Don C Van Dyke

Role of Medical Conditions in the Exacerbation of Self-Injurious Behavior: An Exploratory Study.

Self-injurious behavior (SIB) is common among people with severe mental retardation who may also have multiple complex medical problems coupled with communication difficulties. This combination of factors sometimes makes it difficult to obtain accurate and detailed medical histories. In this exploratory descriptive study of 25 patients with SIB, 28% had previously undiagnosed medical conditions that could be expected to cause pain or discomfort. Six of the 7 patients experienced decreased SIB with treatment of their medical conditions. In patients with SIB, impaired communication skills, and complex medical histories, medical conditions that may be associated with pain or discomfort must be a consideration in determining the etiology of the SIB.

Phenytoin-Folic Acid Interaction

Objective: To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. Data Sources: Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references. Study Selection: All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction. Data Extraction: Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events. Data Synthesis: Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cofactor in phenytoin metabolism and may be responsible for the “pseudo-steady-state,” which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner. Conclusions: Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes Part I: Antiepileptic Drugs, Contraceptives, Smoking, and Folate

OBJECTIVE: Part I of this review examines the relationship between antiepileptic drugs (AEDs) and pregnancy outcomes. Drug-induced folate deficiency and the role of AED metabolism are emphasized. Part II will discuss periconceptional folate supplementation for prevention of birth defects. Part III will discuss the mechanism of folates protective effect, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted for journal articles published through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included phenytoin, carbamazepine, phenobarbital, primidone, valproic acid, oral contraceptives, clomiphene, drug-induced abnormalities, spina bifida, anencephaly, neural tube defect, folate, folic acid, and folic acid deficiency. STUDY SELECTION: Relevant animal and human studies examining the effects of AEDs, smoking, and oral contraceptives on folate status and pregnancy outcome are reviewed. DATA EXTRACTION: Studies and case reports were interpreted. Data extracted included dosing, serum and red blood cell folate concentrations, teratogenicity of anticonvulsant medications, metabolism of AEDs and folate, and genetic susceptibility to AED-induced teratogenicity. DATA SYNTHESIS: Low serum and red blood cell folate concentrations are associated with adverse pregnancy outcomes. Decreases in serum folate are seen with AEDs, oral contraceptives, and smoking. Since similar birth defects are observed with multiple AEDs, metabolism of aromatic AEDs to epoxide metabolites and genetic factors may play a role in teratogenesis. CONCLUSIONS: Adequate prepregnancy planning is essential for women who have epilepsy. Women receiving folate-lowering drugs may be at increased risk of adverse pregnancy outcomes. Therefore, epileptic women contemplating pregnancy should be treated with the minimum number of folate-lowering drugs possible and receive folic acid supplementation.

Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes Part II: Improvement with Folic Acid

OBJECTIVE: To provide a comprehensive review of periconceptional folic acid supplementation and factors affecting folate supplementation trials. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, spina bifida, and anencephaly. STUDY SELECTION: Relevant animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included: type of study, folate dosing, dietary folate intake, serum and red blood cell folate concentrations, type of defect(s) studied, vitamin usage, parental risk factors, factors affecting trial results. DATA SYNTHESIS: Nine key factors have been identified that affect outcomes of folic acid supplementation trials. Daily doses of 0.8 mg decreased the occurrence and doses of 4 mg decreased the recurrence of neural tube defects in randomized clinical trials. Since lower folic acid doses were effective in nonrandomized trials, research is needed to determine the lowest effective dosage. Other benefits involving pregnancy outcome are suggested. CONCLUSIONS: Women of childbearing age should take a daily folic acid supplement to reduce the risk of pregnancies resulting in infants with a neural tube defect and other potential adverse pregnancy outcomes. Further health benefits from folic acid supplementation are reviewed in Part III of this series.

Folic acid and prevention of birth defects

Don C Van Dyke* MD, Professor of Pediatrics, Divisions of Developmental Disabilities and Medical Genetics, The Children’s Hospital of Iowa; Phyllis J Stumbo RD LD PhD, Assistant Research Scientist, Clinical Research Center, The University of Iowa Hospitals and Clinics; Mary J Berg PharmD, Professor, College of Pharmacy, The University of Iowa; Jennifer R Niebyl MD, Professor, Director, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA.

Pharmacogenetic Screening for Susceptibility to Fetal Malformations in Women

OBJECTIVE: To present a review of the literature and research on the pharmacogenetics of congenital defects, with a focus on the need for predictive maternal genotype assays. DATA SOURCE: MEDLINE searches (January 1985–January 1999), past reference reviews, and unpublished research. STUDY SELECTION: Review of relevant human, animal, and basic science studies. DATA EXTRACTION: Data on research on polymorphisms, genotyping, cytochrome P450 enzyme systems, epoxide hydrolase, folate metabolism, metabolism of anticonvulsant medications, molecular genetics of neural tube defects, variations in drug metabolism, and environmental exposures were evaluated. DATA SYNTHESIS: Data synthesis includes not only a review of the literature but suggests ways such data might be used to facilitate the development of maternal genotype assays, with the goal of preventing birth defects. CONCLUSIONS: Individuals vary in how they metabolize drugs and handle toxic environmental exposures. In an ideal pregnancy, there is no or limited exposure to medications and environmental agents. However, in women with chronic medical conditions such as heart disease and seizures, this is often not possible. Unfortunately, no techniques have been available to identify those at risk in this population. Gene polymorphisms for a specific enzyme may result in an absence or reduction in the level of enzyme activity or in no change at all, with little effect on the structure/function of the gene product(s); they are not associated with clinical phenotypes in either the mother or the fetus. Other polymorphisms may be only markers. Thus, developing genotyping assays for women that are predictive of phenotype expression in the fetus is the key to screening for polymorphisms. As more mutations are identified and clinical, pharmacologic, biologic, and pharmacokinetic relationships are established, using these polymorphisms to develop a genotyping assay for women may become a clinical reality, possibly leading to preventive prepregnancy or prenatal treatment that may play an increasingly effective role in maternal care.

Drug and Environmental Factors Associated with Adverse Pregnancy Outcomes Part III: Folic Acid: Pharmacology, Therapeutic Recommendations, and Economics:

OBJECTIVE: To review folic acids mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine–homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 μg of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 μg/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.

Autistic disorder associated with an iso-dicentric Y chromosome.

The relationship between a fragile site on the X chromosome and autism has been well documented. The authors report a three‐year‐old child with partial duplication of the short arm of chromosome Y, who had an autistic disorder. He was microcephalic, but otherwise had a normal phenotype. There was a history of preterm birth and maternal diabetes. This is the sixth case of sex chromosome Y aneuploidy associated with autism, but the first with an isodicentric Y. In well‐substantiated cases of autism, clinicians should now consider abnormalities of the Y as well as the X chromosome.

Differences in Phenytoin Biotransformation and Susceptibility to Congenital Malformations: A Review

The clinical variability of teratogenic response to fetal drug exposure has been well documented. Metabolic differences in biotransformation have been shown to extend to multiple drugs and may involve many steps in drug metabolism with alterations of key intermediates. Although metabolic differences have been reported to be associated with complications of medication use, it has only recently been appreciated that such differences also may be associated in the unborn with the potential for the disruption of normal embryologic development and the production of congenital malformations. It has long been suspected that the teratogenicity of phenytoin may be mediated not only by the parent compound, but also by toxic intermediary metabolites that are produced during the biotransformation of the parent compound. Recent work elucidating differences in isoenzyme forms of cytochrome P-450 enzyme systems, glutathione, and microsomal epoxide hydrolase has provided increased interest in the multiple individual pharmacogenetic differences that may be significant factors affecting increased susceptibility to birth defects in individuals and families with fetal exposure to phenytoin.

Is air-displacement plethysmography a reliable method of detecting ongoing changes in percent body fat within obese children involved in a weight management program?

SUMMARY BACKGROUND The prevalence of childhood obesity in the US has increased considerably over the last few decades and continues to increase. To monitor the progress of patients enrolled in weight management programs, clinicians need accurate methods of detecting changes in body composition (percent body fat) over time. The gold standard method, hydrodensitometry, has severe limitations for the pediatric population. OBJECTIVE This study examines the reliability of air-displacement plethysmography (ADP) in detecting percent body fat changes within obese children over time. METHODS Percent body fat by ADP, weight, and body mass index (BMI) were measured for eight obese children aged 5-12 years enrolled in a weight management program over a 12-month period. These measurements were taken at initial evaluation, 1.5 months, 3 months, 6 months, and 12 months to monitor the progress of the subjects and detect any changes in these measures over time. Statistical analysis was used to determine the reliability of the data collected. RESULTS The reliability estimate for percent body fat by ADP was 0.78. This was much lower than the reliability of BMI, 0.98, and weight measurements, 0.99. The low reliability estimate of ADP indicates a large standard error of measurement by this method. CONCLUSION The measurement error of ADP is large, and in our study, ADP measured changes in percent body fat that far exceeded levels of true change that would have been clinically useful and important to detect. Hence, this method yielded change measures that did not allow meaningful clinical interpretations and often did not reflect true differences in status across time. ADP is not a reliable method for detecting changes in percent body fat over the time intervals employed within this study of obese children.