighted blankets or deep hugging from parents can reduce stress and help to put children into a parasympathetic state. Children can be taught diaphragmatic breathing and learn to take 3 deep breaths to help calm their anxiety. Yoga, guided imagery, and meditation techniques can stimulate a parasympathetic state in children with ASD. Physical therapies, such as chiropractic, massage, and craniosacral therapies, can also help regulate the autonomic nervous system. The best way to incorporate these therapies into a treatment plan for patients with ASD is to enlist the expertise of a variety of healthcare professionals, including those who practice physical or mind-body medicine.
In combination with dietary and lifestyle patterns, nutritional supplements can improve methylation, transulfuration, and mitochondrial dysfunction (Table). These should be introduced cautiously in patients with ASD—1 at a time and beginning at a low dose—in order to monitor the patient’s reaction.
Supplements for Methylation
Supplements to support methylation include folate, vitamin B12, betaine (ie, trimethylglycine), and dimethylglycine (DMG). A study in which children with ASD were given methylcobalamin (75 μg/kg 2x/wk via intramuscular injection) and folinic acid (800 μg/d day orally) for 3 months demonstrated significant improvement in transmethylation metabolites and glutathione redox status.30 In this study, significant improvements in autistic behaviors (according to the Vineland Adaptive Behavior Scales) were observed after treatment, but the scores still remained below normal levels.
The type of folate chosen should depend on the patient’s MTHFR mutation status. L-methylfolate and 5-methyl-tetrahydrofolate are the most biologically active forms; these are the forms that naturally occur in food and are synthesized in body cells. Folinic acid is another active form but requires conversion by MTHFR to become methylfolate. Synthetic folic acid should be avoided because it is the most likely to remain unmetabolized. It is important to remember that folate supplementation will be ineffective unless vitamin B12 status is also adequate; vitamin B12 is required for folate to enter the methionine cycle.
The best evidence for vitamin B12 is in the injectable form of methylcobalamin. Injectable B12 will sometimes produce dramatic improvements—for example, in speech—simply by optimizing methylation. Potential side effects include hyperactivity, stimming (repetitive self-stimulating behaviors such as rocking, spinning, or flapping), mouthing of objects, or sleep changes.
Both betaine and DMG act as methyl donors and can be given in combination with methylcobalamin and folinic acid. A typical daily dose of betaine in a child with ASD is 1000 mg to 3000 mg per day, and a typical dose of DMG is 500 mg to 1000 mg per day. It is best to start DMG at a low dose (125 mg/d) and work up gradually; some children will respond to doses as high as 2000 mg per day.
Supplements for Transsulfuration
Supplements to support transulfuration and glutathione production include vitamin B6, magnesium, and n-acetyl cysteine (NAC). Vitamin B6 is crucial for production of cysteine and glutathione. It should be given in its active form, pyridoxyl-5-phosphate (P5P). A starting dose is 50 mg of P5P, but it can be increased to as high as 250 mg per day. Potential side effects of P5P are hyperactivity or anxiety. This is particularly a concern for patients with ASD who already deal with these symptoms. To minimize the chances of these side effects, magnesium can be paired with P5P. Magnesium has a calming and anxiolytic effect on the nervous system. In addition, magnesium acts as a cofactor in the methylation cycle, which drives the transulfuration cycle.
A variety of magnesium salts are available. Magnesium glycinate, magnesium taurate, and magnesium malate have minimal GI effects, whereas magnesium citrate can act as an osmotic laxative. All of these forms are effective at delivering magnesium, but if the child is constipated, consider giving part of the dose as magnesium citrate. Start with a total dose of 100 mg of magnesium and work up to a dose of 200 mg to 500 mg of magnesium per day.
NAC is a precursor for glutathione production. A randomized controlled trial conducted at Stanford University demonstrated that NAC supplementation was effective at treating irritability in children with ASD.31 Doses in the Stanford study were 900 mg daily for 4 weeks, then 900 mg twice daily for 4 weeks, and then 900 mg 3 times a day for 4 weeks. A case report of a child with ASD given NAC (800 mg/d) demonstrated significant improvement in social interaction and decreased aggression.32
Supplements for Mitochondrial Function
Supplements to support mitochondrial function include L-carnitine, ubiquinol, and B vitamins. L-carnitine transports long-chain fatty acids across the inner membrane of the mitochondria so that they can be used as a substrate for energy production. L-carnitine can be started at a dose of 250 mg to 500 mg twice a day and increased to a dose of up to 100 mg per kg per day. In a randomized controlled trial, L-carnitine (50 mg/kg/d) significantly improved symptoms of ASD after 3 months.33
Ubiquinol, the active form of coenzyme Q10, is a key component of the electron transport chain for mitochondrial energy production. It is also a potent antioxidant. A trial of ubiquinol (50 mg 2x/d) in children with ASD demonstrated improvement in communication, playing games, sleeping, and food acceptance.34
Riboflavin (2.5 mg-5 mg/kg/d), thiamine (2.5 mg-5 mg/kg/d), biotin (5 mg-10 mg/d), and other B vitamins also support mitochondrial function. A randomized trial in 141 children and adults with autism demonstrated that a multivitamin, containing active B vitamins, improved metabolic parameters, hyperactivity, tantrumming, and receptive language.35 Although we know that B vitamins are required for mitochondrial function, this study did not directly assess mitochondrial function, and there could be other mechanisms to explain its success.
Select Tools for Assessment
This review has summarized the mechanisms, assessment, and treatment of 3 metabolic impairments associated with ASD: impairments in methylation, transulfuration, and mitochondrial function. These metabolic impairments can have a cascade of physiological effects, including disrupted immune function and increased oxidative stress. These metabolic impairments can make it impossible for children with ASD to communicate, behave, or achieve their full potentials. In some cases, these impairments will be the key to successful treatment, but in other cases they will not. Each case must be considered individually, and treatment plans should be prioritized based on symptoms and laboratory assessments. Our hope is that this review will give clinicians the tools and confidence to explore and correct metabolic function in their patients with ASD.
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