Genetically determined low maternal serum dopamine ?-hydroxylase levels and the etiology of autism spectrum disorders

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Abstract
Autism, a neurodevelopmental disability characterized by repetitive stereopathies and deficits in reciprocal social interaction and communication, has a strong genetic basis. Since previous findings showed that some families with autistic children have a low level of serum dopamine β-hydroxylase (DβH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in families with two or more children with autism spectrum disorder using the affected sib-pair method. DBH alleles are defined by a polymorphic AC repeat and the presence/absence (DBH+/DBH−) of a 19-bp sequence 118 bp downstream in the 5′ flanking region of the gene. There was no increased concordance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH−), compared to an ethnically similar Canadian comparison group (χ2 = 4.20, df = 1, P = 0.02 for all multiplex mothers; χ2 = 4.71, df = 1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH− allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH− alleles, compared to 19% of controls (χ2 = 5.81, df = 2, P = 0.03). DβH enzyme activity was lower in mothers of autistic children than in controls (mean was 23.20 ± 15.35 iU/liter for mothers vs. 33.14 ± 21.39 iU/liter for controls; t = − 1.749, df = 46, P = 0.044). The DBH− allele was associated with lower mean serum DβH enzyme activity (nondeletion homozygotes: 41.02 ± 24.34 iU/liter; heterozygotes: 32.07 ± 18.10 iU/liter; and deletion homozygotes: 22.31 ± 13.48 iU/liter; F = 5.217, df = 2, P = 0.007) in a pooled sample of mothers and controls. Taken together, these findings suggest that lowered maternal serum DβH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families.