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Based upon our limited data, we conclude that SDR5B1 gene analysis is required for the accurate diagnosis of 3-oxo-Delta(4)-steroid 5beta-reductase deficiency. Moreover, we think that it is important to elucidate whether there is a heterozygous or a compound heterozygous mutation of the SRD5B1 gene in our two patients.

Only 2 patients with an oxysterol 7a-hydroxylase deficiency caused by mutations of the cytochrome P450 7B1 (CYP7B1) gene have been reported; for both, the outcome was fatal. We describe the clinical and laboratory features, the hepatic and renal histological findings, and the results of bile acid and CYP7B1 gene analyses for a third patient. This Japanese infant presented with progressive cholestatic liver disease and underwent successful heterozygous living donor liver transplantation. Sources of relevant data included medical records, hepatic and renal histopathological findings, gas chromatography/ mass spectrometry analyses of bile acids in serum and urine samples, and analyses of the CYP7B1 gene in the DNA of peripheral blood lymphocytes. Large excesses of 3b-hydroxy-5-cholen-24-oic acid were detected in the patient's serum and urine. Cirrhosis and polycystic changes in the kidneys were documented. The demonstration of compound heterozygous mutations (R112X/R417C) of the CYP7B1 gene led to the diagnosis of an oxysterol 7a-hydroxylase deficiency. After liver transplantation with an allograft from a heterozygous living donor (the patient's mother), the features of decompensated hepatocellular failure abated, and the renal abnormalities were resolved. In conclusion, we report the first Japanese patient with an oxysterol 7a-hydroxylase deficiency associated with compound heterozygous mutations of the CYP7B1 gene; in this patient, liver transplantation with an allograft from a parental donor was effective.

Hypoxic events may play a crucial aetiologic role in the pathogenesis of late-onset neonatal intussusception.

ABSTRACT:We report definitive diagnosis and effective chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum ␥-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3␤-hydroxy-⌬ 5 bile acids were detected by gas chromatography-mass spectrometry. HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patients and their parents identified four novel mutations of the HSD3B7 gene in the patients. One had a homozygous mutation, 314delA; the other had compound heterozygous mutations: V132F, T149I, and 973_974insCCTGC. Interestingly, the second patient's mother had V132F and T149I mutations in one allele. Excessive 3␤-hydroxy-⌬ 5 -bile acids such as 3␤,7␣-dihydroxy-and 3␤,7␣,12␣-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3␤-hydroxy-5-cholenoic acid. Liver dysfunction in both patients decreased with ursodeoxycholic acid treatment, but unusual bile acids were still detected. Normalization of the patients' liver function and improvement of bile acid profiles occurred with CDCA treatment. Thus, we found mutations in the HSD3B7 gene accounting for autosomal recessive neonatal cholestasis caused by 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage. (Pediatr Res 68: 258-263, 2010) D eficiency of 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/ isomerase (3␤-HSD) was first described by Clayton et al. in 1987 (1). This inborn error of bile acid synthesis is very rare and shows autosomal recessive inheritance. The main findings in 3␤-HSD deficiency are low or normal concentrations of total bile acid and normal activity of ␥-glutamyltransferase (GGT) in serum, as well as absence of pruritus despite conjugated hyperbilirubinemia, elevated alanine aminotransferase (ALT), and fatty stools. In the synthesis of bile acids from cholesterol, 3␤-HSD catalyzes the second of a series of reactions leading to excretion of 3␤,7␣-dihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣-diol) and 3␤,7␣,12␣-trihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣,12␣-triol) in the urine. In the first reported patient, complete absence of 3␤-HSD activity was found by Buchmann et al. in 1990 (2) based on the study of cultured fibroblasts. In 2000, Schwarz et al. (3) reported that the same patient had a homozygous mutation representing a 2-bp deletion in exon 6 of the 3␤-HSD gene (HSD3B7) on chromosome 16p11.2-12. The human HSD3B7 gene contains six coding exons and encodes 369 amino acids; so far, 13 distinct mutations causing 3␤-HSD deficiency have been reported (4,5).Here, we report genetic analyses of two Japanese patients with 3␤-HSD deficiency: one previously reported patient (6,7) was diagnosed with 3␤-HSD deficiency by bile acid analysis and the ot...

In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles-R40H, R277W, and Y55D-were identified. In a total of 20 informative parent-offspring pairs, father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, indicating that paternal transmission contributes substantially to the pool of these mutant alleles. Relative reproductive fitness of males and females carrying the mutant alleles was calculated to be 0.49 and 0.89, respectively. Comparison of the life span of the mutant alleles, estimated on the basis of these fitness values with those associated with classic phenotype (neonatal onset) in which reproductive fitness of male patients was nil, revealed that mutant alleles associated with the late-onset phenotype were eliminated more slowly. This would allow the late-onset phenotype mutant alleles to be retained more frequently in a population than those associated with classic phenotype. Although heterozygous females carrying the late-onset phenotype mutant alleles were generally asymptomatic, one female carrying the R40H allele died after a hyperammonemic episode at the age of 18 years. Such heterozygous females should be alerted to possible hyperammonemic crisis.

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