Molecular genetic and bile acid profiles in two Japanese patients with 3beta-hydroxy-DELTA5-C27-steroid dehydrogenase/isomerase deficiency.
We report definitive diagnosis and effective chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3[beta]-hydroxy-[DELTA]5-C27-steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum [gamma]-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3[beta]-hydroxy-[DELTA]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[beta]-hydroxy-[DELTA]5-bile acids such as 3[beta],7[alpha]-dihydroxy- and 3[beta],7[alpha],12[alpha]-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3[beta]-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[beta]-hydroxy-[DELTA]5-C27-steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage.
Mizuochi
Tatsuki
T
Department of Pediatrics and Child Health, Division of Gene Therapy and Regenerative Medicine, Kurume University School of Medicine, Kurume, Japan.
Kimura
Akihiko
A
Ueki
Isao
I
Takahashi
Tomoyuki
T
Hashimoto
Takuji
T
Takao
Akira
A
Seki
Yoshitaka
Y
Takei
Hajime
H
Nittono
Hiroshi
H
Kurosawa
Takao
T
Matsuishi
Toyojiro
T
D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency* / Q000235:genetics*; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000652:urine*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D002779:Cholestasis / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D017931:DNA Primers / Q000235:genetics; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology*; D007564:Japan; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA
D001647:Bile Acids and Salts; D017931:DNA Primers; D002635:Chenodeoxycholic Acid; D015096:3-Hydroxysteroid Dehydrogenases; C066485:3 beta-hydroxy-delta 5-C(27)-steroid dehydrogenase