H. D. Bakker

Early statin therapy restores endothelial function in children with familial hypercholesterolemia

OBJECTIVESnThis study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH).nnnBACKGROUNDnEndothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD.nnnMETHODSnThe study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment.nnnRESULTSnAt baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05).nnnCONCLUSIONSnOur data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible.

Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5–12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2 %± 3.4% versus 10.1%±4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% ± 3.4% versus plant sterols: 7.7% ± 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children.

Familial hypercholesterolemia in children.

Purpose of this review This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. Recent findings A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. Summary Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.

Deficiency of the adenine nucleotide translocator in muscle of a patient with myopathy and lactic acidosis: a new mitochondrial defect

ABSTRACT: In a patient with a mitochondrial myopathy, presenting with lactic acidosis, 31P-nuclear magnetic resonance spectroscopy in resting muscle showed half the creatine phosphate level of controls. The creatine phosphate resynthesis rate after aerobic exercise was only 18% of that in controls. However, the activities of complexes I to V catalyzing oxidative phosphorylation and the pyruvate and the 2-oxoglutarate dehydrogenase complexes showed a 2- to 20-fold increase. In line with this, the uncoupled mitochondrial respiration rate was significantly higher than in controls. In contrast, the respiration of the mitochondria from the patient was less stimulated by ADP than that of control mitochondria. This finding could point to a defect in complex V, the enzyme directly involved in ATP synthesis. The activity of complex V, measured as the mitochondrial ATPase activity, and its concentration, as judged from Western blots using antisera against the F1 part of complex V, were, however, also greatly increased in the patient. Alternatively, the transport system, importing ADP into and exporting ATP out of the mitochondrial matrix, the ADP/ATP or adenine nucleotide translocator, could be affected. Immunostaining of Western blots revealed a 4-fold decrease in the concentration of the adenine nucleotide translocator in the patient. Because oxidative phosphorylation was not disturbed in fibroblasts and lymphocytes, we conclude that this patient suffers from a muscle-specific deficiency of his mitochondrial adenine nucleotide translocator, a defect unknown so far.

Clinical and biochemical findings in six patients with pyrimidine degradation defects

Darrow DC (1945) Congenital alkalosis with diarrhea. J Pediatr 26: 519-532. Gamble JL, Fahey KR, Appleton J, MacLachlan E (1945) Congenital alkalosis with diarrhea. J Pediatr 26: 509-518. Groli C (1986) Congenital chloride diarrhea: Antenatal ultrasonographic appearance. J Clin Ultrasound 14: 283-295. Holmberg C, Perheentupa J (1985) Congenital Na diarrhea: A new type of secretory diarrhea. J Pediatr 106: 56-61. Holmberg C, Perheentupa J, Launiala K, Hallman N (1977) Congenital chloride diarrhea; clinical analysis of 21 Finnish patients. Arch Dis Child 52: 255-267. Pasternak A, Perheentupa J, Launiala K, Hallman N (1967) Kidney biopsy findings in familial chloride diarrhea. Acta Endocrinol 55: 1-9. Perheentupa J, Eklund J, Kojo N (1965) Familial chloride diarrhea (congenital alkalosis with diarrhea). Acta Paediatr Scand 159 (supplement): 119-120. Petres RE, Redwine FO (1982) Ultrasound in the intrauterine diagnosis and treatment of fetal abnormalities. Clin Obstet Gynecol 25: 753-771. Yanagisawa M, Obe Y, Yabuta K (1968) A case ofcongenital alkalosis with diarrhea. Paediatr Universit Tokyo 16: 44-47.

Familial mitochondrial DNA depletion in liver: haplotype analysis of candidate genes

Two sons and one daughter of healthy consanguineous parents presented with fatal hepatic failure in association with severe depletion of mitochondrial (mt)DNA in liver; a third son is healthy. Other published cases of mtDNA depletion concern single members of a family, which excludes the use of haplotype analysis. In the family presented here, the inheritance of the genes for mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF-1), mitochondrial single-stranded DNA-binding protein (mtSSBP), and endonuclease G (EndoG) was studied using microsatellite markers linked to these genes. The inheritance of the gene for mtDNA polymerase (pol γ) was studied using a polymorphic CAG repeat present within the coding region of the gene. EndoG and mtSSBP were excluded, but mtTFA remains a candidate. Pol γ or NRF-1 involvement would be compatible only with autosomal dominant inheritance. Coding sequence analysis of NRF-1 and mtTFA revealed no novel mutations in affected individuals.

Vitamin-responsive complex I deficiency in a myopathic patient with increased activity of the terminal respiratory chain and lactic acidosis

SummaryAn 11-year-old gril with exercise intolerance, fatiguability from early childhood, had high blood lactate levels. Histochemistry showed increased activity of succinate dehydrogenase at the periphery of the muscle fibres, whereas aggregates of mitochondria were seen by electron microscopy. Biochemical investigation of isolated mitochondria and homogenate from muscle showed evidence of a severe complex I deficiency. In contrast, succinate dehydrogenase, complex II + III and complex IV were increased in activity. Therapy with biotin, riboflavin, nicotinamide, carnitine and amino acids resulted in an improvement of her endurance.31P NMR spectroscopy of her forearm muscle showed a decreased ratio of phosphocreatine (PCr) over ATP. After exercise the PCr recovery rate was 26% of the average rate in 20 healthy untrained controls. When the therapy was suspended the PCr/ATP ratio at rest decreased from 2.60 to 2.34, and the PCr recovery rate after exercise decreased to 21% of the average control rate. The therapy was reinstituted but only riboflavin and carnitine were given. The PCr/ATP ratio increased to 2.60 and the PCr recovery rate increased to 32% of the control rate. Improvement of the energy metabolism in patients with defects in the oxidative phosphorylation may add to the quality of life;31P NMR spectroscopy can measure these improvements.

The detection of molybdenum cofactor deficiency: Clinical symptomatology and urinary metabolite profile

Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561-570. Mateos FA, Puig JG, Jim6nez ML, Fox IH (1987) Hereditary xanthinuria: evidence for enhanced hypoxanthine salvage. J Clin Invest 79: 847-852. Mizuno T (1986) Long-term follow-up of ten patients with Lesch-Nyhan syndrome. Neuropediatrics 17: 158-161. Page T, Bakay B, Nisinen E, Nyhan WL (1981) Hypoxanthine-guanine phosphoribosyltransferase variants: Correlation of clinical phenotype with enzyme activity. J Inher Metab Dis 4: 203-206. Puig JG, Mateos FA, Jim6nez ML, Areas J, Miranda ME, Ortiz-Vfizquez J (in press) Espectro clinico de la deficiencia de hipoxantina-guanina fosforribosiltransferasa: estudio de 12 pacientes. Med Clin (Bare) Rijksen G, Staal GEJ, Van der Vlist MJM (1981) Partial hypoxanthine-guanine phosphoribosyltransferase deficiency with full expression of the Lesch-Nyhan syndrome. Hum Genet 57: 39-47. Stout JT, Caskey CT (1989) Hypoxanthine phosphoribosyltransferase deficiency: The LeschNyhan syndrome and gouty arthritis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill, 1007-1028.

Combined deficiencies of NADPH- and NADH-dependent dihydropyrimidine dehydrogenases, a new finding in a family with thymine-uraciluria

Dihydropyrimidine dehydrogenase (DHPD, EC 1.3.1.2) catalyses the first step of pyrimidine degradation. Patients suffering from a deficiency of this enzyme present with thymine-uraciluria, which is used for their detection (Van Gennip et al 1993). Clinical symptomatology is not very characteristic. The most frequently occurring symptoms appear to be convulsions and mental retardation, and accordingly most patients were detected by analysis of urinary pyrimidines within a framework of metabolite screening because of a suspected inborn error (Van Gennip et al 1994). The other patients were diagnosed after presenting with neurotoxic symptoms during treatment of their malignancies with 5-fluorouracil (5-FU), which is catabolized via the same pathway as uracil (Diasio et al t988). The mode of inheritance of DHPD deficiency is autosomal recessive. The gene frequency is not known but, based on the Dutch experience (13 patients within a decade), must be rather high. This observation together with the frequent use of 5-FU in chemotherapeutic drug regimens contribute significantly to the clinical relevance of the defect. DHPD activity can be measured in many cells and tissues, such as lymphocytes, monocytes, fibroblasts and liver. The DHPD enzyme in human tissues is known to be dependent on NADH as a co-substrate. However, we discovered recently that NADHdependent activity can also be measured in human liver, fibroblasts and leukocytes (Van Kuilenburg et al, unpublished). It is not known whether the deficiency of the enzyme is equally expressed in the tissues mentioned and whether both the NADPHdependent and NADH-dependent activities of DHPD are involved. Carrier detection of DHPD deficiency by analysis of enzyme activity in leukocytes and fibroblasts seems not to be reliable. However, the enzyme activity shows a

Steady-State Pharmacokinetics of Pravastatin in Children with Familial Hypercholesterolaemia

AbstractObjective: To determine pharmacokinetic data for pravastatin in children, since current data are insufficient in this age group.n Subjects and methods: A 2-week, multiple-dose, steady-state pharmacokinetic study was carried out with pravastatin 20mg daily in 24 children with familial hypercholesterolaemia (aged 8–16 years; 12 prepubertal, 12 pubertal). A plasma concentration-time curve was performed on day 14. Pharmacokinetic curves for each individual were constructed using nonparametric methods, yielding area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax) and half-life (t1/2). Clearance values and volumes of distribution were calculated from these parameters. Cholesterol lowering was observed on day 14 and 6 weeks after the start of pravastatin.n Results: The Cmax in prepubertal (group A) children (52.1 ± 27.0 μ/L [mean ±SD]) differed, although not significantly (p = 0.09, unpaired two-tailed t-test), from the Cmax in adolescents (group B) [31.7 ± 29.2 μ/L]. There was a moderate negative correlation between Cmax and age (Spearman correlation r = −0.42; p = 0.04). The AUC in prepubertal children (91.3 ± 39.7 μ ⋅ h/L) did not differ significantly from the AUC in adolescents (69.3 ± 57.0 μ ⋅ h/L). The t1/2 was the same for the two groups: 2.5 ± 1.1h. Clearance values (CL/f) varied widely between the two groups (group A: 4.3 ± 1.8 L/min; group B: 11.0 ± 11.9 L/min; p = 0.08). A moderate positive correlation was found between clearance and age (Spearman correlation r = 0.36; p = 0.09). A large variation was found in the volumes of distribution within the two groups (group A: 31.2 mL/kg [SD 26.7], group B:37.0 mL/kg [SD 29.6]; p = 0.12). A very weak positive correlation was found between age and volume of distribution (Spearman correlation r = 0.11; p = 0.61). A 27% low-density lipoprotein-cholesterol reduction from baseline was achieved at day 14.n Conclusions: Body surface area and gender did not influence the pharmacokinetics of pravastatin in children aged 8–16 years. On the basis of our findings there are no reasons to use pravastatin at a dosage according to bodyweight or to use different dosage regimens from those in adults. However, for prepubertal children half the advised starting dose for adults may be sufficient.