Aranka László

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency

Hepatocellular carcinoma (HCC) is rare in young children. We attempted to see if immunohistochemical and mutational‐analysis studies could demonstrate that deficiency of the canalicular bile acid transporter bile salt export pump (BSEP) and mutation in ABCB11, encoding BSEP, underlay progressive familial intrahepatic cholestasis (PFIC)—or “neonatal hepatitis” suggesting PFIC—that was associated with HCC in young children. We studied 11 cases of pediatric HCC in the setting of PFIC or “neonatal hepatitis” suggesting PFIC. Archival liver were retrieved and immunostained for BSEP. Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents. Among the 11 nonrelated children studied aged 13‐52 months at diagnosis of HCC, 9 (and a full sibling, with neonatal hepatitis suggesting PFIC, of a tenth from whom liver was not available) had immunohistochemical evidence of BSEP deficiency; the eleventh child did not. Mutations in ABCB11 were demonstrated in all patients with BSEP deficiency in whom leukocyte DNA could be studied (n = 7). These mutations were confirmed in the parents (n = 14). With respect to the other 3 children with BSEP deficiency, mutations in ABCB11 were demonstrated in all 5 parents in whom leukocyte DNA could be studied. Thirteen different mutations were found. In conclusion, PFIC associated with BSEP deficiency represents a previously unrecognized risk for HCC in young children. Immunohistochemical evidence of BSEP deficiency correlates well with demonstrable mutation in ABCB11. (HEPATOLOGY 2006;44:478–486.)

Antioxidant enzyme activities are decreased in preterm infants and in neonates born via caesarean section

OBJECTIVES To investigate the antioxidant defense potential of human neonates according to gestational age and mode of delivery. STUDY DESIGN Four study groups were established, full-term normal spontaneous vaginal delivery (FT-NSVD, n=24), full-term caesarean section (FT-CS, n=19), preterm normal spontaneous vaginal delivery (PT-NSVD, n=15) preterm caesarean section (PT-CS, n=21). The activity of catalase (CAT), glutathion peroxidase (GPX), Cu/Zn superoxide dismutase (Cu/Zn-SOD) were determined from cord blood. Statistical analysis was made by ANOVA. RESULTS CAT activity was significantly higher in full-term than in preterm newborns. In both the categories, neonates born via caesarean section had significantly lower CAT activities. GPX activity was significantly higher in the FT-NSVD group than in any other group. Cu/Zn-SOD activity was significantly higher in full-term neonates than in preterms and no difference was found related to the mode of delivery. CONCLUSIONS Prematurity and caesarean section may cause a deficiency of antioxidant defense in human newborn.

Altered peroxide metabolism in erythrocytes from children with cystic fibrosis

The superoxide dismutase and catalase activities and the lipid peroxidation values in the blood of healthy volunteers were compared with those of children of various ages and of both sexes with cystic fibrosis and with those of the heterozygous parents of these children. The red blood cell superoxide dismutase and catalase activities in children with cystic fibrosis and in their parents are significantly increased. At the same time, the lipid peroxidation of the red blood cells (the quantity of thiobarbituric acid reactive substance) is significantly reduced.

Diversity of cystathionine β‐synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta‐synthase (CBS) gene represents the most common cause of pyridoxine‐responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (qc.833C ≊ 3.3 × 10–3), is ∼20‐fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (qc.833C ≊ 0.18 × 10–3), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68‐bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C‐bearing chromosomes and to determine whether the pathogenic c.[833C; −] chromosomes are identical‐by‐descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub‐Saharan African wild‐type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; −] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild‐type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; −] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates. Hum Mutat 28(3), 255–264, 2007. Published 2006 Wiley‐Liss, Inc.

Molecular Genetic Diagnostic Difficulties in Two Hungarian Gypsy Samples with Cystic Fibrosis

Abstract The frequency of ΔF508 mutation in the CFTR gene was compared in Gypsy and European samples from 3 different geographical regions of Hungary. The frequency of ΔF508 mutation in a total of 21 Gypsy patients was 43%, with 0.144 homozygosity index. This frequency was 50% with 0.127 homozygosity index in a total of 531 European Hungarian patients. Among the Gypsy patients 52 % had unknown mutations, but not the G542X, G551D, R553X and N1303K ones. However, there was a geographical difference in the distribution of homozygous ΔF508 mutations. In the two Gypsy samples of 13 Gipsy patients from North-East Hungary, only one possessed ΔF508 homozygote genotype, while all 7 Gypsy patients harboured this genotype from South-West Hungary. The difference in the occurrence of this mutation between the two geographically different Hungarian Gypsy samples can be explained by their different gene pools connected with their previous and present location, genetic drift and their isolation from each other. These findings need to be considered when planning any population screening programme for CF.