RARE DISEASE
Congenital bile acid synthesis defect type 3
Congenital bile acid synthesis defect type 3
Congenital bile acid synthesis defect type 3
Synonyms: BASD3, Oxysterol 7-alpha-hydroxylase deficiency
Synonyms: BASD3, Oxysterol 7-alpha-hydroxylase deficiency
Synonyms: BASD3, Oxysterol 7-alpha-hydroxylase deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Congenital bile acid synthesis defect type 3 (CBAS3) is a rare autosomal recessive disorder caused by CYP7B1 mutations, disrupting oxysterol 7α-hydroxylase activity. This results in toxic bile acid accumulation, leading to severe neonatal cholestasis, hepatosplenomegaly, coagulopathy, cirrhosis, and progressive liver failure. Diagnosis relies on urine bile acid profiling (sulfated/glycosulfated unsaturated monohydroxy-cholenoic acids) and genetic confirmation. Early mortality is common despite primary bile acid replacement therapy [1][2][3][6][16].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
22 drug discovery papers about Congenital bile acid synthesis defect type 3, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
22 drug discovery papers about Congenital bile acid synthesis defect type 3, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-08-28 | [Congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variation in 2 cases and literature review].
Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.
2022-06-28 | Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing: Case reports.
Congenital bile acid synthesis defect (BASD) is a rare disease caused by mutations in the aldo-keto reductase 1D1 gene, which encodes the primary Δ4-3-oxosteroid 5β-reductase enzyme. Early disease diagnosis is critical for early treatment with bile acid replacement therapy, with an excellent chance for recovery. In contrast, protracted diagnosis and treatment may lead to poor outcomes, including decompensated hepatic cirrhosis, liver transplant, and even death. Three clinical congenital bile acid synthesis defect cases in the Vietnamese population are herein reported. These pediatric patients presented with symptoms of prolonged postpartum jaundice and abnormal loose stool (mucus, lipids, and white). The clinical examinations showed hepatosplenomegaly. Urinalysis showed a very low fraction of primary bile acids and atypical 3-oxo-Δ4- bile acids in all three patients. The patients were diagnosed with primary Δ4-3-oxosteroid 5β-reductase deficiency. Next-generation gene sequencing revealed two homozygous mutations in the aldo-keto reductase family 1 member D1 gene. The first is a documented variant, c.797G>A (p.Arg266Gln), and the second is a novel mutation at c.155T>C (p.Ile52Thr). Immediately after diagnosis, patients were treated with oral chenodeoxycholate 5 mg/kg/d. The patients' symptoms, signs, and primary bile acids levels improved significantly. Clinicians should consider genetic disorders related to cholestasis for effective and life-saving treatment. A prompt genetic analysis by next-generation gene sequencing enables patients to access bile acid replacement therapy earlier, significantly improving short- and long-term outcomes.
2022-04-06 | Successful treatment of an infant with congenital bile acid synthesis disorder type 3 by ursodeoxycholic acid: a case report
Congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency is an extremely rare genetic liver disease. As it may cause rapid progression to end-stage liver disease, a high cautiousness in diagnosis and early treatment are required. Here we describe the first case of congenital bile acid synthesis disorder type 3 in China that was confirmed by genetic analysis.A 5-month-old Chinese male infant suffered skin yellowing since birth. The patient showed significantly increased alanine transaminase, aspartate transaminase, and total and direct bilirubin levels, and enlarged liver at admission. Whole-exome sequencing confirmed homozygous mutation in the CYB7B1 gene that encodes oxysterol 7α-hydroxylase. Ursodeoxycholic acid treatment significantly mitigated the condition of the patient and lowered biochemical indicators. Unfortunately, the patient developed septicemia and gave up treatment.The patient was successfully treated with ursodeoxycholic acid, which has not been reported previously. Ursodeoxycholic acid replacement therapy is an effective and affordable treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency.
2021-11-29 | Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment.
We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21 years between 1996 and 2017. We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency. Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography-mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems. Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. We concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.
2021-06-18 | Open-label Phase 3 Continuation Study of Cholic Acid in Patients With Inborn Errors of Bile Acid Synthesis.
In patients with bile acid synthesis disorders (BASD), impairment in the primary bile acid synthetic pathway leads to reduced primary bile acids, upregulated synthesis of cholesterol, and production and accumulation of hepatotoxic atypical bile acids. Primary bile acid therapy downregulates bile acid synthesis, reduces the production of hepatotoxic intermediates, and produces a functional bile acid pool fostering normal liver function. This phase 3, open-label, single-arm study included patients with BASD who had received cholic acid (10-15 mg · kg · day) as part of a previous study, or were newly diagnosed. Efficacy assessments included urinary atypical bile acids; serum liver chemistries; body weight and height. Efficacy analyses compared baseline with worst postbaseline response (primary) or best postbaseline response (sensitivity). Treatment-emergent adverse events (TEAEs) were summarized. Of 53 total patients (single enzyme defects, n = 41; Zellweger spectrum disorders, n = 12), 22 (42%) were treatment-naïve, and 31 (58%) were on cholic acid from a previous study. Mean age at diagnosis was 55 months, and at present study, baseline was 9 years. Using baseline-to-best postbaseline analyses, statistically significant improvements in urinary bile acids (P = 0.003), height (P < 0.001), and body weight (P < 0.001) were observed. Serum alanine aminotransferase and aspartate aminotransferase levels tended to decrease from baseline in treatment-naïve patients following cholic acid treatment and remained stable in previously treated patients. Treatment-naïve patients improved in all baseline-to-best postbaseline analyses. The most common TEAE was upper respiratory tract infection (17%). Oral cholic acid provides a safe and efficacious short- and long-term therapy for patients with BASD.
gene therapies
2024-04-02 | Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns
Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.
small molecules
2024-08-28 | [Congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variation in 2 cases and literature review].
Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.
2022-06-28 | Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing: Case reports.
Congenital bile acid synthesis defect (BASD) is a rare disease caused by mutations in the aldo-keto reductase 1D1 gene, which encodes the primary Δ4-3-oxosteroid 5β-reductase enzyme. Early disease diagnosis is critical for early treatment with bile acid replacement therapy, with an excellent chance for recovery. In contrast, protracted diagnosis and treatment may lead to poor outcomes, including decompensated hepatic cirrhosis, liver transplant, and even death. Three clinical congenital bile acid synthesis defect cases in the Vietnamese population are herein reported. These pediatric patients presented with symptoms of prolonged postpartum jaundice and abnormal loose stool (mucus, lipids, and white). The clinical examinations showed hepatosplenomegaly. Urinalysis showed a very low fraction of primary bile acids and atypical 3-oxo-Δ4- bile acids in all three patients. The patients were diagnosed with primary Δ4-3-oxosteroid 5β-reductase deficiency. Next-generation gene sequencing revealed two homozygous mutations in the aldo-keto reductase family 1 member D1 gene. The first is a documented variant, c.797G>A (p.Arg266Gln), and the second is a novel mutation at c.155T>C (p.Ile52Thr). Immediately after diagnosis, patients were treated with oral chenodeoxycholate 5 mg/kg/d. The patients' symptoms, signs, and primary bile acids levels improved significantly. Clinicians should consider genetic disorders related to cholestasis for effective and life-saving treatment. A prompt genetic analysis by next-generation gene sequencing enables patients to access bile acid replacement therapy earlier, significantly improving short- and long-term outcomes.
2022-04-06 | Successful treatment of an infant with congenital bile acid synthesis disorder type 3 by ursodeoxycholic acid: a case report
Congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency is an extremely rare genetic liver disease. As it may cause rapid progression to end-stage liver disease, a high cautiousness in diagnosis and early treatment are required. Here we describe the first case of congenital bile acid synthesis disorder type 3 in China that was confirmed by genetic analysis.A 5-month-old Chinese male infant suffered skin yellowing since birth. The patient showed significantly increased alanine transaminase, aspartate transaminase, and total and direct bilirubin levels, and enlarged liver at admission. Whole-exome sequencing confirmed homozygous mutation in the CYB7B1 gene that encodes oxysterol 7α-hydroxylase. Ursodeoxycholic acid treatment significantly mitigated the condition of the patient and lowered biochemical indicators. Unfortunately, the patient developed septicemia and gave up treatment.The patient was successfully treated with ursodeoxycholic acid, which has not been reported previously. Ursodeoxycholic acid replacement therapy is an effective and affordable treatment for congenital bile acid synthesis disorder type 3 caused by oxysterol 7α-hydroxylase deficiency.
2021-11-29 | Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment.
We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3β-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5β-reductase (5β-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21 years between 1996 and 2017. We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3β-HSD deficiency or 5β-reductase deficiency. Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography-mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems. Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. We concluded that CDCA treatment is effective in 3β-HSD deficiency and 5β-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.
2021-06-18 | Open-label Phase 3 Continuation Study of Cholic Acid in Patients With Inborn Errors of Bile Acid Synthesis.
In patients with bile acid synthesis disorders (BASD), impairment in the primary bile acid synthetic pathway leads to reduced primary bile acids, upregulated synthesis of cholesterol, and production and accumulation of hepatotoxic atypical bile acids. Primary bile acid therapy downregulates bile acid synthesis, reduces the production of hepatotoxic intermediates, and produces a functional bile acid pool fostering normal liver function. This phase 3, open-label, single-arm study included patients with BASD who had received cholic acid (10-15 mg · kg · day) as part of a previous study, or were newly diagnosed. Efficacy assessments included urinary atypical bile acids; serum liver chemistries; body weight and height. Efficacy analyses compared baseline with worst postbaseline response (primary) or best postbaseline response (sensitivity). Treatment-emergent adverse events (TEAEs) were summarized. Of 53 total patients (single enzyme defects, n = 41; Zellweger spectrum disorders, n = 12), 22 (42%) were treatment-naïve, and 31 (58%) were on cholic acid from a previous study. Mean age at diagnosis was 55 months, and at present study, baseline was 9 years. Using baseline-to-best postbaseline analyses, statistically significant improvements in urinary bile acids (P = 0.003), height (P < 0.001), and body weight (P < 0.001) were observed. Serum alanine aminotransferase and aspartate aminotransferase levels tended to decrease from baseline in treatment-naïve patients following cholic acid treatment and remained stable in previously treated patients. Treatment-naïve patients improved in all baseline-to-best postbaseline analyses. The most common TEAE was upper respiratory tract infection (17%). Oral cholic acid provides a safe and efficacious short- and long-term therapy for patients with BASD.
gene therapies
2024-04-02 | Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns
Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.
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