RARE DISEASE
Congenital bile acid synthesis defect type 4
Congenital bile acid synthesis defect type 4
Congenital bile acid synthesis defect type 4
Synonyms: 2-methylacyl-CoA racemase deficiency, AMACR deficiency, Alpha-methyl-acyl-CoA racemase deficiency, BASD4, Liver disease-retinitis pigmentosa-polyneuropathy-epilepsy syndrome
Synonyms: 2-methylacyl-CoA racemase deficiency, AMACR deficiency, Alpha-methyl-acyl-CoA racemase deficiency, BASD4, Liver disease-retinitis pigmentosa-polyneuropathy-epilepsy syndrome
Synonyms: 2-methylacyl-CoA racemase deficiency, AMACR deficiency, Alpha-methyl-acyl-CoA racemase deficiency, BASD4, Liver disease-retinitis pigmentosa-polyneuropathy-epilepsy syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Congenital bile acid synthesis defect type 4 (BASD4), caused by AMACR gene mutations, is an autosomal recessive peroxisomal disorder disrupting bile acid synthesis. It manifests variably: infants present with cholestasis, fat-soluble vitamin malabsorption, and failure to thrive, while adults may develop liver dysfunction (e.g., cirrhosis, elevated transaminases) or neurological complications like peripheral neuropathy [1][2][7][12]. Diagnosis involves genetic testing, urine/serum bile acid profiling via mass spectrometry, and clinical evaluation (normal γ-glutamyl transpeptidase levels, low primary bile acids). Early intervention with bile acid replacement therapy (e.g., cholic acid, ursodeoxycholic acid) improves outcomes, though untreated cases risk progressive liver failure [1][2][8][13].
Therapies
Primary bile acid replacement: Cholic acid (FDA-approved) or ursodeoxycholic acid to restore bile flow and suppress toxic intermediates [2][8][13].
Dietary management: Restriction of phytanic/pristanic acids to mitigate neurotoxicity [2][7].
Supportive care: Fat-soluble vitamin supplementation and monitoring for cirrhosis [1][8].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
25 drug discovery papers about Congenital bile acid synthesis defect type 4, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
25 drug discovery papers about Congenital bile acid synthesis defect type 4, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-09-20 | Pediatric Liver Transplant Complications: EBV-Associated Tumors and Infection Management Strategies.
BACKGROUND EBV-associated smooth muscle tumors (EBV-SMTs) are rare malignancies in pediatric transplant recipients under chronic immunosuppression, with fewer than100 cases reported globally. Diagnosis is challenging due to nonspecific imaging findings and overlapping features with other post-transplant malignancies, necessitating histopathological confirmation. This underscores the need for heightened clinical suspicion in high-risk cohorts. CASE REPORT Here, we present a pediatric case from our liver transplant (LT) center involving a patient who developed both post-transplant lymphoproliferative disorder (PTLD) and EBV-SMT following liver transplantation. Clinical data and comprehensive treatment details of this rare case were retrospectively reviewed. The patient, diagnosed with a congenital bile acid synthesis defect, underwent liver transplantation at the age of 5 months. Pre-transplant screening confirmed that both the donor and recipient were negative for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. However, EBV DNA became detectable in peripheral blood at 22.5 months after transplantation and showed a progressive increase over time. At 30.9 months after LT, PTLD and hepatic EBV-SMT were simultaneously diagnosed through histopathological examination. Treatment strategies included stepwise immunosuppression reduction, administration of rituximab targeting PTLD, and subsequent sirolimus therapy for EBV-SMT and surgical resection of the liver and splenic tumor. This multidisciplinary approach successfully achieved complete remission. CONCLUSIONS EBV-SMT necessitates multidisciplinary management balancing immunosuppression with targeted therapies. mTOR inhibitors are a strategic option for concurrent rejection prevention and tumor control. Sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, demonstrates promise by simultaneously preventing rejection and inhibiting tumor progression.
2025-08-26 | Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis.
Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by 'product replacement'. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.
2025-07-11 | Effectiveness and Safety of Personalized Cholic Acid Treatment in Patients With Bile Acid Synthesis Defects.
Bile acid synthesis defects (BASDs) comprise a group of rare, often severe, metabolic disorders. Bile acid replacement therapy decreases toxic bile acid intermediates production and improves biochemical profiles, potentially delaying or stabilizing disease progression. An open label, non-randomized trial with cholic acid (CA) supplementation included six patients with α-methylacyl-CoA racemase (AMACR) deficiency and one patient with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. Patients received up to 20 mg/kg/day CA for 3.5 years, adjusted for biochemical response, side effects, and clinical evaluation. Bile acid metabolites, liver enzymes, liver stiffness, and neurological symptoms were evaluated at baseline and during follow-up. CA was well tolerated in children (n = 3), allowing for higher doses. Adults (n = 4) experienced more side effects, primarily diarrhea and other gastrointestinal symptoms. Children's transaminase levels normalized during treatment, while adults' levels remained normal throughout. Elevated C27-bile acid intermediates, C29-dicarboxylic acid, and pristanic acid were observed in all AMACR patients. C27-bile acids and C29-dicarboxylic acid decreased with treatment, while pristanic acid fluctuated and remained elevated. No clinically relevant changes were observed in liver elasticity, fat-soluble vitamin levels, neurological assessment, or growth (in children). One adult developed hepatocellular carcinoma during treatment. CA treatment is generally safe, with acceptable tolerance and a marked biochemical response observed in children, although biomarker levels remained markedly elevated. In adults, however, the balance shifts negatively, with side effects outweighing the (biochemical) benefits. A longer study is necessary to evaluate the impact of CA treatment on the clinical relevance of the observed biochemical response.
2024-12-20 | The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review.
Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C27-bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients. A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms. From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1-35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders (n = 73), 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 62), cerebrotendinous xanthomatosis (n = 22), Δ4-3-oxosteroid 5β-reductase deficiency (n = 13), and α-methylacyl-CoA racemase deficiency (n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies). More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.
2023-02-26 | Product Validation and Stability Testing of Pharmacy Compounded Cholic Acid Capsules for Dutch Patients with Rare Bile Acid Synthesis Defects
Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25-250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.
small molecules
2025-09-20 | Pediatric Liver Transplant Complications: EBV-Associated Tumors and Infection Management Strategies.
BACKGROUND EBV-associated smooth muscle tumors (EBV-SMTs) are rare malignancies in pediatric transplant recipients under chronic immunosuppression, with fewer than100 cases reported globally. Diagnosis is challenging due to nonspecific imaging findings and overlapping features with other post-transplant malignancies, necessitating histopathological confirmation. This underscores the need for heightened clinical suspicion in high-risk cohorts. CASE REPORT Here, we present a pediatric case from our liver transplant (LT) center involving a patient who developed both post-transplant lymphoproliferative disorder (PTLD) and EBV-SMT following liver transplantation. Clinical data and comprehensive treatment details of this rare case were retrospectively reviewed. The patient, diagnosed with a congenital bile acid synthesis defect, underwent liver transplantation at the age of 5 months. Pre-transplant screening confirmed that both the donor and recipient were negative for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections. However, EBV DNA became detectable in peripheral blood at 22.5 months after transplantation and showed a progressive increase over time. At 30.9 months after LT, PTLD and hepatic EBV-SMT were simultaneously diagnosed through histopathological examination. Treatment strategies included stepwise immunosuppression reduction, administration of rituximab targeting PTLD, and subsequent sirolimus therapy for EBV-SMT and surgical resection of the liver and splenic tumor. This multidisciplinary approach successfully achieved complete remission. CONCLUSIONS EBV-SMT necessitates multidisciplinary management balancing immunosuppression with targeted therapies. mTOR inhibitors are a strategic option for concurrent rejection prevention and tumor control. Sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, demonstrates promise by simultaneously preventing rejection and inhibiting tumor progression.
2025-08-26 | Treatment of Inborn Errors by Product Replacement: The Example of Inborn Errors of Bile Acid Synthesis.
Many inborn errors of metabolism affect pathways involved in the synthesis of a metabolite that has an important biochemical or physiological function, and adverse effects of the disorder can be attributed to the lack of this metabolite. Thus, there is the opportunity for treatment by 'product replacement'. One of the disorders in the pathways for the synthesis of bile acids from cholesterol, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency, causes cholestatic liver disease in infancy that can be treated very effectively with chenodeoxycholic acid (CDCA) and/or cholic acid (CA). There are several other enzyme deficiencies that can cause liver disease in infancy that improve with CDCA or CA or both (alongside a reduction of abnormal bile acids or alcohols); however, individuals with the same gene variant(s) may remain asymptomatic or have transient liver dysfunction that resolves spontaneously. In some disorders, the more usual presentation is with neurological disease later in childhood or in adolescence or adult life, for example, cerebrotendinous xanthomatosis (CTX), α-methylacyl-CoA racemase deficiency, and oxysterol 7α-hydroxylase deficiency. Treatment with CDCA has been dramatically effective in the neurological disease of CTX. In the disorders of peroxisome biogenesis, liver disease is a part of the clinical picture although neurological symptoms tend to be predominant. Treatment with CDCA and CA (or CA alone) leads to a reduction in the levels of C27 bile acids. Some trials suggest this treatment leads to significant improvement in clinical status and liver function tests; others do not. Defects in individual peroxisomal enzymes and transporters vary in their clinical presentations. Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.
2025-07-11 | Effectiveness and Safety of Personalized Cholic Acid Treatment in Patients With Bile Acid Synthesis Defects.
Bile acid synthesis defects (BASDs) comprise a group of rare, often severe, metabolic disorders. Bile acid replacement therapy decreases toxic bile acid intermediates production and improves biochemical profiles, potentially delaying or stabilizing disease progression. An open label, non-randomized trial with cholic acid (CA) supplementation included six patients with α-methylacyl-CoA racemase (AMACR) deficiency and one patient with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. Patients received up to 20 mg/kg/day CA for 3.5 years, adjusted for biochemical response, side effects, and clinical evaluation. Bile acid metabolites, liver enzymes, liver stiffness, and neurological symptoms were evaluated at baseline and during follow-up. CA was well tolerated in children (n = 3), allowing for higher doses. Adults (n = 4) experienced more side effects, primarily diarrhea and other gastrointestinal symptoms. Children's transaminase levels normalized during treatment, while adults' levels remained normal throughout. Elevated C27-bile acid intermediates, C29-dicarboxylic acid, and pristanic acid were observed in all AMACR patients. C27-bile acids and C29-dicarboxylic acid decreased with treatment, while pristanic acid fluctuated and remained elevated. No clinically relevant changes were observed in liver elasticity, fat-soluble vitamin levels, neurological assessment, or growth (in children). One adult developed hepatocellular carcinoma during treatment. CA treatment is generally safe, with acceptable tolerance and a marked biochemical response observed in children, although biomarker levels remained markedly elevated. In adults, however, the balance shifts negatively, with side effects outweighing the (biochemical) benefits. A longer study is necessary to evaluate the impact of CA treatment on the clinical relevance of the observed biochemical response.
2024-12-20 | The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review.
Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C27-bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients. A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms. From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1-35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders (n = 73), 3β-Hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 62), cerebrotendinous xanthomatosis (n = 22), Δ4-3-oxosteroid 5β-reductase deficiency (n = 13), and α-methylacyl-CoA racemase deficiency (n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies). More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.
2023-02-26 | Product Validation and Stability Testing of Pharmacy Compounded Cholic Acid Capsules for Dutch Patients with Rare Bile Acid Synthesis Defects
Bile acid synthesis defects (BASDs) comprise a group of rare diseases that can be severely disabling. Bile acid supplementation with 5 to 15 mg/kg cholic acid (CA) has been hypothesized to decrease endogenous bile acid production, stimulate bile secretion, and improve bile flow and micellar solubilization, thereby improving the biochemical profile and potentially slowing down disease progression. Currently, CA treatment is unavailable in the Netherlands, and CA capsules were compounded by the Amsterdam UMC Pharmacy from CA raw material. This study aims to determine the pharmaceutical quality and stability of the pharmacy compounded CA capsules. Pharmaceutical quality tests were performed on 25 mg and 250 mg CA capsules according to general monographs of the European Pharmacopoeia 10th ed. For the stability study, the capsules were stored under long-term conditions (25 °C ± 2 °C/60% ± 5% RH) and accelerated conditions (40 °C ± 2 °C/75% ± 5% RH). Samples were analyzed at 0, 3, 6, 9 and 12 months. The findings demonstrate that the pharmacy compounded CA capsules within a range of 25-250 mg that complied with the European regulations in regard to product quality and safety. The pharmacy compounded CA capsules are suitable for use in patients with BASD, as clinically indicated. With its simple formulation, pharmacies are provided a guidance on product validation and stability testing when commercial CA capsules are unavailable.
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