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Cases of severely hypercholesterolemic HIV-infected children taking protease inhibitors (PIs) have been reported. Because high cholesterol levels (> or =15 mmol/L), as seen in homozygous familial hypercholesterolemia (FH), may lead to heart disease in childhood, the authors performed a systematic retrospective survey of all plasma lipid levels recorded for children who had received ritonavir or nelfinavir between 1995 and 2001 in Switzerland. Administration of PIs was associated with a significant increase in plasma cholesterol levels, which was more pronounced for those given ritonavir (from 3.3 +/- 0.7 mmol/L, n = 5 to 6.3 +/- 2.8 mmol/L, n = 19 [mean +/- SD]; p =.03) than for nelfinavir (from 3.0 +/- 0.7 mmol/L, n = 11 to 4.9 +/- 1.0 mmol/L, n = 30; p = <.001). Cholesterol levels exceeded 10.0 mmol/L in 3 of 49 (6%) PI-treated children and culminated at 13.8 mmol/L. Plasma cholesterol levels in PI-treated children were comparable with levels reported for heterozygous FH children but were all lower than in homozygous FH children. Because heterozygous FH patients usually develop heart disease in middle age, the authors conclude that the risk for heart disease in PI-treated children is minimal. Long-term monitoring of these children, however, will be necessary.

Background: The epithelial sodium channel (ENaC) is composed of three homologous subunits: alpha, beta, and gamma. Mutations in the Scnn1b and Scnn1g genes, which encode the beta and the gamma subunits of ENaC, cause a severe form of hypertension (Liddle syndrome). The contribution of genetic variants within the Scnn1a gene, which codes for the alpha subunit, has not been investigated., Methods: We screened for mutations in the COOH termini of the alpha and beta subunits of ENaC. Blood from 184 individuals from 31 families participating in a study on the genetics of hypertension were analyzed. Exons 13 of Scnn1a and Scnn1b, which encode the second transmembrane segment and the COOH termini of alpha- and beta-ENaC, respectively, were amplified from pooled DNA samples of members of each family by PCR. Constant denaturant capillary electrophoresis (CDCE) was used to detect mutations in PCR products of the pooled DNA samples., Results: The detection limit of CDCE for ENaC variants was 1%, indicating that all members of any family or up to 100 individuals can be analyzed in one CDCE run. CDCE profiles of the COOH terminus of alpha-ENaC in pooled family members showed that the 31 families belonged to four groups and identified families with genetic variants. Using this approach, we analyzed 31 rather than 184 samples. Individual CDCE analysis of members from families with different pooled CDCE profiles revealed five genotypes containing 1853G-->T and 1987A-->G polymorphisms. The presence of the mutations was confirmed by DNA sequencing. For the COOH terminus of beta-ENaC, only one family showed a different CDCE profile. Two members of this family (n = 5) were heterozygous at 1781C-->T (T594M)., Conclusion: CDCE rapidly detects point mutations in these candidate disease genes.

Background: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect., Objective: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome., Design: Cross-sectional comparison., Setting: University hospital in Lausanne, Switzerland., Participants: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L (> or =89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L (< or =9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated., Measurements: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype., Results: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59]), and hyperinsulinemia (insulin-glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene., Conclusion: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Plasma levels of lipoprotein(a) (Lp(a)), an atherogenic particle, are elevated in kidney disease, which suggests a role of this organ in the metabolism of Lp(a). Additional evidence for a role of the kidney in the clearance of Lp(a) is provided by the fact that circulating N-terminal fragments of apolipoprotein(a) (apo(a)) are processed and eliminated by the renal route. To further understand the mechanism underlying such renal excretion, the levels of apo(a) fragments in plasma and urine relative to plasma Lp(a) levels were determined in patients with nephrotic syndrome (n = 15). In plasma, the absolute (24.7 +/- 20.4 versus 2.16 +/- 2.99 microg/ml, P < 0.0001) as well as the relative amounts of apo(a) fragments (4.6 +/-3.4% versus 2.1 +/- 3.3% of total Lp(a), P < 0.0001) were significantly elevated in nephrotic patients compared with a control, normolipidemic population. In addition, urinary apo(a) excretion in patients with nephrotic syndrome was markedly elevated compared with that in control subjects (578 +/- 622 versus 27.7 +/- 44 ng/ml per mg creatinine, P < 0.001). However, the fractional catabolic rates of apo(a) fragments were similar in both groups (0.68 +/- 0.67% and 0.62 +/- 0.47% in nephrotic and control subjects, respectively), suggesting that increased plasma concentrations of apo(a) fragments in nephrotic subjects are more dependent on the rate of synthesis rather than on the catabolic rate. Molecular analysis of apo(a) immunoreactive material in urine revealed that the patterns of apo(a) fragments in nephrotic patients were distinct from those of control subjects. Full-length apo(a), large N-terminal apo(a) fragments similar in size to those present in plasma, as well as C-terminal fragments of apo(a) were detected in urine from nephrotic patients but not in urine from controls. All of these apo(a) forms were in addition to smaller N-terminal apo(a) fragments present in normal urine. This study also demonstrated the presence of Lp(a) in urine from nephrotic patients by ultracentrifugal fractionation. These data suggest that in nephrotic syndrome, Lp(a) and large fragments of apo(a) are passively filtered by the kidney through the glomerulus, whereas smaller apo(a) fragments are secreted into the urine.