Neurology -- Correspondence for Bromley et al., 71 (23) 1923-1924

Correspondence published:

AUTISM SPECTRUM DISORDERS FOLLOWING IN UTERO EXPOSURE TO ANTIEPILEPTIC DRUGS: Marian L. Evatt, Mahlon DeLong,William B. Grant, John J. Cannell, and Vin Tangpricha (29 January 2009)

AUTISM SPECTRUM DISORDERS FOLLOWING IN UTERO EXPOSURE TO ANTIEPILEPTIC DRUGS 29 January 2009

Marian L. Evatt,
Emory University
1841 Clifton Road, Atlanta, GA 30329,
Mahlon DeLong,William B. Grant, John J. Cannell, and Vin Tangpricha
Send Correspondence to journal:
Re: AUTISM SPECTRUM DISORDERS FOLLOWING IN UTERO EXPOSURE TO ANTIEPILEPTIC DRUGS

mevatt{at}emory.edu Marian L. Evatt, et al.

We find Bromley et al.’s report of an increased incidence of autism spectrum disorders in the offspring of mothers taking antiepileptic drugs (AEDs) during pregnancy intriguing and suggest low vitamin D as a possible mechanism deserving further investigation. [1]
Several AEDs are known to bind to the pregnane X receptor (PXR) to increase the catabolism of vitamin D by up regulating the mitochondrial enzyme CYP24. AEDs, including VPA, are known to decrease 25-hydroxyvitamin D levels. [2] It has been reported that babies born to women taking AEDs during pregnancy had significantly lower 25-hydroxyvitamin D concentrations compared to healthy control newborns. [3] Vitamin D is a secosteroid hormone that has important extra-skeletal functions. Vitamin D deficiency, and in particular gestational deficiency, has been implicated in an expanding list of extra skeletal neuropsychiatric disorders including schizophrenia and autism. [4,5]
The vitamin D receptor (VDR) and 1-alpha-hydroxylase, the enzyme that converts the circulating form of vitamin D and (25-hydroxyvitamin D) the hormonal form of vitamin D, (1,25-dihydroxyvitamin D) have been found throughout the central nervous system. Furthermore, vitamin D regulates production of neurotrophins and growth factors that have an integral role in neuronal differentiation, growth and survival.
An ecological study of autism suggested that there was a significant increase in the prevalence of autism with increasing latitude, varying from 1.3/100,000 at 32 degrees to about 6.1/100,000 at 57 degrees. [5] It was also noted that children born in winter months, when vitamin D levels are lower, are at increased risk of developing autism. We suspect that children born to women taking AEDs during pregnancy are at increased risk for vitamin D insufficiency compared to the children whose mothers did not take AEDs.
The increasing incidence of vitamin D insufficiency is likely also associated with the increased risk of autism spectrum disorders as reported in this cohort, thus supporting the hypothesis that gestational vitamin D deficiency is autism's environmental trigger, one that allows the phenotypic expression of autism in genetically susceptible children. [5]
References
1. Bromley RL, Mawer G, Clayton-Smith J, Baker GA, On behalf of the Liverpool and Manchester Neurodevelopment G. Autism Spectrum Disorders Following in Utero Exposure to Antiepileptic Drugs. Neurology 2008;71:1923-1924.
2. Kulak CA, Borba VZ, Bilezikian JP, Silvado CE, Paola L, Boguszewski CL. Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs. Arq Neuropsiquiatr 2004;62:940-948.
3. Markestad T, Ulstein M, Strandjord RE, Aksnes L, Aarskog D. Anticonvulsant drug therapy in human pregnancy: effects on serum concentrations of vitamin D metabolites in maternal and cord blood. Am J Obstet Gynecol 1984;150:254-258.
4. Holick MF. Vitamin D deficiency. New England Journal of Medicine 2007;357:266-281.
5. Cannell JJ. Autism and vitamin D. Med Hypotheses 2008;70:750-759.
Disclosures: MLE, MRD, and VT have no relevant disclosures; WBG receives funding from the UV Foundation (McLean, VA); JJC is president of the non-profit educational organization, the Vitamin D Council.
Editor’s Note: The authors of the article were offered the opportunity to respond but declined.