May 31, 2011 (Denver, Colorado) — A new study has documented the presence of a polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) — essential for the metabolism of vitamin B 9 (folate) — which almost doubles the chance of autism spectrum disorder (ASD). The data provide further genetic evidence for a link between folate and autism.

Daniel Schulteis, MD, from Nationwide Children's Hospital in Columbus, Ohio, presented the study results here at the Pediatric Academic Societies and Asian Society for Pediatric Research 2011 Annual Meeting.

Although autism is generally regarded as having a genetic basis with environmental triggering factors, the details have yet to be completely defined, and no single theory has prevailed, Dr. Schulteis noted. Dietary supplementation with folate has been anecdotally liked to the improvement of symptoms of ASD, "despite a lack of medical evidence and endorsement," Dr. Schulteis told Medscape Medical News.

Indeed, a converse link between autism and excess folate has been suggested. Genetic evidence for a folate connection with autism was first reported in a study of 168 autistic children that chronicled the doubled prevalence of MTHFR polymorphisms in those with autism, compared with those in the control group (J Am Phys Surg. 2004;9[4]:106-108).

Dr. Schulteis and his colleagues established the MTHFR registry in 2002, and used the accumulated data to examine the reported genetic link in detail. The database contains information on patients who have been screened for the 677A→T and 1298A→C MTHFR polymorphisms in connection with other clinical concerns.

Scrutiny of the records of 487 patients younger than 26 years of age revealed that 246 (51%) had 1 of the 2 mutations. The 677A→T mutation was predominate, affecting 67% of the patients. Fourteen of these individuals had ASD, which is appreciably greater than the accepted Centers for Disease Control and Prevention predicted prevalence of 4.43 (or 1 in 110) in young people. The prevalence rate of ADS in the control subjects conformed to the 1 in 110 rate.

Of the 14 cases, 9 (64.3%) harbored either a homozygous (n = 2) or heterozygous (n = 7) MTHFR polymorphism (χ2, 24.06; P < .001; risk ratio [RR], 1.76). The 677A→T polymorphism displayed the greatest statistical risk (χ2, 17.81; P < .001; RR, 1.459), especially the heterozygous polymorphism (χ2, 18.507; P < .001; RR, 1.647).

The prevalence of ASD in those with MTHFR polymorphisms was 1.7 times greater than it was in the control population.

"Our results add credence to the folate hypothesis, at least in this select number of ASD cases. These data should not be taken as a recommendation for change regarding folate supplementation, but are an indication of the need for further prospective studies," Dr. Schulteis explained to Medscape Medical News.

"The study design appears good. The number of samples evaluated was somewhat limited, but were selected based on conditions often associated with the MTHFR C677T polymorphism. The conclusions are appropriate based on these data, and support the hypothesis that individuals with this particular polymorphism are at increased risk to develop autism," Eugene J. Rogers, PhD, professor and chair, Department of Clinical Laboratory and Nutritional Sciences, University of Massachusetts Lowell, told Medscape Medical News.

Dr. Schulteis pointed out that the study was specifically intended to address the role of the 2 particular mutations.

"Other genes that impair folate transport and metabolism may also contribute to the risk of abnormal neurodevelopment, but MTHFR C677T is also a known risk for placental abruption (miscarriage) under 'normal' folate nutritional status, which is minimized under conditions that enhance maternal folate status during pregnancy."

"Therefore, it is highly likely that the folic acid food fortification/supplementation era has increased the birthrate of individuals with this polymorphism. They require more folic acid for neurodevelopment after birth, and are more susceptible to functional folate deficiency and neurodevelopment disorders, such as autism, than those without this polymorphism," Dr. Rogers noted.

"This study was small but was statistically significant, implying that larger studies will most likely show a stronger association between the presence of MTHFR C677T and autism. These studies need to be done now," he added.

The authors and Dr. Rogers have disclosed no relevant financial relationships.

Pediatric Academic Societies (PAS) and Asian Society for Pediatric Research 2011 Annual Meeting: Abstract 3843.506. Presented May 3, 2011.