DOI: 10.1097/01.mop.0000236393.87203.85
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PMID: 16914998
Issn Print: 1040-8703
Publication Date: 2006/08/01
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Excerpt
ADHD is a ‘chronic behavioral disorder characterized by persistent hyperactivity, impulsivity, and inattention that impairs educational achievement and/or social functioning’ [1]. It is a distressingly common behavioral abnormality of childhood and adolescence occurring in 3–7% of school-aged subjects. Among the several factors thought to be involved in the pathogenesis of ADHD are genetics, as ADHD is at times familial, in-utero insults such as exposure to toxins (tobacco, alcohol, illicit drugs) and subnormal growth, and adverse psychosocial conditions. Although multifactorial in origin, ADHD is associated with dysregulation of catecholaminergic neural pathways. Administration of ‘stimulant’ catecholamine agonists such as dextroamphetamine and methylphenidate often ameliorates many of the symptoms of ADHD, but these agents have been reported to increase irritability and impair sleep, decrease appetite and impede growth of treated children. Poulton's critical review of the effects of these drugs on the growth and sexual development of children with ADHD leads her to the conclusions that these agents do slow growth shortly after initiation of treatment, but that growth rate increases during prolonged administration, and that adult heights of treated ADHD children are likely to be normal. Atomoxetine is a nonstimulant, selective norepinephrine re-uptake inhibitor that has been efficacious in the treatment of children with ADHD and has not been associated with clinically significant impairment of growth or weight gain during the first 2 years of administration in group analyses [2]. Interestingly, in the study of Spencer et al.[2] those children in the smallest quartiles of height and weight at the beginning of treatment with atomoxetine apparently increased their rates of growth during the first 2 years of its administration. Heights and weights of children less than 9 years of age when starting drug therapy, however, did falter over 2 years of treatment but resumed normal growth patterns with continued treatment.
Individual enzymatic defects in the steroid biosynthesis pathway give rise to distinct clinical and biochemical forms of congenital adrenal hyperplasia (CAH) [3]. There has, however, been a group of subjects with CAH who appeared to have a combination of two enzymatic defects – 17α-hydroxylase/17,20-lyase (P450cl7) and 21-hydroxylase (P450c21). In l986, Dr Walter Miller postulated that this form of CAH might be due to an abnormality in P450 oxidoreductase (POR), an enzyme that donates crucially important electrons to both P450cl7 and P450c21 without which neither enzyme functions well. P450cl7 and P450c21 respectively place hydroxyl groups on carbons number 17 and 21 of the steroid molecular frame. P450cl7 has a second functional domain that removes carbons number 20 and 21 from the steroid structure (17,20-lyase) thereby generating 19-carbon androgens. In 2004, Miller and his associates proved this hypothesis by documenting mutations in POR in patients with apparent combined enzymatic defects. Deficiency of POR is also associated with skeletal defects – including craniosynostosis, radial-humeral synostosis, arachnodactyly, and mid-face hypoplasia. In this issue of Current Opinion in Pediatrics, Fluck and Miller lucidly review the exceptionally broad spectrum of clinical and laboratory findings and POR mutations found in these patients and clearly illustrate the underlying molecular defect in electron transport.
