Disease Basis

Until relatively recently, controversy surrounded the status of ADHD as a genuine medical condition. It was commonly believed that ADHD was a childhood reaction to poor parenting or family stress. However, recent findings that ADHD is found in a variety of cultures and that there is a strong genetic component bolster the validity of designating ADHD as a medical disorder.11 ADHD is likely a polygenic disorder, meaning that multiple genes contribute, each conferring a small risk.

Candidate gene searches have focused on the dopaminergic system, in part due to the effective medications acting primarily on this neurotransmitter system (for a review of pharmacogenomic ADHD studies, see 13). Genes that have been associated with ADHD include the dopamine transporter (DAT1), dopamine D2 (DRD2) and D4 (DRD4) and D5 receptor (DRD5) subtypes, and the dopa-b-hydroxylase gene (DBH).13

Recently, an intron mutation in the gene coding for the a4 subunit of neuronal nicotinic receptors (NNRs) was associated with ADHD characterized by severe inattention. The functional consequence of this mutation is unknown but its location is suggestive of effects on pre-mRNA stability or splicing.14 Interestingly, adolescents with ADHD have at least a twofold higher rate of smoking cigarettes than the average smoking population (excluding individuals with other neurological disorders) and this finding continues into adulthood.

Polymorphisms within the gene encoding synaptosomal-associated protein of 25kDa (SNAP-25), a presynaptic plasma membrane protein with an integral role in synaptic transmission, have also been implicated in ADHD. SNAP-25 forms a complex with syntaxin 1a and synaptic vesicle proteins such as VAMP-2 (synaptobrevin 2) and synaptotagmin, which mediates calcium-dependent exocytosis of neurotransmitter from the synaptic vesicle into the synaptic cleft.15 SNAP-25 is differentially expressed in the brain, with high levels found in regions such as the hippocampus, neocortex, thalamus, substantia nigra, and cerebellum. In a recent study of 93 ADHD nuclear families in Ireland, significant increased preferential transmission of the SNAP-25 polymorphism Ddel allele 1 was found.16 In a separate study of Canadian families with ADHD, significant increased preferential transmission of the SNAP-25 polymorphism Ddel allele 2 was found.17 Additional haplotype analysis of SNAP-25 implicates SNAP-25 in the etiology of ADHD.

Imaging studies have also supported the characterization of ADHD as a medical condition, suggesting that ADHD appears to be associated with decreased activity of the prefrontal cortex, which is consistent with the impaired attention and executive function characteristic of the disease.11

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