MTHFR in Children: Signs, Symptoms and Risk Factors

Parents searching for MTHFR symptoms in children often encounter long lists of behavioral, developmental and physical findings. However, current evidence does not associate the common MTHFR C677T or A1298C variants with a specific, clinically recognized pattern of symptoms. These variants are common in healthy populations, and a child’s genotype alone cannot establish that MTHFR is causing a health concern.¹

Tiredness, irritability, difficulty concentrating, poor growth and developmental concerns are nonspecific and can have many possible causes. They should receive an appropriate pediatric evaluation rather than being attributed to a common MTHFR variant. Rare MTHFR deficiency - also called homocystinuria due to MTHFR deficiency - is a distinct inherited metabolic disorder identified through characteristic biochemical abnormalities and pathogenic variants affecting both copies of the MTHFR gene.²

Rare homocystinuria due to MTHFR deficiency is distinct from carrying a common MTHFR variant such as C677T or A1298C. It is an autosomal recessive metabolic disorder caused by pathogenic variants affecting both copies of the MTHFR gene. Depending on the severity, affected babies may develop feeding difficulties, poor growth, developmental delay, seizures, breathing pauses or abnormal muscle tone and movement. Characteristic laboratory findings include markedly elevated homocysteine, low methionine and low 5-MTHF concentrations.⁴

If the condition is suspected because of an out-of-range newborn-screening result, characteristic clinical and biochemical findings or a relevant family history, prompt evaluation by a pediatric metabolic specialist or clinical geneticist is appropriate. Diagnosis is established through compatible clinical and laboratory findings together with molecular genetic testing. These features should not be used as a checklist for identifying a common MTHFR variant at home.

Common MTHFR C677T and A1298C variants are not associated with a specific behavioral symptom pattern, and behavior alone cannot identify an MTHFR-related disorder. Folate or vitamin B12 deficiency can cause megaloblastic anemia and symptoms such as fatigue, weakness, irritability and difficulty concentrating. However, these symptoms are nonspecific and can have many nutritional, medical, sleep-related or emotional causes.⁵

If symptoms persist, a pediatric healthcare professional may review the child’s diet, growth, medications, sleep and medical history. Depending on the findings, a blood count and tests for iron, folate, vitamin B12 or other possible causes may be more clinically useful than testing for common MTHFR variants.

Congenital heart defects and neural tube defects arise during prenatal development. They are congenital conditions - not symptoms that develop in an older child because of a common MTHFR variant - and they cannot be attributed to the child’s later folate status. Population studies have reported associations between some MTHFR variants and susceptibility to certain congenital conditions, but results vary across populations and study designs. An association cannot establish that an MTHFR variant caused a particular child’s condition.⁶

A stork bite usually refers to a nevus simplex on the nape of the neck. Nevus simplex is a common, flat, pink or red capillary birthmark caused by dilated blood vessels close to the skin’s surface. It is reported in approximately 30–50% of newborns, although prevalence estimates vary by population. Most lesions are harmless and require no treatment. Facial lesions commonly fade during the first one to two years, while those on the back of the neck are more likely to persist.⁷

No peer-reviewed clinical evidence has established that a common MTHFR variant causes nevus simplex. Online terms such as MTHFR gene mutation stork bite or stork bite gene mutation are not recognized medical diagnoses. Claims linking stork bites and MTHFR should therefore be presented as unsupported rather than as diagnostic clues.

A sacral dimple is a small indentation in the skin over the lower back, usually near the crease between the buttocks, that is present at birth. Most simple sacral dimples are harmless and do not require imaging or treatment. Their exact cause is usually unknown. No reliable clinical evidence currently supports an association between a typical sacral dimple and MTHFR variants.⁸

A pediatric healthcare professional may recommend further evaluation if a dimple is unusually large, located higher on the back or accompanied by a tuft of hair, skin tag, lump, certain types of skin discoloration or other unusual findings. These features can occasionally be associated with an underlying spinal abnormality, but they are not signs of an MTHFR variant.⁹

Tongue-tie occurs when the band of tissue beneath the tongue restricts tongue movement. No reliable evidence establishes MTHFR and tongue-tie as related conditions. A 2023 systematic review also found insufficient evidence for a proposed relationship between maternal folic acid supplementation and tongue-tie. The authors emphasized that unsupported claims should not discourage recommended folic acid use before or during pregnancy.¹⁰

How a common MTHFR variant relates to folate status and homocysteine can vary according to the specific genotype. Folate and homocysteine levels are also influenced by diet, folate, vitamin B12 and riboflavin status, age, kidney function, certain medications, absorption-related conditions and other genetic factors. A genotype alone does not establish that a child has folate deficiency or explain a particular symptom.

The C677T variant can reduce MTHFR enzyme activity. On average, people with two copies of the 677T variant - the TT genotype - have slightly lower blood folate than people with the CC genotype when their folic acid intake is the same. However, folic acid increases blood folate across MTHFR genotypes. The CDC also states that there is insufficient evidence that A1298C alone significantly affects how the body processes folate.¹¹

Clinical decisions should therefore be based on the child’s medical history, diet, symptoms, examination and relevant laboratory findings - not on a common MTHFR result in isolation. 

Some case-control studies and meta-analyses have reported a statistical association between MTHFR C677T and autism spectrum disorder. A 2026 meta-analysis of 22 studies, involving 4,391 people with autism and 9,522 controls, reported a pooled association for C677T but found no overall statistical support for an association with A1298C. However, substantial differences remained among the included studies. These findings suggest a possible susceptibility association; they do not show that MTHFR causes autism or establish MTHFR testing as a diagnostic test for autism.¹²

Evidence concerning MTHFR in kids with ADHD remains limited and inconsistent. A 2022 meta-analysis of five retrospective studies reported a statistical association between A1298C and ADHD but not between C677T and ADHD. Because the analysis was based on a small number of candidate-gene studies, larger and more diverse studies are needed. The findings do not establish that an MTHFR variant causes ADHD or validate MTHFR testing for diagnosis or treatment selection.¹³

At present, testing for common MTHFR variants is not a validated way to diagnose autism or ADHD, predict symptom severity or determine whether a child needs a particular supplement. Children with developmental, learning, attention or behavioral concerns should receive standard pediatric and developmental assessment regardless of MTHFR status.

Folate and vitamin B12 are required for normal cell division and red blood cell formation. Deficiency may cause loss of appetite, gastrointestinal symptoms and mouth or tongue soreness. Vitamin B12 deficiency can also cause neurological symptoms, sometimes even when anemia is not present.

Deficiency of either nutrient may contribute to elevated homocysteine, but this finding is not specific to folate or vitamin B12 deficiency. None of these symptoms or laboratory findings establishes an MTHFR-related problem, and they can have many other nutritional or medical causes.¹⁴

One possible consequence of folate or vitamin B12 deficiency is megaloblastic anemia, a condition in which the body produces abnormally large and poorly developed red blood cells. Possible symptoms include fatigue, weakness, irritability, difficulty concentrating, headache, shortness of breath and heart palpitations.¹⁵

Having a common MTHFR variant such as C677T or A1298C does not establish that a child is folate deficient or that the variant caused the anemia. If anemia is suspected, a healthcare professional may assess the child’s blood count and relevant nutrient levels and investigate possible dietary, absorption-related, medication-related or medical causes before recommending treatment.¹⁶

Homocysteine levels in children and adolescents are influenced by many factors and should not be interpreted as a direct measure of MTHFR function. A 2023 population-based study of 1,900 adolescents ages 14–19 found associations between homocysteine and age, sex, body mass index, kidney-function measures and aspects of diet quality in unadjusted analyses. In the multivariable analysis, sex and creatinine were the strongest independent predictors. Vitamin B6, vitamin B12 and folate status were not measured. In addition, MTHFR C677T testing was completed for only 13 participants selected from those with homocysteine above the 97th percentile, so the study could not determine the contribution of C677T across the full population.¹⁷

2019 pediatric study comparing 195 healthy 9-year-olds with 128 healthy 17-year-olds found that homocysteine differed by MTHFR C677T genotype among the 17-year-olds, with the TT group having the highest concentrations, but not among the 9-year-olds. The older group also had higher average homocysteine and lower folate and total vitamin B12 concentrations. These findings suggest that the relationship between MTHFR genotype and homocysteine may vary with age and B-vitamin status.¹⁸ An elevated homocysteine result should therefore be interpreted using age-appropriate reference values and considered alongside the child’s diet, nutrient status, kidney function, medications and wider clinical context.

If you’re preparing to have a baby, are already pregnant, or have children, you may be wondering whether MTHFR testing would be helpful. Clinical MTHFR testing can be performed using DNA from a blood sample or, depending on the laboratory, a buccal (cheek) swab. The test generally examines common variants such as C677T and A1298C and reports whether one or two copies of a tested variant are present.¹⁹

Routine testing for common MTHFR variants is not recommended for every baby or child. These variants are widespread, and most children who carry them do not experience health problems because of them. Testing can identify a child’s genotype, but it cannot establish that a common MTHFR variant is responsible for nonspecific symptoms such as tiredness, irritability, difficulty concentrating or developmental concerns.²⁰

If symptoms persist, a healthcare professional may first review the child’s diet, medications, growth, medical history and family history. Tests should be selected according to the child’s symptoms and clinical findings. Depending on the situation, these may include a complete blood count and tests assessing iron, folate or vitamin B12 status. Homocysteine may also be measured when clinically appropriate.

Elevated homocysteine does not automatically indicate an MTHFR-related problem. It can also be influenced by folate, vitamin B12 or vitamin B6 status, kidney function, certain medications, absorption-related conditions and other medical factors. Treatment should address the underlying cause. A common MTHFR variant alone does not mean that a child needs methylfolate. The CDC states that people with common MTHFR variants can process folic acid and that there are no clinical recommendations to alter folate or folic-acid intake solely on the basis of a common MTHFR genotype.^21,22

Rare homocystinuria due to MTHFR deficiency is different from having a common C677T or A1298C variant. It is an autosomal recessive metabolic disorder caused by pathogenic variants affecting both copies of the MTHFR gene. Characteristic laboratory findings include markedly elevated homocysteine, low methionine and low 5-MTHF concentrations.²³ If the condition is suspected because of an out-of-range newborn-screening result, compatible neurological or developmental findings, abnormal biochemical results or a relevant family history, prompt evaluation by a pediatric metabolic or genetics specialist is appropriate. Diagnosis is based on the clinical and biochemical findings and confirmed through molecular genetic testing.²⁴

If testing shows that your child has one or two copies of a common MTHFR variant, such as C677T or A1298C, the first step is to discuss the result with a pediatric healthcare professional. These variants are common and do not, by themselves, establish folate deficiency, a clinically significant disruption of folate metabolism or a need for treatment. The result should be considered alongside the child’s diet, symptoms, medications and medical history and, when clinically appropriate, folate, vitamin B12 and homocysteine levels.²⁵

If folate supplementation is clinically appropriate, the form and amount should be selected according to the reason for supplementation, the child’s age, diet and relevant laboratory findings. Options may include folic acid or L-5-methyltetrahydrofolate, commonly called L-methylfolate or 5-MTHF. The latter does not require the MTHFR-dependent conversion step that produces 5-MTHF. However, having a common MTHFR variant does not automatically mean that a child needs methylfolate or cannot use folate from food or folic acid.

The CDC states that people with common MTHFR variants can process all forms of folate, including folic acid. People with the 677 TT genotype have slightly lower average blood folate concentrations than those with the 677 CC genotype when consuming the same amount of folic acid, but folic acid still increases blood folate across MTHFR genotypes. Current evidence is also insufficient to show that A1298C alone significantly affects folate processing.²⁶

Evidence supporting the routine use of methylfolate in children based solely on MTHFR genotype remains limited. In a 2022 retrospective study of 412 children and adolescents with unipolar depressive disorders, L-methylfolate use was not significantly associated with treatment response, regardless of MTHFR C677T genotype or dose. Because the study was retrospective and involved young people receiving psychiatric treatment, it cannot establish the effectiveness or lack of effectiveness of methylfolate in children generally or for indications outside depressive disorders.²⁷

Folic acid can sometimes be detected in the bloodstream as unmetabolized folic acid (UMFA), particularly when intake exceeds the amount processed at one time. However, current evidence does not confirm that UMFA from recommended folic-acid intake or fortified foods causes cancer. The CDC’s 2026 safety review reports no confirmed health risks from circulating UMFA, and an analysis of 13 randomized trials involving approximately 50,000 participants found no overall increase or decrease in cancer incidence with folic-acid supplementation.²⁸

When a healthcare professional recommends L-methylfolate, it can provide an available form of folate and support folate-dependent pathways. However, it should not be described as automatically restoring methylation or resolving symptoms in every child. The appropriate folate form and amount should be selected according to the child’s age, diet, clinical needs and laboratory findings.

Contact the child’s pediatric healthcare professional if there are persistent concerns about growth, feeding, development, weakness, possible anemia, nutrition or a significant change in behavior or school functioning. A clinician can evaluate common causes and determine whether laboratory testing, genetic counseling or referral to a pediatric metabolic specialist is appropriate.

Seek urgent medical care if a child experiences their first seizure, breathing difficulty, loss of consciousness or rapid deterioration in their condition.