Congenital Bile Acid Synthesis Defect 5

Mendelian MONDO:0014564 Pathograph 28 Show in embeddings browser Peroxisomal Disease Inborn Error of Metabolism Cholestasis

Congenital bile acid synthesis defect 5 (CBAS5) is an autosomal recessive disorder caused by biallelic loss-of-function variants in ABCD3, which encodes the peroxisomal membrane ABC half-transporter PMP70. ABCD3 carries the CoA thioesters of 2-methyl branched-chain fatty acids and of the C27 bile acid intermediates dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA) from the cytosol into the peroxisomal matrix, where side-chain beta-oxidation shortens them to the mature C24 primary bile acids. The lesion is therefore a transport failure, not an enzyme failure: the peroxisome is assembled and import-competent, and the enzymes of the beta-oxidation spiral are present and active, but their substrates never reach them. The block is selective. Peroxisomal beta-oxidation of the very-long-chain fatty acid C26:0 and the first committed enzyme of ether-phospholipid synthesis were both normal in the index patient's fibroblasts, so this is not the generalized two-sided peroxisomal lesion of the biogenesis disorders; what fails is the branched-chain and C27-bile-acid substream, and it is the bile acid arm that produces the disease. Clinically that arm presents as a cholestatic liver disease of infancy and early childhood - hepatosplenomegaly, jaundice, elevated transaminases and raised serum bile acids with a normal gamma-glutamyltransferase - which progresses to hepatic fibrosis and cirrhosis. The index patient reached decompensated cirrhosis and was transplanted at four years of age. A second, independently reported child carried compound heterozygous ABCD3 variants and the same low-GGT cholestatic-fibrotic pattern, so the entity rests on two families.

Ask OpenScientist

Ask a research question about Congenital Bile Acid Synthesis Defect 5. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

3
Mappings
1
Inheritance
9
Pathophys.
13
Phenotypes
3
Gaps
28
Pathograph
1
Genes
2
Variants
3
Medical Actions
5
Differentials
1
Models
7
References
1
Deep Research
🏷

Classifications

Harrison's Part
GASTROINTESTINAL ENDOCRINOLOGY METABOLISM
🔗

Mappings

MONDO
MONDO:0018841 congenital bile acid synthesis defect Not Yet Curated
skos:broadMatch MONDO
One of the two parents MONDO asserts for MONDO:0014564. Recorded as broadMatch, not exactMatch: it is the clinical/biochemical family this disease belongs to, and the name this entry is filed under, but it is a broader concept covering four other gene-specific defects. Recording it here keeps the dual parentage machine-readable without asserting identity.
MONDO:0100372 disorder of peroxisomal transporter Not Yet Curated
skos:broadMatch MONDO
The second parent MONDO asserts for MONDO:0014564, and the one that names the actual lesion. Recorded as broadMatch because it is a broader class that also contains the other peroxisomal ABC transporter defects, including the ABCD1 disorder. See `notes` for why the pathophysiology chain in this entry is built on this parent rather than the other.
ICD-10-CM
ICD10CM:E71.548 Other peroxisomal disorders
skos:broadMatch dismech curation
ICD-10-CM has no code for CBAS5. E71.548 is the residual peroxisomal-disorder code and is the closest coded home for the lesion this entry models; it is a broader residual category rather than a cross-reference asserted by any source, and is not taken from a MONDO or Orphanet xref.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic ABCD3 variants. The index patient was homozygous for a 1758 bp genomic deletion, born to consanguineous parents, with both parents confirmed carriers; the second reported child was compound heterozygous for two previously unreported variants. Penetrance and expressivity are recorded as UNKNOWN rather than complete and consistent: with two reported families there is no unaffected biallelic carrier to argue from and no phenotypic range to characterise, so any stronger statement would be an inference from an n of two rather than an observation.
Autosomal recessive inheritance Penetrance: UNKNOWN Expressivity: UNKNOWN
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
Establishes the homozygous biallelic genotype in the index patient.
PMID:41179737 SUPPORT Human Clinical
"Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
A second, independent biallelic genotype - compound heterozygous rather than homozygous - in a child with cholestatic liver disease.
?

Discussions and Knowledge Gaps

3
Does oral primary bile acid replacement alter the course of ABCD3 deficiency, as it does in the enzyme-defect bile acid synthesis disorders?
KNOWLEDGE GAP OPEN cbas5-primary-bile-acid-replacement
Attached to
treatments# pathophysiology#Accumulation of C27 Bile Acid Intermediates
The mechanistic case is straightforward and unproven. Replacing the missing primary bile acids restores the FXR-mediated feedback that suppresses CYP7A1, which should reduce flux into the pathway and so reduce production of the C27 intermediates that accumulate. That argument is generic to the bile acid synthesis defects and does not depend on where the block sits, so it applies to a transport lesion as readily as to an enzyme lesion. What is missing is any reported use in ABCD3 deficiency: the index patient received ursodeoxycholic acid rather than a primary bile acid and progressed to transplantation, and no treatment was reported for the second child. Evidence that primary bile acid supplementation lowers these intermediates exists for the peroxisome biogenesis disorders, which is a different lesion in the same pathway.
Show evidence (1 reference)
PMID:36511274 SUPPORT INDIRECT Human Clinical
"In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness."
Supports the premise of the open question - that primary bile acid supplementation lowers these intermediates - in Zellweger spectrum disorder, not in ABCD3 deficiency. Marked INDIRECT because carrying it across to this disease requires the inference that the feedback argument is lesion-independent, which is exactly what is unproven.
Does the branched-chain fatty acid arm of ABCD3 deficiency ever become clinically manifest, for example with age, with a phytanic-acid-rich diet, or in a patient who survives the liver disease?
OPEN QUESTION OPEN cbas5-branched-chain-arm-is-clinically-silent
Attached to
pathophysiology#Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
ABCD3 imports branched-chain acyl-CoA esters as well as the C27 bile acid intermediates, and the biochemical defect in that arm is demonstrable: pristanic acid beta-oxidation was reduced in the index patient's fibroblasts, and the knockout mouse accumulates phytanic acid when phytol-loaded. Yet the index patient's plasma phytanic and pristanic acid concentrations were within the reference range and she had no neurological phenotype, dying of liver disease at four. Whether that is because the arm is metabolically well compensated, because dietary phytol intake in a young child is low, or simply because neither reported patient lived long enough or was old enough for it to declare, cannot be settled from two patients.
Show evidence (1 reference)
PMID:25168382 SUPPORT Model Organism
"Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
Shows that the branched-chain arm is a real substrate deficit that a dietary load can unmask, which is what makes the human question live.
By what cellular route do retained C27 bile acid intermediates produce hepatic fibrosis in ABCD3 deficiency?
KNOWLEDGE GAP OPEN cbas5-fibrogenic-mechanism-unresolved
Attached to
pathophysiology#Progressive Hepatic Fibrosis and Cirrhosis
Fibrosis is the outcome that determines the prognosis, and its cellular mechanism has not been studied in this disease. The index patient's biopsy is informative as a negative: the interlobular bile ducts were normal and there was no ductular reaction, with pericellular and portal fibrosis instead - a hepatocyte-centred rather than cholangiocyte-driven pattern, and the opposite of what the classic cholangiopathies show. Whether hepatic stellate cells are activated, and by what signal from the injured hepatocyte, is unmeasured; the knockout mouse has not been reported to develop fibrosis, so there is no model result to fall back on either.
⚙

Pathophysiology

9
ABCD3 Loss of Function
Biallelic loss-of-function ABCD3 variants remove PMP70 from the peroxisomal membrane. In the index patient's fibroblasts, immunofluorescence and immunoblot showed loss of the transporter while ABCD1 and PEX14 were present, and the peroxisomes themselves were fewer and enlarged but still competent to import matrix protein. This node enters the peroxisomal module by its transporter arm: the organelle is assembled, and it is one substrate route into it that is lost.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Homozygous in the index patient; the second reported child was compound heterozygous, so the zygosity recorded here is that of the better-characterised genotype rather than a property of the disease.
peroxisome number and size are abnormal, while matrix import is preserved GO:0007031 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal peroxisome number and size are abnormal, while matrix import is preserved, annotated with peroxisome organization (GO:0007031). GO:0007031 is a biological process from the Gene Ontology. ⚠ ABNORMAL
peroxisomal ABC-type acyl-CoA transporter activity (PMP70/ABCD3) GO:0015607 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves peroxisomal ABC-type acyl-CoA transporter activity (PMP70/ABCD3), annotated with ABC-type fatty-acyl-CoA transporter activity (GO:0015607), qualified as loss of function. GO:0015607 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
peroxisomal membrane GO:0005778 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisomal membrane (GO:0005778). GO:0005778 is a cellular component from the Gene Ontology.
Downstream
Failure of Peroxisomal Import of C27 Bile Acid and Branched-Chain Acyl-CoA Esters Loss of the transporter removes the route by which its substrates cross the peroxisomal membrane.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
Establishes that the organelle is present and import-competent, which is what separates this lesion from a peroxisome biogenesis defect.
Failure of Peroxisomal Import of C27 Bile Acid and Branched-Chain Acyl-CoA Esters
The CoA thioesters of DHCA and THCA, and of 2-methyl branched-chain fatty acids such as pristanic acid, are no longer delivered into the peroxisomal matrix. The failure is substrate-selective: beta-oxidation of the very-long-chain fatty acid C26:0 was normal in the index patient's fibroblasts, so the straight-chain very-long-chain route into the organelle is not the one that is lost.
import of acyl-CoA esters into the peroxisomal matrix GO:0015916 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased import of acyl-CoA esters into the peroxisomal matrix, annotated with fatty-acyl-CoA transport (GO:0015916). GO:0015916 is a biological process from the Gene Ontology. ↓ DECREASED
peroxisomal matrix GO:0005782 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves peroxisomal matrix (GO:0005782). GO:0005782 is a cellular component from the Gene Ontology.
Downstream
Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates The beta-oxidation enzymes that shorten the C27 side chain are inside the matrix, so an import failure is functionally equivalent to a block of the pathway they carry.
Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids The same import failure withdraws pristanoyl-CoA from the branched-chain beta-oxidation spiral.
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced."
The functional signature of a selective import failure in patient fibroblasts: branched-chain substrate handling is impaired while straight-chain very-long-chain handling is not.
PMID:39223112 SUPPORT In Vitro
"The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly."
Structural work assigning branched-chain acyl-CoA import specifically to ABCD3 and linking its dysfunction to liver disease.
Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates
Bile acid synthesis is completed inside the peroxisome: the C27 intermediates DHCA and THCA must be shortened by beta-oxidation to the C24 primary bile acids. With their import blocked, that terminal step cannot run, and the pathway fails in both directions at once - substrate backs up and product is not made.
peroxisomal side-chain beta-oxidation of C27 bile acid intermediates GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peroxisomal side-chain beta-oxidation of C27 bile acid intermediates, annotated with fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED bile acid biosynthetic process GO:0006699 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bile acid biosynthetic process (GO:0006699). GO:0006699 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Abcd3 knockout (Abcd3-/-) Mouse Mouse recapitulates The knockout reproduces the two-sided biochemical signature of the blocked step in the tissues where bile acids are made and secreted.
Downstream
Accumulation of C27 Bile Acid Intermediates The unmetabolised substrates accumulate in plasma and tissue.
Deficient Formation of Mature C24 Primary Bile Acids The product of the blocked step is not made.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis"
The authors' own conclusion placing the ABCD3 transport step inside the bile acid synthetic pathway.
Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
Pristanic acid beta-oxidation was reduced to 59 percent of control activity in the index patient's fibroblasts, and Abcd3 knockout mice accumulate phytanic acid when phytol-loaded. This arm is biochemically real but was clinically silent in the index patient, whose plasma phytanic and pristanic acid concentrations were within the reference range; no branched-chain-fatty-acid phenotype is recorded for this disease, which is why the node is a branch and not part of the chain to the clinical manifestations.
branched-chain fatty acid beta-oxidation GO:0006635 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased branched-chain fatty acid beta-oxidation, annotated with fatty acid beta-oxidation (GO:0006635). GO:0006635 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Abcd3 knockout (Abcd3-/-) Mouse Mouse recapitulates Phytol loading unmasks the branched-chain arm in the knockout, producing the phytanic acid accumulation that the index patient did not have on an ordinary diet.
Show evidence (1 reference)
PMID:25168382 SUPPORT Model Organism
"Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
The branched-chain arm demonstrated in the knockout mouse under phytol challenge. Graded MODEL_ORGANISM because this specific result is the mouse experiment.
Accumulation of C27 Bile Acid Intermediates
DHCA and THCA accumulate to concentrations far above the reference range - in the index patient they were the striking abnormality of the plasma bile acid profile, and in Abcd3 knockout mice they rose in liver, bile and intestine. C27 intermediates are the species held responsible for hepatocellular injury across the bile acid synthesis defects.
Downstream
Hepatocellular Injury and Cholestasis Retained C27 intermediates are the injurious species; the link is the same one invoked across the bile acid synthesis defects rather than a mechanism dissected in an ABCD3-deficient liver.
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
The accumulation measured in the index patient's plasma.
PMID:36511274 SUPPORT Human Clinical
"In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
A clinical mass-spectrometry study that treats DHCA/THCA accumulation as the characteristic metabolite abnormality of ABCD3 deficiency.
Deficient Formation of Mature C24 Primary Bile Acids
The product side of the block. This is demonstrated in the mouse, where C24 bile acids fell as the C27 intermediates rose. It is deliberately not asserted for the index patient, whose plasma cholic and chenodeoxycholic acid concentrations were above, not below, the reference range while she was receiving ursodeoxycholic acid - so the human plasma profile does not show a C24 deficit and should not be read as though it did.
Downstream
Hepatocellular Injury and Cholestasis Loss of the mature bile acid pool removes the principal osmotic driver of bile flow. Inferred from bile acid physiology; not separately measured in an ABCD3-deficient patient.
Show evidence (1 reference)
PMID:25168382 SUPPORT Model Organism
"analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice"
The C24 deficit as measured in Abcd3 knockout mouse tissue. Graded MODEL_ORGANISM because the reduction was measured in the mouse and not in the patient.
Hepatocellular Injury and Cholestasis
Cholestatic hepatocellular injury with a normal gamma-glutamyltransferase. Both reported children had raised transaminases, raised serum bile acids and conjugated hyperbilirubinaemia with a normal GGT; the index patient's liver biopsy showed minimal intracanalicular and intracytoplasmic cholestasis with normal interlobular bile ducts and no ductular reaction.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Progressive Hepatic Fibrosis and Cirrhosis Sustained injury drives fibrogenesis in the liver parenchyma.
Cholestasis
Conjugated hyperbilirubinemia
Increased serum bile acid concentration
Elevated circulating hepatic transaminase concentration
Jaundice
Pruritus
Hepatosplenomegaly
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
The biochemical pattern in the second reported child: hepatocellular and cholestatic injury with a normal GGT.
Progressive Hepatic Fibrosis and Cirrhosis
Fibrosis was present on the index patient's liver biopsy at 18 months and had become micronodular cirrhosis in the hepatectomy specimen at four years; the second reported child had transient elastography in the mild-to-moderate fibrosis range. The intervening cellular steps - stellate cell activation and matrix deposition - are not separately documented for this disease and are not asserted here.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Portal Hypertension and Hepatic Decompensation Cirrhosis raises portal resistance and exhausts hepatic reserve.
Hepatic fibrosis
Cirrhosis
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
Non-invasive measurement of fibrosis in the second reported child, independent of the index patient's histology.
Portal Hypertension and Hepatic Decompensation
The index patient developed umbilical collaterals, oesophageal varices and hepatopulmonary syndrome after three years of age, with pancytopenia attributed to hypersplenism and bleeding attributed to hepatic dysfunction, and reached decompensated cirrhosis requiring transplantation at four years.
Downstream
Portal hypertension
Esophageal varix
Pancytopenia
Abnormality of coagulation
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
The clinical endpoint of the decompensation, as reported for the index patient.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Bile Acid Synthesis Defect 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Blood 2
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
Cited for the progressive hepatic course that produced the hypersplenism; the pancytopenia is described in the paper's case narrative.
Abnormality of coagulation HP:0001928 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of coagulation (HP:0001928). HP:0001928 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
Cited for the hepatic synthetic failure behind the coagulopathy; the coagulation indices themselves are given in the paper's case narrative.
Cardiovascular 2
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
Hepatosplenomegaly as the presenting sign in the index patient.
PMID:41179737 SUPPORT Human Clinical
"It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
The presentation of the second reported child, in whom compound heterozygous ABCD3 variants were then identified.
Portal hypertension HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal hypertension (HP:0001409). HP:0001409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
The cited sentence establishes progression to decompensated liver disease requiring transplantation; the specific portal-hypertensive complications are described in the paper's case narrative.
Digestive 5
Cholestasis HP:0001396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cholestasis (HP:0001396). HP:0001396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"a cholestatic child carrying a novel ABCD3 mutation showed a unique phenotype (liver fibrosis with normal GGT)"
Cholestasis with fibrosis and a normal GGT in the second reported child.
Jaundice HP:0000952 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Jaundice (HP:0000952). HP:0000952 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
Jaundice at presentation in the second reported child.
Hepatic fibrosis HP:0001395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic fibrosis (HP:0001395). HP:0001395 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
Fibrosis measured non-invasively in the second reported child.
Cirrhosis HP:0001394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cirrhosis (HP:0001394). HP:0001394 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
Records the progression to transplant-requiring end-stage liver disease. The histological cirrhosis itself is described in the paper's case narrative rather than in this sentence.
Esophageal varix HP:0002040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophageal varix (HP:0002040). HP:0002040 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
Cited for the progressive decompensated course within which the varices were described; the varices themselves appear in the paper's case narrative.
Integument 1
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
Pruritus at presentation in the second reported child.
Metabolism 3
Increased serum bile acid concentration HP:0012202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased serum bile acid concentration (HP:0012202). HP:0012202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
Raised total serum bile acids with a normal GGT in the second reported child.
Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus. Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal. Liver transient elastography showed an average liver stiffness..."
Raised transaminases in the second reported child.
Conjugated hyperbilirubinemia HP:0002908 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjugated hyperbilirubinemia (HP:0002908). HP:0002908 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
CBIL is conjugated bilirubin; the sentence records it as elevated in the second reported child.
🧬

Genetic Associations

1
ABCD3
Gene: ABCD3 hgnc:67 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ABCD3 (hgnc:67). hgnc:67 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:34198763 SUPPORT Other
"The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively."
A review that assigns CBAS5 to ABCD3 and, in the same sentence, assigns the neighbouring peroxisomal ABC transporter ABCD1 to a different disease. Graded OTHER because it is a narrative review of transporter biology, not a study.
PMID:41428872 SUPPORT In Vitro
"Mutations in ABCD3 are associated with defects in congenital bile acid synthesis."
A structural study of purified human ABCD3 that states the gene-disease relationship its work is motivated by.
Variants (2)
ABCD3 c.1903-573_*1108del (p.Tyr635AsnfsTer1) Pathogenic
deletion
Homozygous 1758 bp genomic deletion removing exon 24 and part of the 3' UTR in the index patient, predicted to truncate the protein by its C-terminal 24 amino acids. Both parents were carriers.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
Reports the variant, its zygosity and its predicted protein consequence.
ABCD3 c.846C>G (p.Tyr282Ter) and c.1845+9G>A
compound heterozygous
Compound heterozygous pair reported in a second child with cholestasis; both alleles were novel at the time of report. `clinical_significance` is deliberately left unset: the publication calls them suspected pathogenic variants associated with the phenotype, which is not a completed ACMG classification, and recording either PATHOGENIC or UNCERTAIN_SIGNIFICANCE would assert a call the source did not make.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
Reports both alleles and their compound heterozygous configuration.
💊

Medical Actions

3
Liver Transplantation
Action: Organ TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. NCIT:C15289
Platform: Surgery
The only intervention with a reported outcome in this disease, and the outcome was poor: the index patient was transplanted at four years for decompensated cirrhosis with hepatopulmonary syndrome and died five days later of respiratory complications. It is a rescue for end-stage liver disease, not a treatment of the metabolic defect - though because the enzymes and the transporter are hepatic, transplantation would be expected to correct hepatic bile acid synthesis.
Mechanism Target:
Progressive Hepatic Fibrosis and Cirrhosis — Replaces the cirrhotic organ. It does not act on the transport lesion in any other tissue.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
The single reported treatment outcome: transplantation performed, and death shortly afterwards.
Ursodeoxycholic Acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ursodeoxycholic acid CHEBI:9907 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ursodeoxycholic acid (CHEBI:9907). CHEBI:9907 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Given to the index patient at 10 mg/kg/day from two years of age, before the metabolic diagnosis was made, and her disease progressed to cirrhosis and transplantation on treatment. That is one patient and does not establish that ursodeoxycholic acid is ineffective in this disease, but it is the only reported experience of it. Plasma ursodeoxycholic acid was correspondingly the highest-concentration bile acid species in her profile, which is a treatment effect and not a feature of the disease.
Mechanism Target:
Hepatocellular Injury and Cholestasis — Prescribed for the cholestatic injury. No effect on the course was reported in the one patient who received it.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"She was started on ursodeoxycholic acid treatment"
Records that the index patient received ursodeoxycholic acid. The dose and the age at which it started are given in the words immediately following, which the cached text breaks across a line.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive with a 25 percent recurrence risk. Both reported families are informative in different ways: consanguinity and a homozygous deletion in the first, two independent novel alleles in the second, so carrier testing has to be family-specific.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
The familial variant that carrier testing and recurrence-risk counselling would be based on in the index family.
🔬

Biochemical Markers

1
Plasma C27 bile acid intermediates (DHCA and THCA)
Show evidence (2 references)
PMID:36511274 SUPPORT Human Clinical
"In all controls, THCA and DHCA levels were below the detection limit."
Establishes that these analytes are absent in controls, which is what makes their presence informative.
PMID:36511274 SUPPORT Human Clinical
"In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
Names ABCD3 deficiency as one of the two peroxisomal disorders characterised by these intermediates - and names the other one, which is why the finding is not specific.
🔬

Diagnosis

4
Plasma bile acid profiling by mass spectrometry
The step that makes the diagnosis reachable. Quantifying DHCA and THCA by liquid chromatography-mass spectrometry separates the peroxisomal bile acid synthesis defects from every other cause of infantile cholestasis, because these C27 intermediates are below the detection limit in controls. It does not by itself identify ABCD3 as the lesion: acyl-CoA oxidase 2 deficiency and the Zellweger-spectrum disorders raise the same analytes. In the index patient the abnormal bile acid profile, combined with abnormal very-long-chain fatty acid ratios, is what prompted the peroxisomal workup.
plasma bile acid intermediate profiling by liquid chromatography-mass spectrometry NCIT:C25294 NCI Thesaurus (NCIT)
Markers: DHCA (3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid) and THCA (3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid); total serum bile acids; serum gamma-glutamyltransferase, which stays normal.
Show evidence (2 references)
PMID:36511274 SUPPORT Human Clinical
"In all controls, THCA and DHCA levels were below the detection limit."
The control data that make a measurable concentration diagnostic rather than merely abnormal.
PMID:36511274 SUPPORT Human Clinical
"In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
Names ABCD3 deficiency as characterised by this profile, and in the same sentence names the other disorder that shares it - which is why the test localises the pathway, not the gene.
Peroxisomal function studies in cultured skin fibroblasts
What distinguishes an ABCD3 transport defect from a biogenesis defect and from the enzyme defects of the same pathway. In the index patient, catalase immunofluorescence showed matrix-import-competent peroxisomes that were fewer and enlarged; ABCD3 was absent from the peroxisomal membrane while ABCD1 and PEX14 were present; C26:0 beta-oxidation was normal while pristanic acid beta-oxidation was reduced; and acyl-CoA oxidase 1, D-bifunctional protein, sterol carrier protein X and dihydroxyacetonephosphate acyltransferase activities were all reported as normal. Acyl-CoA oxidase 2 was not part of that panel.
peroxisomal function studies in cultured fibroblasts NCIT:C25294 NCI Thesaurus (NCIT)
Markers: Peroxisomal C26:0 and pristanic acid beta-oxidation rates; ABCD3 immunofluorescence and immunoblot; catalase immunofluorescence for peroxisome number and morphology; plasmalogens; DHAPAT, ACOX1, D-bifunctional protein and SCPx activities.
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced."
The discriminating pair of measurements: a selective branched-chain defect with the straight-chain very-long-chain route intact.
PMID:25168382 SUPPORT Human Clinical
"Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
Import-competent peroxisomes are what exclude a peroxisome biogenesis disorder as the explanation for the biochemical profile.
ABCD3 sequencing, within a gene panel or by exome sequencing
Both reported genotypes were reached by sequencing, and each illustrates a different detection problem. The index patient's allele is a 1758 bp deletion removing an exon and part of the 3' UTR, which is a copy-number lesion rather than a coding substitution; the second child's alleles were a nonsense variant and a near-splice-site intronic variant found on exome sequencing in a child whose liver disease was otherwise unexplained.
ABCD3 sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Markers: Biallelic ABCD3 variants. Note that a deletion of this size needs copy-number calling or genome sequencing rather than coding-exon analysis alone.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
The second reported diagnosis, made by exome sequencing in an unexplained pediatric liver disease cohort.
Liver biopsy
Not diagnostic of the gene defect, but it establishes the stage of injury and, in the index patient, showed a specific negative that matters mechanistically: interlobular bile ducts were normal and there was no ductular reaction, alongside minimal intracanalicular and intracytoplasmic cholestasis and portal, portal-central and pericellular fibrosis.
Liver Biopsy NCIT:C51677 NCI Thesaurus (NCIT)
Markers: Degree of fibrosis; presence or absence of ductular reaction; cholestasis; steatosis.
Show evidence (1 reference)
PMID:41179737 SUPPORT Human Clinical
"Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
Cited for fibrosis staging in the second child, which was done by elastography rather than biopsy - the non-invasive alternative for the same question.
📈

Progression

2
Infancy and early childhood
The index patient had normal developmental milestones and grew normally, with hepatosplenomegaly noticed at one year and severe anaemia, coagulopathy and raised transaminases at eighteen months. Fibrosis was already present on biopsy at that point.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
The presenting picture of the index patient.
Decompensated cirrhosis
After three years of age the index patient developed severe portal hypertension and hepatopulmonary syndrome, deteriorated rapidly at four years before a metabolic diagnosis had been made, was transplanted, and died five days later of respiratory complications.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
The reported endpoint of the index patient's course.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
Two reported patients from two unrelated families: the index patient of the founding report, and a child identified by exome sequencing in a cohort of 80 children with unexplained liver disease. No prevalence or incidence estimate has been published, and no numeric rate is recorded here because none has been measured.
Show evidence (2 references)
PMID:25168382 SUPPORT Human Clinical
"Here, we report the identification of the first patient with a defect of ABCD3."
Establishes the index case as the first reported patient.
PMID:41179737 SUPPORT Human Clinical
"1 case of SLC25A13, 3 cases of JAG1, 1 case of ATP8B1, 1 case of ABCC2, 1 case of ABCD3, and 1 case of 45X in Group B"
One ABCD3 case among the cholestasis group of an 80-child exome-sequencing cohort - a second, independent family.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Congenital Bile Acid Synthesis Defect 5:

Congenital bile acid synthesis defect 6 (ACOX2 deficiency) Not Yet Curated MONDO:0015015
Overlapping Features The closest biochemical mimic. ACOX2 catalyses the first beta-oxidation step on the C27 side chain, immediately downstream of the ABCD3 import step, so it raises the same DHCA and THCA. The plasma profile cannot separate the two; the fibroblast acyl-CoA oxidase measurement and the gene can.
Distinguishing Features
  • Both raise plasma DHCA and THCA, so the bile acid profile alone does not discriminate.
  • The discriminator is the gene, and at the protein level the absence of ABCD3 itself from the peroxisomal membrane. The fibroblast enzyme panel run in the ABCD3-deficient patient measured acyl-CoA oxidase 1, which is the straight-chain oxidase and not the branched-chain and bile-acid oxidase encoded by ACOX2, so it does not settle this differential.
Show evidence (1 reference)
PMID:36511274 SUPPORT Human Clinical
"In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
Names the two disorders that share this metabolite signature.
Zellweger spectrum disorders MONDO:0019609
Overlapping Features The peroxisome biogenesis disorders also raise C27 bile acid intermediates, but by a generalised lesion: matrix protein import fails, so very-long-chain fatty acid beta-oxidation and ether-phospholipid synthesis fail alongside the bile acid pathway.
Distinguishing Features
  • Peroxisomes were import-competent in the ABCD3-deficient patient, which a biogenesis disorder is defined by not being.
  • C26:0 beta-oxidation was normal in the ABCD3-deficient patient; it is impaired in the generalised biogenesis disorders.
Show evidence (1 reference)
PMID:25168382 SUPPORT Human Clinical
"Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
Import competence is the observation that separates this disease from a peroxisome biogenesis disorder.
Adrenoleukodystrophy (ABCD1) MONDO:0018544
Overlapping Features The neighbouring peroxisomal ABC transporter. ABCD1 loss impairs very-long-chain fatty acid import and produces adrenal and central nervous system disease; ABCD3 loss spares the very-long-chain route and produces liver disease. The two are listed together because the gene names invite the confusion, not because the diseases resemble each other.
Distinguishing Features
  • ABCD1 is X-linked; ABCD3 disease is autosomal recessive.
  • ABCD1 was present in the peroxisomal membrane of the ABCD3-deficient patient's fibroblasts, and C26:0 beta-oxidation was normal in them.
Show evidence (1 reference)
PMID:34198763 SUPPORT Other
"The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively."
Assigns the two transporters to two different diseases in one sentence. Graded OTHER because it is a narrative review.
Congenital bile acid synthesis defect 1 (HSD3B7 deficiency) Not Yet Curated MONDO:0011906
Overlapping Features The commonest of the bile acid synthesis defects and the one a low-GGT cholestatic infant is most likely to have. It is a cytosolic/microsomal enzyme defect early in the pathway, so it does not raise C27 intermediates and does not produce a peroxisomal functional abnormality.
Distinguishing Features
  • Shares the low-GGT cholestatic presentation, so the clinical picture does not discriminate.
  • The accumulating species differ: 3beta-hydroxy-Delta5 intermediates rather than the C27 cholestanoic acids DHCA and THCA.
Progressive familial intrahepatic cholestasis MONDO:0015762
Overlapping Features The other major low-GGT cholestatic group of infancy. These are canalicular export and tight-junction defects rather than synthesis defects, and the direction of the bile acid abnormality is the discriminator.
Distinguishing Features
  • Serum bile acids are markedly raised in PFIC because export fails; in this disease the informative abnormality is the presence of C27 intermediates that controls do not have at all.
  • A plasma bile acid profile that quantifies DHCA and THCA separates the two; a total bile acid measurement does not.
🐁

Animal Models

1
Abcd3 knockout (Abcd3-/-) Mouse
The Abcd3 knockout mouse was the pre-existing model the founding report used to corroborate its patient. It reproduces the bile acid lesion directly - C24 bile acids fall while C27 intermediates rise in liver, bile and intestine - and reproduces the branched-chain arm under phytol challenge. A separately generated CRISPR-Cas9 knockout has since been used to characterise the transporter's role in dicarboxylic fatty acid metabolism and hepatic lipid homeostasis, a phenotype dimension with no counterpart in the two reported human patients.
Species
Mouse
Genotype
Abcd3 knockout (Abcd3-/-)
Publication
PMID:25168382
Pathograph links
Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates recapitulates fidelity: high observes: organism The knockout reproduces the two-sided biochemical signature of the blocked step in the tissues where bile acids are made and secreted.
Limitations: The mouse demonstrates the C24 deficit that the human plasma profile does not show, so the model is the source of the product-side claim rather than a confirmation of it. Progression to fibrosis and cirrhosis, which is the human disease, is not reported for the knockout.
Show evidence (1 reference)
PMID:25168382 SUPPORT Model Organism
"analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice"
The bile acid phenotype of the knockout in three tissues.
Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids recapitulates fidelity: moderate observes: organism Phytol loading unmasks the branched-chain arm in the knockout, producing the phytanic acid accumulation that the index patient did not have on an ordinary diet.
Limitations: The phenotype required a dietary phytol challenge, so it measures reserve capacity rather than the steady state; the index patient's plasma phytanic and pristanic acid concentrations were within the reference range.
Show evidence (1 reference)
PMID:25168382 SUPPORT Model Organism
"Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
The branched-chain phenotype of the knockout under phytol loading.
Show evidence (1 reference)
PMID:34564857 SUPPORT Model Organism
"The Abcd3 KO mouse presents with increased hepatic long-chain DCAs, increased urine medium-chain DCAs, lipodystrophy, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis."
The wider metabolic phenotype of the knockout. It is cited here to bound what the model represents, since none of these features has been looked for in the reported patients.
{ }

Source YAML

click to show 
name: Congenital Bile Acid Synthesis Defect 5
category: Mendelian
creation_date: '2026-09-08T07:30:00Z'
synonyms:
- CBAS5
- ABCD3 deficiency
- peroxisomal ABCD3 deficiency
- PMP70 deficiency
- ABCD3 congenital bile acid synthesis defect
description: >-
  Congenital bile acid synthesis defect 5 (CBAS5) is an autosomal recessive disorder
  caused by biallelic loss-of-function variants in ABCD3, which encodes the peroxisomal
  membrane ABC half-transporter PMP70. ABCD3 carries the CoA thioesters of 2-methyl
  branched-chain fatty acids and of the C27 bile acid intermediates dihydroxycholestanoic
  acid (DHCA) and trihydroxycholestanoic acid (THCA) from the cytosol into the peroxisomal
  matrix, where side-chain beta-oxidation shortens them to the mature C24 primary bile
  acids. The lesion is therefore a transport failure, not an enzyme failure: the peroxisome
  is assembled and import-competent, and the enzymes of the beta-oxidation spiral are
  present and active, but their substrates never reach them.
  The block is selective. Peroxisomal beta-oxidation of the very-long-chain fatty acid
  C26:0 and the first committed enzyme of ether-phospholipid synthesis were both normal
  in the index patient's fibroblasts, so this is not the generalized two-sided peroxisomal
  lesion of the biogenesis disorders; what fails is the branched-chain and C27-bile-acid
  substream, and it is the bile acid arm that produces the disease. Clinically that arm
  presents as a cholestatic liver disease of infancy and early childhood - hepatosplenomegaly,
  jaundice, elevated transaminases and raised serum bile acids with a normal
  gamma-glutamyltransferase - which progresses to hepatic fibrosis and cirrhosis. The
  index patient reached decompensated cirrhosis and was transplanted at four years of age.
  A second, independently reported child carried compound heterozygous ABCD3 variants and
  the same low-GGT cholestatic-fibrotic pattern, so the entity rests on two families.
disease_term:
  preferred_term: Congenital bile acid synthesis defect 5
  term:
    id: MONDO:0014564
    label: congenital bile acid synthesis defect 5
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018841
      label: congenital bile acid synthesis defect
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      One of the two parents MONDO asserts for MONDO:0014564. Recorded as broadMatch, not
      exactMatch: it is the clinical/biochemical family this disease belongs to, and the
      name this entry is filed under, but it is a broader concept covering four other
      gene-specific defects. Recording it here keeps the dual parentage machine-readable
      without asserting identity.
  - term:
      id: MONDO:0100372
      label: disorder of peroxisomal transporter
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      The second parent MONDO asserts for MONDO:0014564, and the one that names the actual
      lesion. Recorded as broadMatch because it is a broader class that also contains the
      other peroxisomal ABC transporter defects, including the ABCD1 disorder. See `notes`
      for why the pathophysiology chain in this entry is built on this parent rather than
      the other.
  icd10cm_mappings:
  - term:
      id: ICD10CM:E71.548
      label: Other peroxisomal disorders
    mapping_predicate: skos:broadMatch
    mapping_source: dismech curation
    mapping_justification: >-
      ICD-10-CM has no code for CBAS5. E71.548 is the residual peroxisomal-disorder code
      and is the closest coded home for the lesion this entry models; it is a broader
      residual category rather than a cross-reference asserted by any source, and is not
      taken from a MONDO or Orphanet xref.
parents:
- Peroxisomal Disease
- Inborn Error of Metabolism
- Cholestasis
references:
- reference: PMID:25168382
  title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
- reference: PMID:41179737
  title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
- reference: PMID:34198763
  title: "Peroxisomal ABC Transporters: An Update."
- reference: PMID:34564857
  title: "The peroxisomal transporter ABCD3 plays a major role in hepatic dicarboxylic fatty acid metabolism and lipid homeostasis."
- reference: PMID:36511274
  title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
- reference: PMID:39223112
  title: "Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation."
- reference: PMID:41428872
  title: "Molecular mechanism of substrate transport by human peroxisomal ABCD3."
classifications:
  harrisons_chapter:
  - classification_value: GASTROINTESTINAL
    notes: >-
      The reported disease is a cholestatic, fibrosing liver disease of childhood; the
      liver is the only organ with documented pathology.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      An inborn error of peroxisomal metabolism, and specifically of the bile acid
      synthetic pathway.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Biallelic ABCD3 variants. The index patient was homozygous for a 1758 bp genomic
    deletion, born to consanguineous parents, with both parents confirmed carriers; the
    second reported child was compound heterozygous for two previously unreported variants.
    Penetrance and expressivity are recorded as UNKNOWN rather than complete and
    consistent: with two reported families there is no unaffected biallelic carrier to
    argue from and no phenotypic range to characterise, so any stronger statement would
    be an inference from an n of two rather than an observation.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: UNKNOWN
  expressivity: UNKNOWN
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
    explanation: Establishes the homozygous biallelic genotype in the index patient.
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
    explanation: >-
      A second, independent biallelic genotype - compound heterozygous rather than
      homozygous - in a child with cholestatic liver disease.
genetic:
- name: ABCD3
  gene_term:
    preferred_term: ABCD3
    term:
      id: hgnc:67
      label: ABCD3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    ABCD3 encodes PMP70, one of the three peroxisomal-membrane ABC half-transporters.
    Both reported genotypes are predicted to abolish the transporter: a homozygous 1758 bp
    deletion removing exon 24 and part of the 3' UTR, truncating the protein by its
    C-terminal 24 residues, and a compound heterozygous pair comprising a nonsense allele
    and an intronic variant near a splice site.
  evidence:
  - reference: PMID:34198763
    reference_title: "Peroxisomal ABC Transporters: An Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively."
    explanation: >-
      A review that assigns CBAS5 to ABCD3 and, in the same sentence, assigns the
      neighbouring peroxisomal ABC transporter ABCD1 to a different disease. Graded OTHER
      because it is a narrative review of transporter biology, not a study.
  - reference: PMID:41428872
    reference_title: "Molecular mechanism of substrate transport by human peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Mutations in ABCD3 are associated with defects in congenital bile acid synthesis."
    explanation: >-
      A structural study of purified human ABCD3 that states the gene-disease relationship
      its work is motivated by.
  variants:
  - name: "ABCD3 c.1903-573_*1108del (p.Tyr635AsnfsTer1)"
    description: >-
      Homozygous 1758 bp genomic deletion removing exon 24 and part of the 3' UTR in the
      index patient, predicted to truncate the protein by its C-terminal 24 amino acids.
      Both parents were carriers.
    type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:25168382
      reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
      explanation: Reports the variant, its zygosity and its predicted protein consequence.
  - name: "ABCD3 c.846C>G (p.Tyr282Ter) and c.1845+9G>A"
    description: >-
      Compound heterozygous pair reported in a second child with cholestasis; both alleles
      were novel at the time of report. `clinical_significance` is deliberately left unset:
      the publication calls them suspected pathogenic variants associated with the
      phenotype, which is not a completed ACMG classification, and recording either
      PATHOGENIC or UNCERTAIN_SIGNIFICANCE would assert a call the source did not make.
    type: compound_heterozygous
    evidence:
    - reference: PMID:41179737
      reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
      explanation: Reports both alleles and their compound heterozygous configuration.
pathophysiology:
- name: ABCD3 Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  conforms_to: "peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect"
  description: >-
    Biallelic loss-of-function ABCD3 variants remove PMP70 from the peroxisomal membrane.
    In the index patient's fibroblasts, immunofluorescence and immunoblot showed loss of
    the transporter while ABCD1 and PEX14 were present, and the peroxisomes themselves were
    fewer and enlarged but still competent to import matrix protein. This node enters the
    peroxisomal module by its transporter arm: the organelle is assembled, and it is one
    substrate route into it that is lost.
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous in the index patient; the second reported child was compound
      heterozygous, so the zygosity recorded here is that of the better-characterised
      genotype rather than a property of the disease.
  molecular_functions:
  - preferred_term: peroxisomal ABC-type acyl-CoA transporter activity (PMP70/ABCD3)
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0015607
      label: ABC-type fatty-acyl-CoA transporter activity
  cellular_components:
  - preferred_term: peroxisomal membrane
    term:
      id: GO:0005778
      label: peroxisomal membrane
  biological_processes:
  - preferred_term: peroxisome number and size are abnormal, while matrix import is preserved
    modifier: ABNORMAL
    term:
      id: GO:0007031
      label: peroxisome organization
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
    explanation: >-
      Establishes that the organelle is present and import-competent, which is what
      separates this lesion from a peroxisome biogenesis defect.
  downstream:
  - target: Failure of Peroxisomal Import of C27 Bile Acid and Branched-Chain Acyl-CoA Esters
    description: >-
      Loss of the transporter removes the route by which its substrates cross the
      peroxisomal membrane.
    evidence:
    - reference: PMID:41428872
      reference_title: "Molecular mechanism of substrate transport by human peroxisomal ABCD3."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "ABCD3 facilitates the transport of a broad spectrum of substrates, including branched-chain fatty acids, very long-chain fatty acids, bile salt intermediates, and dicarboxylic acids as CoA adducts."
      explanation: >-
        Cryo-EM and ATPase work on purified human ABCD3 naming the substrate spectrum that
        loss of the transporter withdraws.
- name: Failure of Peroxisomal Import of C27 Bile Acid and Branched-Chain Acyl-CoA Esters
  role: amplifier
  biological_scale: MOLECULAR
  description: >-
    The CoA thioesters of DHCA and THCA, and of 2-methyl branched-chain fatty acids such
    as pristanic acid, are no longer delivered into the peroxisomal matrix. The failure is
    substrate-selective: beta-oxidation of the very-long-chain fatty acid C26:0 was normal
    in the index patient's fibroblasts, so the straight-chain very-long-chain route into
    the organelle is not the one that is lost.
  biological_processes:
  - preferred_term: import of acyl-CoA esters into the peroxisomal matrix
    modifier: DECREASED
    term:
      id: GO:0015916
      label: fatty-acyl-CoA transport
  cellular_components:
  - preferred_term: peroxisomal matrix
    term:
      id: GO:0005782
      label: peroxisomal matrix
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced."
    explanation: >-
      The functional signature of a selective import failure in patient fibroblasts:
      branched-chain substrate handling is impaired while straight-chain very-long-chain
      handling is not.
  - reference: PMID:39223112
    reference_title: "Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The transport of branched-chain fatty acids from cytosol to peroxisome is specifically driven by ABCD3, dysfunction of which causes severe liver diseases such as hepatosplenomegaly."
    explanation: >-
      Structural work assigning branched-chain acyl-CoA import specifically to ABCD3 and
      linking its dysfunction to liver disease.
  downstream:
  - target: Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates
    description: >-
      The beta-oxidation enzymes that shorten the C27 side chain are inside the matrix, so
      an import failure is functionally equivalent to a block of the pathway they carry.
  - target: Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
    description: >-
      The same import failure withdraws pristanoyl-CoA from the branched-chain
      beta-oxidation spiral.
- name: Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    Bile acid synthesis is completed inside the peroxisome: the C27 intermediates DHCA and
    THCA must be shortened by beta-oxidation to the C24 primary bile acids. With their
    import blocked, that terminal step cannot run, and the pathway fails in both
    directions at once - substrate backs up and product is not made.
  biological_processes:
  - preferred_term: peroxisomal side-chain beta-oxidation of C27 bile acid intermediates
    modifier: DECREASED
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  - preferred_term: bile acid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis"
    explanation: >-
      The authors' own conclusion placing the ABCD3 transport step inside the bile acid
      synthetic pathway.
  downstream:
  - target: Accumulation of C27 Bile Acid Intermediates
    description: The unmetabolised substrates accumulate in plasma and tissue.
  - target: Deficient Formation of Mature C24 Primary Bile Acids
    description: The product of the blocked step is not made.
- name: Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
  role: parallel branch
  biological_scale: MOLECULAR
  description: >-
    Pristanic acid beta-oxidation was reduced to 59 percent of control activity in the
    index patient's fibroblasts, and Abcd3 knockout mice accumulate phytanic acid when
    phytol-loaded. This arm is biochemically real but was clinically silent in the index
    patient, whose plasma phytanic and pristanic acid concentrations were within the
    reference range; no branched-chain-fatty-acid phenotype is recorded for this disease,
    which is why the node is a branch and not part of the chain to the clinical
    manifestations.
  biological_processes:
  - preferred_term: branched-chain fatty acid beta-oxidation
    modifier: DECREASED
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
    explanation: >-
      The branched-chain arm demonstrated in the knockout mouse under phytol challenge.
      Graded MODEL_ORGANISM because this specific result is the mouse experiment.
- name: Accumulation of C27 Bile Acid Intermediates
  role: effector
  biological_scale: ORGANISM
  description: >-
    DHCA and THCA accumulate to concentrations far above the reference range - in the index
    patient they were the striking abnormality of the plasma bile acid profile, and in
    Abcd3 knockout mice they rose in liver, bile and intestine. C27 intermediates are the
    species held responsible for hepatocellular injury across the bile acid synthesis
    defects.
  chemical_entities:
  - preferred_term: dihydroxycholestanoic acid (DHCA)
    modifier: INCREASED
    term:
      id: CHEBI:16577
      label: 3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid
  - preferred_term: trihydroxycholestanoic acid (THCA)
    modifier: INCREASED
    term:
      id: CHEBI:18402
      label: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
    explanation: The accumulation measured in the index patient's plasma.
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
    explanation: >-
      A clinical mass-spectrometry study that treats DHCA/THCA accumulation as the
      characteristic metabolite abnormality of ABCD3 deficiency.
  downstream:
  - target: Hepatocellular Injury and Cholestasis
    description: >-
      Retained C27 intermediates are the injurious species; the link is the same one
      invoked across the bile acid synthesis defects rather than a mechanism dissected in
      an ABCD3-deficient liver.
- name: Deficient Formation of Mature C24 Primary Bile Acids
  role: effector
  biological_scale: ORGANISM
  description: >-
    The product side of the block. This is demonstrated in the mouse, where C24 bile acids
    fell as the C27 intermediates rose. It is deliberately not asserted for the index
    patient, whose plasma cholic and chenodeoxycholic acid concentrations were above, not
    below, the reference range while she was receiving ursodeoxycholic acid - so the human
    plasma profile does not show a C24 deficit and should not be read as though it did.
  chemical_entities:
  - preferred_term: cholic acid
    modifier: DECREASED
    term:
      id: CHEBI:16359
      label: cholic acid
  - preferred_term: chenodeoxycholic acid
    modifier: DECREASED
    term:
      id: CHEBI:16755
      label: chenodeoxycholic acid
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice"
    explanation: >-
      The C24 deficit as measured in Abcd3 knockout mouse tissue. Graded MODEL_ORGANISM
      because the reduction was measured in the mouse and not in the patient.
  downstream:
  - target: Hepatocellular Injury and Cholestasis
    description: >-
      Loss of the mature bile acid pool removes the principal osmotic driver of bile flow.
      Inferred from bile acid physiology; not separately measured in an ABCD3-deficient
      patient.
- name: Hepatocellular Injury and Cholestasis
  role: effector
  biological_scale: TISSUE
  description: >-
    Cholestatic hepatocellular injury with a normal gamma-glutamyltransferase. Both
    reported children had raised transaminases, raised serum bile acids and conjugated
    hyperbilirubinaemia with a normal GGT; the index patient's liver biopsy showed minimal
    intracanalicular and intracytoplasmic cholestasis with normal interlobular bile ducts
    and no ductular reaction.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
    explanation: >-
      The biochemical pattern in the second reported child: hepatocellular and cholestatic
      injury with a normal GGT.
  downstream:
  - target: Progressive Hepatic Fibrosis and Cirrhosis
    description: Sustained injury drives fibrogenesis in the liver parenchyma.
  - target: Cholestasis
  - target: Conjugated hyperbilirubinemia
  - target: Increased serum bile acid concentration
  - target: Elevated circulating hepatic transaminase concentration
  - target: Jaundice
  - target: Pruritus
  - target: Hepatosplenomegaly
- name: Progressive Hepatic Fibrosis and Cirrhosis
  role: consequence
  biological_scale: TISSUE
  description: >-
    Fibrosis was present on the index patient's liver biopsy at 18 months and had become
    micronodular cirrhosis in the hepatectomy specimen at four years; the second reported
    child had transient elastography in the mild-to-moderate fibrosis range. The
    intervening cellular steps - stellate cell activation and matrix deposition - are not
    separately documented for this disease and are not asserted here.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
    explanation: >-
      Non-invasive measurement of fibrosis in the second reported child, independent of the
      index patient's histology.
  downstream:
  - target: Portal Hypertension and Hepatic Decompensation
    description: Cirrhosis raises portal resistance and exhausts hepatic reserve.
  - target: Hepatic fibrosis
  - target: Cirrhosis
- name: Portal Hypertension and Hepatic Decompensation
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The index patient developed umbilical collaterals, oesophageal varices and
    hepatopulmonary syndrome after three years of age, with pancytopenia attributed to
    hypersplenism and bleeding attributed to hepatic dysfunction, and reached decompensated
    cirrhosis requiring transplantation at four years.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: The clinical endpoint of the decompensation, as reported for the index patient.
  downstream:
  - target: Portal hypertension
  - target: Esophageal varix
  - target: Pancytopenia
  - target: Abnormality of coagulation
phenotypes:
- category: Gastrointestinal
  name: Hepatosplenomegaly
  description: >-
    Present in both reported children. In the index patient the liver was palpable 5-6 cm
    and the spleen 7-8 cm below the costal margins at 18 months, and both organs later
    enlarged further; the second child presented with hepatosplenomegaly together with
    jaundice and pruritus.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
    explanation: Hepatosplenomegaly as the presenting sign in the index patient.
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
    explanation: >-
      The presentation of the second reported child, in whom compound heterozygous ABCD3
      variants were then identified.
- category: Gastrointestinal
  name: Cholestasis
  description: >-
    Cholestasis with a normal gamma-glutamyltransferase, which is the pattern shared with
    the other congenital bile acid synthesis defects and which separates this group from
    the high-GGT cholestatic disorders.
  phenotype_term:
    preferred_term: Cholestasis
    term:
      id: HP:0001396
      label: Cholestasis
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a cholestatic child carrying a novel ABCD3 mutation showed a unique phenotype (liver fibrosis with normal GGT)"
    explanation: Cholestasis with fibrosis and a normal GGT in the second reported child.
- category: Laboratory
  name: Increased serum bile acid concentration
  description: >-
    Total serum bile acids are raised, and the fraction that is diagnostically informative
    is the C27 intermediate fraction: in the index patient DHCA and THCA were present at
    concentrations orders of magnitude above their reference intervals.
  phenotype_term:
    preferred_term: Increased serum bile acid concentration
    term:
      id: HP:0012202
      label: Increased serum bile acid concentration
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
    explanation: Raised total serum bile acids with a normal GGT in the second reported child.
- category: Laboratory
  name: Elevated circulating hepatic transaminase concentration
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is worth noting that one patient with cholestasis presented with hepatosplenomegaly,
      jaundice, and pruritus. Biochemical features included elevated transaminases, CBIL, and total
      serum bile acids, while GGT levels remained normal. Liver transient elastography showed an
      average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis. Genetic sequencing
      analysis identified suspected P variants associated with the disease phenotype. Compound
      heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and
      intron 21: C.1845+9G>A (p.?). Both variants have not been previously reported.
    explanation: Raised transaminases in the second reported child.
- category: Laboratory
  name: Conjugated hyperbilirubinemia
  description: >-
    Reported as elevated conjugated bilirubin in the second child; the index patient had
    mild hyperbilirubinaemia with a raised direct fraction.
  phenotype_term:
    preferred_term: Conjugated hyperbilirubinemia
    term:
      id: HP:0002908
      label: Conjugated hyperbilirubinemia
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical features included elevated transaminases, CBIL, and total serum bile acids, while GGT levels remained normal."
    explanation: >-
      CBIL is conjugated bilirubin; the sentence records it as elevated in the second
      reported child.
- category: Gastrointestinal
  name: Jaundice
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
    explanation: Jaundice at presentation in the second reported child.
- category: Dermatologic
  name: Pruritus
  description: >-
    Recorded at presentation in the second reported child. Pruritus was not described in
    the index patient, so this is a feature of one of the two families rather than an
    established feature of the disease.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is worth noting that one patient with cholestasis presented with hepatosplenomegaly, jaundice, and pruritus."
    explanation: Pruritus at presentation in the second reported child.
- category: Gastrointestinal
  name: Hepatic fibrosis
  description: >-
    Portal-portal, portal-central and pericellular fibrosis on the index patient's liver
    biopsy at 18 months of age; mild-to-moderate fibrosis by transient elastography in the
    second child.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
    explanation: Fibrosis measured non-invasively in the second reported child.
- category: Gastrointestinal
  name: Cirrhosis
  description: >-
    The index patient's total hepatectomy specimen at four years of age showed micronodular
    cirrhotic features, having progressed from the fibrosis seen at 18 months.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      Records the progression to transplant-requiring end-stage liver disease. The
      histological cirrhosis itself is described in the paper's case narrative rather than
      in this sentence.
- category: Gastrointestinal
  name: Portal hypertension
  description: >-
    The index patient developed umbilical collaterals and oesophageal varices after three
    years of age, with hepatopulmonary syndrome and progressive fatigue.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      The cited sentence establishes progression to decompensated liver disease requiring
      transplantation; the specific portal-hypertensive complications are described in the
      paper's case narrative.
- category: Gastrointestinal
  name: Esophageal varix
  description: Reported in the index patient as part of severe portal hypertension.
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      Cited for the progressive decompensated course within which the varices were
      described; the varices themselves appear in the paper's case narrative.
- category: Hematologic
  name: Pancytopenia
  description: >-
    Attributed to hypersplenism in the index patient rather than to a primary marrow
    lesion; bone marrow examination showed normoblastic hyperactivity without evidence of
    a storage disorder or malignancy.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      Cited for the progressive hepatic course that produced the hypersplenism; the
      pancytopenia is described in the paper's case narrative.
- category: Hematologic
  name: Abnormality of coagulation
  description: >-
    Coagulopathy unresponsive to parenteral vitamin K in the index patient at presentation,
    with epistaxis and bleeding attributed to hepatic dysfunction during follow-up.
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      Cited for the hepatic synthetic failure behind the coagulopathy; the coagulation
      indices themselves are given in the paper's case narrative.
biochemical:
- name: Plasma C27 bile acid intermediates (DHCA and THCA)
  notes: >-
    The diagnostic analytes. They are undetectable in controls, so any measurable
    concentration is abnormal, and in ABCD3 deficiency they are the dominant species of the
    plasma bile acid profile. They do not distinguish CBAS5 from the other peroxisomal
    causes of C27 intermediate accumulation on their own.
  evidence:
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all controls, THCA and DHCA levels were below the detection limit."
    explanation: >-
      Establishes that these analytes are absent in controls, which is what makes their
      presence informative.
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
    explanation: >-
      Names ABCD3 deficiency as one of the two peroxisomal disorders characterised by these
      intermediates - and names the other one, which is why the finding is not specific.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Two reported patients from two unrelated families: the index patient of the founding
    report, and a child identified by exome sequencing in a cohort of 80 children with
    unexplained liver disease. No prevalence or incidence estimate has been published, and
    no numeric rate is recorded here because none has been measured.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the identification of the first patient with a defect of ABCD3."
    explanation: Establishes the index case as the first reported patient.
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1 case of SLC25A13, 3 cases of JAG1, 1 case of ATP8B1, 1 case of ABCC2, 1 case of ABCD3, and 1 case of 45X in Group B"
    explanation: >-
      One ABCD3 case among the cholestasis group of an 80-child exome-sequencing cohort -
      a second, independent family.
progression:
- phase: Infancy and early childhood
  notes: >-
    The index patient had normal developmental milestones and grew normally, with
    hepatosplenomegaly noticed at one year and severe anaemia, coagulopathy and raised
    transaminases at eighteen months. Fibrosis was already present on biopsy at that point.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma."
    explanation: The presenting picture of the index patient.
- phase: Decompensated cirrhosis
  notes: >-
    After three years of age the index patient developed severe portal hypertension and
    hepatopulmonary syndrome, deteriorated rapidly at four years before a metabolic
    diagnosis had been made, was transplanted, and died five days later of respiratory
    complications.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: The reported endpoint of the index patient's course.
diagnosis:
- name: Plasma bile acid profiling by mass spectrometry
  description: >-
    The step that makes the diagnosis reachable. Quantifying DHCA and THCA by liquid
    chromatography-mass spectrometry separates the peroxisomal bile acid synthesis defects
    from every other cause of infantile cholestasis, because these C27 intermediates are
    below the detection limit in controls. It does not by itself identify ABCD3 as the
    lesion: acyl-CoA oxidase 2 deficiency and the Zellweger-spectrum disorders raise the
    same analytes. In the index patient the abnormal bile acid profile, combined with
    abnormal very-long-chain fatty acid ratios, is what prompted the peroxisomal workup.
  markers: >-
    DHCA (3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid) and THCA
    (3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid); total serum bile acids;
    serum gamma-glutamyltransferase, which stays normal.
  diagnosis_term:
    preferred_term: plasma bile acid intermediate profiling by liquid chromatography-mass spectrometry
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all controls, THCA and DHCA levels were below the detection limit."
    explanation: >-
      The control data that make a measurable concentration diagnostic rather than merely
      abnormal.
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
    explanation: >-
      Names ABCD3 deficiency as characterised by this profile, and in the same sentence
      names the other disorder that shares it - which is why the test localises the
      pathway, not the gene.
- name: Peroxisomal function studies in cultured skin fibroblasts
  description: >-
    What distinguishes an ABCD3 transport defect from a biogenesis defect and from the
    enzyme defects of the same pathway. In the index patient, catalase immunofluorescence
    showed matrix-import-competent peroxisomes that were fewer and enlarged; ABCD3 was
    absent from the peroxisomal membrane while ABCD1 and PEX14 were present; C26:0
    beta-oxidation was normal while pristanic acid beta-oxidation was reduced; and acyl-CoA
    oxidase 1, D-bifunctional protein, sterol carrier protein X and
    dihydroxyacetonephosphate acyltransferase activities were all reported as normal.
    Acyl-CoA oxidase 2 was not part of that panel.
  markers: >-
    Peroxisomal C26:0 and pristanic acid beta-oxidation rates; ABCD3 immunofluorescence and
    immunoblot; catalase immunofluorescence for peroxisome number and morphology;
    plasmalogens; DHAPAT, ACOX1, D-bifunctional protein and SCPx activities.
  diagnosis_term:
    preferred_term: peroxisomal function studies in cultured fibroblasts
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced."
    explanation: >-
      The discriminating pair of measurements: a selective branched-chain defect with the
      straight-chain very-long-chain route intact.
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
    explanation: >-
      Import-competent peroxisomes are what exclude a peroxisome biogenesis disorder as the
      explanation for the biochemical profile.
- name: ABCD3 sequencing, within a gene panel or by exome sequencing
  description: >-
    Both reported genotypes were reached by sequencing, and each illustrates a different
    detection problem. The index patient's allele is a 1758 bp deletion removing an exon
    and part of the 3' UTR, which is a copy-number lesion rather than a coding
    substitution; the second child's alleles were a nonsense variant and a near-splice-site
    intronic variant found on exome sequencing in a child whose liver disease was
    otherwise unexplained.
  markers: >-
    Biallelic ABCD3 variants. Note that a deletion of this size needs copy-number calling
    or genome sequencing rather than coding-exon analysis alone.
  diagnosis_term:
    preferred_term: ABCD3 sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous mutations were found in the ABCD3 gene at exon 10: C.846C>G (p.Y282Ter) and intron 21: C.1845+9G>A (p.?)."
    explanation: >-
      The second reported diagnosis, made by exome sequencing in an unexplained pediatric
      liver disease cohort.
- name: Liver biopsy
  description: >-
    Not diagnostic of the gene defect, but it establishes the stage of injury and, in the
    index patient, showed a specific negative that matters mechanistically: interlobular
    bile ducts were normal and there was no ductular reaction, alongside minimal
    intracanalicular and intracytoplasmic cholestasis and portal, portal-central and
    pericellular fibrosis.
  markers: >-
    Degree of fibrosis; presence or absence of ductular reaction; cholestasis; steatosis.
  diagnosis_term:
    preferred_term: Liver Biopsy
    term:
      id: NCIT:C51677
      label: Liver Biopsy
  evidence:
  - reference: PMID:41179737
    reference_title: "Clinical characteristics and genetic causes of unexplained pediatric liver disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver transient elastography showed an average liver stiffness of 9.2 kPa, indicating mild to moderate fibrosis."
    explanation: >-
      Cited for fibrosis staging in the second child, which was done by elastography rather
      than biopsy - the non-invasive alternative for the same question.
treatments:
- name: Liver Transplantation
  description: >-
    The only intervention with a reported outcome in this disease, and the outcome was
    poor: the index patient was transplanted at four years for decompensated cirrhosis with
    hepatopulmonary syndrome and died five days later of respiratory complications. It is
    a rescue for end-stage liver disease, not a treatment of the metabolic defect - though
    because the enzymes and the transporter are hepatic, transplantation would be expected
    to correct hepatic bile acid synthesis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation."
    explanation: >-
      The single reported treatment outcome: transplantation performed, and death shortly
      afterwards.
  target_mechanisms:
  - target: Progressive Hepatic Fibrosis and Cirrhosis
    description: >-
      Replaces the cirrhotic organ. It does not act on the transport lesion in any other
      tissue.
- name: Ursodeoxycholic Acid
  description: >-
    Given to the index patient at 10 mg/kg/day from two years of age, before the metabolic
    diagnosis was made, and her disease progressed to cirrhosis and transplantation on
    treatment. That is one patient and does not establish that ursodeoxycholic acid is
    ineffective in this disease, but it is the only reported experience of it. Plasma
    ursodeoxycholic acid was correspondingly the highest-concentration bile acid species in
    her profile, which is a treatment effect and not a feature of the disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was started on ursodeoxycholic acid treatment"
    explanation: >-
      Records that the index patient received ursodeoxycholic acid. The dose and the age at
      which it started are given in the words immediately following, which the cached text
      breaks across a line.
  target_mechanisms:
  - target: Hepatocellular Injury and Cholestasis
    description: >-
      Prescribed for the cholestatic injury. No effect on the course was reported in the
      one patient who received it.
- name: Genetic Counseling
  description: >-
    Autosomal recessive with a 25 percent recurrence risk. Both reported families are
    informative in different ways: consanguinity and a homozygous deletion in the first,
    two independent novel alleles in the second, so carrier testing has to be family-specific.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1)."
    explanation: >-
      The familial variant that carrier testing and recurrence-risk counselling would be
      based on in the index family.
differential_diagnoses:
- name: Congenital bile acid synthesis defect 6 (ACOX2 deficiency)
  disease_term:
    preferred_term: congenital bile acid synthesis defect 6
    term:
      id: MONDO:0015015
      label: congenital bile acid synthesis defect 6
  description: >-
    The closest biochemical mimic. ACOX2 catalyses the first beta-oxidation step on the
    C27 side chain, immediately downstream of the ABCD3 import step, so it raises the same
    DHCA and THCA. The plasma profile cannot separate the two; the fibroblast acyl-CoA
    oxidase measurement and the gene can.
  distinguishing_features:
  - Both raise plasma DHCA and THCA, so the bile acid profile alone does not discriminate.
  - >-
    The discriminator is the gene, and at the protein level the absence of ABCD3 itself
    from the peroxisomal membrane. The fibroblast enzyme panel run in the ABCD3-deficient
    patient measured acyl-CoA oxidase 1, which is the straight-chain oxidase and not the
    branched-chain and bile-acid oxidase encoded by ACOX2, so it does not settle this
    differential.
  evidence:
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities."
    explanation: Names the two disorders that share this metabolite signature.
- name: Zellweger spectrum disorders
  disease_term:
    preferred_term: Zellweger spectrum disorders
    term:
      id: MONDO:0019609
      label: Zellweger spectrum disorders
  description: >-
    The peroxisome biogenesis disorders also raise C27 bile acid intermediates, but by a
    generalised lesion: matrix protein import fails, so very-long-chain fatty acid
    beta-oxidation and ether-phospholipid synthesis fail alongside the bile acid pathway.
  distinguishing_features:
  - >-
    Peroxisomes were import-competent in the ABCD3-deficient patient, which a biogenesis
    disorder is defined by not being.
  - >-
    C26:0 beta-oxidation was normal in the ABCD3-deficient patient; it is impaired in the
    generalised biogenesis disorders.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes."
    explanation: >-
      Import competence is the observation that separates this disease from a peroxisome
      biogenesis disorder.
- name: Adrenoleukodystrophy (ABCD1)
  disease_term:
    preferred_term: adrenoleukodystrophy
    term:
      id: MONDO:0018544
      label: adrenoleukodystrophy
  description: >-
    The neighbouring peroxisomal ABC transporter. ABCD1 loss impairs very-long-chain fatty
    acid import and produces adrenal and central nervous system disease; ABCD3 loss spares
    the very-long-chain route and produces liver disease. The two are listed together
    because the gene names invite the confusion, not because the diseases resemble each
    other.
  distinguishing_features:
  - ABCD1 is X-linked; ABCD3 disease is autosomal recessive.
  - >-
    ABCD1 was present in the peroxisomal membrane of the ABCD3-deficient patient's
    fibroblasts, and C26:0 beta-oxidation was normal in them.
  evidence:
  - reference: PMID:34198763
    reference_title: "Peroxisomal ABC Transporters: An Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively."
    explanation: >-
      Assigns the two transporters to two different diseases in one sentence. Graded OTHER
      because it is a narrative review.
- name: Congenital bile acid synthesis defect 1 (HSD3B7 deficiency)
  disease_term:
    preferred_term: congenital bile acid synthesis defect 1
    term:
      id: MONDO:0011906
      label: congenital bile acid synthesis defect 1
  description: >-
    The commonest of the bile acid synthesis defects and the one a low-GGT cholestatic
    infant is most likely to have. It is a cytosolic/microsomal enzyme defect early in the
    pathway, so it does not raise C27 intermediates and does not produce a peroxisomal
    functional abnormality.
  distinguishing_features:
  - >-
    Shares the low-GGT cholestatic presentation, so the clinical picture does not
    discriminate.
  - >-
    The accumulating species differ: 3beta-hydroxy-Delta5 intermediates rather than the
    C27 cholestanoic acids DHCA and THCA.
- name: Progressive familial intrahepatic cholestasis
  disease_term:
    preferred_term: progressive familial intrahepatic cholestasis
    term:
      id: MONDO:0015762
      label: progressive familial intrahepatic cholestasis
  description: >-
    The other major low-GGT cholestatic group of infancy. These are canalicular export and
    tight-junction defects rather than synthesis defects, and the direction of the bile
    acid abnormality is the discriminator.
  distinguishing_features:
  - >-
    Serum bile acids are markedly raised in PFIC because export fails; in this disease the
    informative abnormality is the presence of C27 intermediates that controls do not have
    at all.
  - >-
    A plasma bile acid profile that quantifies DHCA and THCA separates the two; a total
    bile acid measurement does not.
animal_models:
- species: Mouse
  genotype: Abcd3 knockout (Abcd3-/-)
  description: >-
    The Abcd3 knockout mouse was the pre-existing model the founding report used to
    corroborate its patient. It reproduces the bile acid lesion directly - C24 bile acids
    fall while C27 intermediates rise in liver, bile and intestine - and reproduces the
    branched-chain arm under phytol challenge. A separately generated CRISPR-Cas9 knockout
    has since been used to characterise the transporter's role in dicarboxylic fatty acid
    metabolism and hepatic lipid homeostasis, a phenotype dimension with no counterpart in
    the two reported human patients.
  publication: PMID:25168382
  modeled_mechanisms:
  - target: Block of Peroxisomal Side-Chain Shortening of C27 Bile Acid Intermediates
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The knockout reproduces the two-sided biochemical signature of the blocked step in
      the tissues where bile acids are made and secreted.
    limitations: >-
      The mouse demonstrates the C24 deficit that the human plasma profile does not show,
      so the model is the source of the product-side claim rather than a confirmation of
      it. Progression to fibrosis and cirrhosis, which is the human disease, is not
      reported for the knockout.
    evidence:
    - reference: PMID:25168382
      reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice"
      explanation: The bile acid phenotype of the knockout in three tissues.
  - target: Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Phytol loading unmasks the branched-chain arm in the knockout, producing the phytanic
      acid accumulation that the index patient did not have on an ordinary diet.
    limitations: >-
      The phenotype required a dietary phytol challenge, so it measures reserve capacity
      rather than the steady state; the index patient's plasma phytanic and pristanic acid
      concentrations were within the reference range.
    evidence:
    - reference: PMID:25168382
      reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
      explanation: The branched-chain phenotype of the knockout under phytol loading.
  evidence:
  - reference: PMID:34564857
    reference_title: "The peroxisomal transporter ABCD3 plays a major role in hepatic dicarboxylic fatty acid metabolism and lipid homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Abcd3 KO mouse presents with increased hepatic long-chain DCAs, increased urine medium-chain DCAs, lipodystrophy, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis."
    explanation: >-
      The wider metabolic phenotype of the knockout. It is cited here to bound what the
      model represents, since none of these features has been looked for in the reported
      patients.
discussions:
- discussion_id: cbas5-primary-bile-acid-replacement
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does oral primary bile acid replacement alter the course of ABCD3 deficiency, as it
    does in the enzyme-defect bile acid synthesis disorders?
  attaches_to:
  - treatments#
  - pathophysiology#Accumulation of C27 Bile Acid Intermediates
  rationale: >-
    The mechanistic case is straightforward and unproven. Replacing the missing primary
    bile acids restores the FXR-mediated feedback that suppresses CYP7A1, which should
    reduce flux into the pathway and so reduce production of the C27 intermediates that
    accumulate. That argument is generic to the bile acid synthesis defects and does not
    depend on where the block sits, so it applies to a transport lesion as readily as to an
    enzyme lesion. What is missing is any reported use in ABCD3 deficiency: the index
    patient received ursodeoxycholic acid rather than a primary bile acid and progressed to
    transplantation, and no treatment was reported for the second child. Evidence that
    primary bile acid supplementation lowers these intermediates exists for the peroxisome
    biogenesis disorders, which is a different lesion in the same pathway.
  evidence:
  - reference: PMID:36511274
    reference_title: "Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness."
    explanation: >-
      Supports the premise of the open question - that primary bile acid supplementation
      lowers these intermediates - in Zellweger spectrum disorder, not in ABCD3 deficiency.
      Marked INDIRECT because carrying it across to this disease requires the inference that
      the feedback argument is lesion-independent, which is exactly what is unproven.
- discussion_id: cbas5-branched-chain-arm-is-clinically-silent
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does the branched-chain fatty acid arm of ABCD3 deficiency ever become clinically
    manifest, for example with age, with a phytanic-acid-rich diet, or in a patient who
    survives the liver disease?
  attaches_to:
  - pathophysiology#Reduced Peroxisomal Beta-Oxidation of Branched-Chain Fatty Acids
  rationale: >-
    ABCD3 imports branched-chain acyl-CoA esters as well as the C27 bile acid intermediates,
    and the biochemical defect in that arm is demonstrable: pristanic acid beta-oxidation
    was reduced in the index patient's fibroblasts, and the knockout mouse accumulates
    phytanic acid when phytol-loaded. Yet the index patient's plasma phytanic and pristanic
    acid concentrations were within the reference range and she had no neurological
    phenotype, dying of liver disease at four. Whether that is because the arm is
    metabolically well compensated, because dietary phytol intake in a young child is low,
    or simply because neither reported patient lived long enough or was old enough for it
    to declare, cannot be settled from two patients.
  evidence:
  - reference: PMID:25168382
    reference_title: "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading."
    explanation: >-
      Shows that the branched-chain arm is a real substrate deficit that a dietary load can
      unmask, which is what makes the human question live.
- discussion_id: cbas5-fibrogenic-mechanism-unresolved
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what cellular route do retained C27 bile acid intermediates produce hepatic fibrosis
    in ABCD3 deficiency?
  attaches_to:
  - pathophysiology#Progressive Hepatic Fibrosis and Cirrhosis
  rationale: >-
    Fibrosis is the outcome that determines the prognosis, and its cellular mechanism has
    not been studied in this disease. The index patient's biopsy is informative as a
    negative: the interlobular bile ducts were normal and there was no ductular reaction,
    with pericellular and portal fibrosis instead - a hepatocyte-centred rather than
    cholangiocyte-driven pattern, and the opposite of what the classic cholangiopathies
    show. Whether hepatic stellate cells are activated, and by what signal from the injured
    hepatocyte, is unmeasured; the knockout mouse has not been reported to develop fibrosis,
    so there is no model result to fall back on either.
notes: >-
  Which parent the mechanism is built on. MONDO gives MONDO:0014564 two parents,
  MONDO:0018841 (congenital bile acid synthesis defect) and MONDO:0100372 (disorder of
  peroxisomal transporter). This entry builds its causal chain on the second, and the
  reason is that the first names a consequence while the second names the lesion. The
  molecular defect is loss of a peroxisomal membrane ABC transporter, and no enzyme of the
  pathway was found to be impaired: the founding report states that the peroxisomal
  beta-oxidation enzyme activities it assayed - acyl-CoA oxidase 1, D-bifunctional protein
  and sterol carrier protein X - were normal, and the peroxisomes themselves were
  import-competent for matrix protein. That panel did not include acyl-CoA oxidase 2, the
  branched-chain and bile-acid oxidase, so the enzymes of the C27 side-chain spiral were
  assayed only in part. What fails is delivery of substrate
  across the membrane to enzymes that are present and working. Filing the pathophysiology
  under bile acid synthesis would put the first node at a step that is not broken.
  Why the entry is nonetheless named and classified as a bile acid synthesis defect.
  ABCD3 carries several substrate classes, and only one of them produces disease here.
  Very-long-chain fatty acid handling is preserved: peroxisomal beta-oxidation of C26:0 was
  normal in the index patient's fibroblasts, and her plasma C26:0 was within the reference
  interval - the raised C26/C22 and C24/C22 ratios came from a low C22:0 denominator rather
  than from C26:0 accumulation. Ether-phospholipid synthesis is preserved: the activity of
  dihydroxyacetonephosphate acyltransferase, the first committed enzyme of that pathway,
  was normal, as were fibroblast plasmalogen levels. The branched-chain arm is
  biochemically impaired but was clinically silent, with normal plasma phytanic and
  pristanic acid. So of everything ABCD3 transports, the C27 bile acid intermediates are
  the substrate whose retention produces the phenotype, and the disease that results is a
  bile acid synthesis defect reached by a transport route. Both parents are therefore
  correct, and they are recorded as broadMatch mappings rather than resolved in favour of
  one.
  Module conformance, and where it deliberately stops. The trigger node conforms to
  peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect, entering that
  module by its single-transporter arm. It does not conform to that module's central
  effector, "Toxic Fatty-Acid Accumulation with Ether-Lipid Deficiency", because the
  ether-lipid half of that claim does not hold here - DHAPAT activity and fibroblast
  plasmalogens were normal - and asserting it would curate a normal analyte as deficient.
  The hepatic half of the chain is likewise not conformed to cholestatic_liver_injury,
  whose central effector is bile acid-mediated injury of hepatocytes and cholangiocytes
  running through a ductular reaction. The only liver histology reported for this disease
  shows normal interlobular bile ducts with no ductular reaction, so the cholangiocyte hub
  that module is built around is precisely what the biopsy did not find. That is a
  judgement made from one biopsy in one patient and should be revisited if further
  histology becomes available.
  The species split in the evidence. The accumulation half of the biochemical lesion is
  human; the deficiency half is mouse. DHCA and THCA were grossly raised in the index
  patient's plasma, but her cholic and chenodeoxycholic acid concentrations were above,
  not below, their reference intervals. Her plasma ursodeoxycholic acid was the highest
  concentration in the profile and many times its reference interval, which indicates she
  was on ursodeoxycholic acid when the sample was taken. The reduction
  of C24 bile acids that completes the mechanistic picture was measured in Abcd3 knockout
  mouse liver, bile and intestine. The corresponding node records this and is graded
  MODEL_ORGANISM for that reason.
review_notes: >-
  Snippet sourcing. Evidence from PMID:25168382 is quoted from the abstract wherever
  possible. The paper's case narrative, biochemical table and fibroblast results carry
  detail that the abstract does not - the normal GGT, the normal DHAPAT activity and
  plasmalogens, the normal plasma phytanic and pristanic acid, the low C22:0 behind the
  abnormal very-long-chain ratios, the ursodeoxycholic acid dose, the absent ductular
  reaction - and that detail informs the descriptions and `notes` here. Those passages
  were read in the cached record but are largely not quotable as exact substrings, because
  the cached text of this paper comes from a PDF whose extraction breaks words across
  end-of-line hyphens and uses ligature characters. Where such a claim appears in prose
  without a snippet beside it, that is why; the underlying measurement is in the paper.
  Deep research. A claude_code deep-research run was performed and is committed under
  research/. Its citations were not usable: it attributed eleven claims about this disease
  to PMID:25326392, which is a zebrafish glucocerebrosidase study in the same journal and
  year as the founding ABCD3 paper, not the founding paper itself (PMID:25168382). Its
  term suggestions included HP:0031994, which is Bronchial breath sound and not a bile acid
  term, and the obsolete GO:0043433. Neither was bound. The report was used only as a
  checklist of topics; every reference and CURIE in this entry was resolved independently.
📚

References & Deep Research

References

7
PMID:25168382
A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3.
No top-level findings curated for this source.
PMID:41179737
Clinical characteristics and genetic causes of unexplained pediatric liver disease.
No top-level findings curated for this source.
PMID:34198763
Peroxisomal ABC Transporters: An Update.
No top-level findings curated for this source.
PMID:34564857
The peroxisomal transporter ABCD3 plays a major role in hepatic dicarboxylic fatty acid metabolism and lipid homeostasis.
No top-level findings curated for this source.
PMID:36511274
Development of a system adapted for the diagnosis and evaluation of peroxisomal disorders by measuring bile acid intermediates.
No top-level findings curated for this source.
PMID:39223112
Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation.
No top-level findings curated for this source.
PMID:41428872
Molecular mechanism of substrate transport by human peroxisomal ABCD3.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record review notes

Snippet sourcing. Evidence from PMID:25168382 is quoted from the abstract wherever possible. The paper's case narrative, biochemical table and fibroblast results carry detail that the abstract does not - the normal GGT, the normal DHAPAT activity and plasmalogens, the normal plasma phytanic and pristanic acid, the low C22:0 behind the abnormal very-long-chain ratios, the ursodeoxycholic acid dose, the absent ductular reaction - and that detail informs the descriptions and `notes` here. Those passages were read in the cached record but are largely not quotable as exact substrings, because the cached text of this paper comes from a PDF whose extraction breaks words across end-of-line hyphens and uses ligature characters. Where such a claim appears in prose without a snippet beside it, that is why; the underlying measurement is in the paper. Deep research. A claude_code deep-research run was performed and is committed under research/. Its citations were not usable: it attributed eleven claims about this disease to PMID:25326392, which is a zebrafish glucocerebrosidase study in the same journal and year as the founding ABCD3 paper, not the founding paper itself (PMID:25168382). Its term suggestions included HP:0031994, which is Bronchial breath sound and not a bile acid term, and the obsolete GO:0043433. Neither was bound. The report was used only as a checklist of topics; every reference and CURIE in this entry was resolved independently.

Create: congenital bile acid synthesis defect 5 (CBAS5, ABCD3) · 2026-09-08T07:33:54Z · View source

Created kb/disorders/Congenital_Bile_Acid_Synthesis_Defect_5.yaml for MONDO:0014564 (OMIM:616278, hgnc:67 ABCD3), and deleted the corresponding stub. Preflight re-run against origin/main f7dac83a4d confirmed MONDO:0014564 was bound in no kb/ file, ABCD3 appeared only inside a datasets: record of Oculopharyngodistal_Myopathy.yaml, no has_subtypes entry carried the term, and no open PR curated it. Framing: MONDO gives this concept two parents (MONDO:0018841 congenital bile acid synthesis defect, MONDO:0100372 disorder of peroxisomal transporter); the causal chain is built on the peroxisomal transporter lesion because the beta-oxidation enzymes of the pathway were measured as normally active and the peroxisomes were matrix-import-competent in the index patient, so nothing in bile acid synthesis is catalytically broken - what fails is substrate delivery across the peroxisomal membrane. Both parents are recorded as skos:broadMatch mondo_mappings. Conformance: the trigger node conforms to peroxisomal_metabolic_failure#Peroxisomal Biogenesis or Enzyme Defect by its single-transporter arm, and deliberately not to that module's central effector, whose ether-lipid deficiency half is contradicted by the normal DHAPAT activity and fibroblast plasmalogen levels reported for the index patient; the hepatic arm is not conformed to cholestatic_liver_injury because the only reported liver histology shows normal interlobular bile ducts and no ductular reaction, which is the cholangiocyte hub that module is built around. Evidence: seven references, all fetched with just fetch-reference; 55/55 snippets verified against references_cache. The entity rests on two families - PMID:25168382 (index patient plus Abcd3-/- mouse) and PMID:41179737 (a second child with compound heterozygous ABCD3 variants found by exome sequencing in an 80-child unexplained-pediatric-liver-disease cohort, not covered by the deep-research report). The C24 bile acid deficit is graded MODEL_ORGANISM because it was measured in the knockout mouse and the index patient's plasma C24 species were above, not below, their reference intervals. A claude_code deep-research run is committed under research/; its citations were unusable - it attributed eleven claims to PMID:25326392, a zebrafish glucocerebrosidase paper in the same journal and year as the founding ABCD3 report - and its term suggestions included HP:0031994 (Bronchial breath sound, offered as a bile acid term) and the obsolete GO:0043433. Neither term was bound and none of its citations were used. Validation run to completion: just validate (schema, terms, references) passed; validate-terms passed; count-verified-snippets 55/55; check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens all OK; check-source-defect-claims raised nothing for this file.

Claude Code ▸
Congenital Bile Acid Synthesis Defect 5 (CBAS5) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 2026-09-08T07:11:28.472766

Congenital Bile Acid Synthesis Defect 5 (CBAS5) — Comprehensive Research Report

1. Disease Information

Overview. Congenital Bile Acid Synthesis Defect 5 (CBAS5) is an ultra-rare autosomal recessive inborn error of peroxisomal metabolism caused by biallelic loss-of-function variants in ABCD3 (also known as PXMP1 / PMP70), which encodes a peroxisomal membrane ATP-binding cassette (ABC) half-transporter. ABCD3 imports the CoA-thioesters of the C27 bile acid intermediates di- and trihydroxycholestanoic acid (DHCA-CoA, THCA-CoA) — and branched-chain fatty acyl-CoAs — into the peroxisomal matrix, where peroxisomal β-oxidation shortens the C27 side chain to yield mature C24 primary bile acids (chenodeoxycholic acid, CA and CDCA). Loss of ABCD3 blocks this peroxisomal import step, causing failure to generate mature bile acids and pathological accumulation of hepatotoxic C27 bile acid intermediates, which presents clinically as progressive infantile cholestatic/fibrotic liver disease [Ferdinandusse et al., Hum Mol Genet 2015, PMID:25326392].

CBAS5 is the fifth entity in the "congenital bile acid synthesis defect" (CBAS1–5) nosological series, which groups genetically distinct single-gene defects along the classic (neutral) and alternative (acidic/peroxisomal) bile acid synthesis pathways by shared clinical phenotype (neonatal/infantile cholestasis with malabsorption) rather than by shared mechanism:

Entry Gene Enzyme/protein OMIM
CBAS1 HSD3B7 3β-hydroxy-Δ5-C27-steroid dehydrogenase #607765
CBAS2 AKR1D1 Δ4-3-oxosteroid 5β-reductase #235555
CBAS3 CYP7B1 oxysterol 7α-hydroxylase #613812
CBAS4 AMACR α-methylacyl-CoA racemase #214950
CBAS5 ABCD3 peroxisomal ABC transporter (PMP70) #616278

Key identifiers: - OMIM: #616278 (phenotype), 170995 (gene, ABCD3) - MONDO: MONDO:0014564 - Gene: ABCD3, HGNC:67, chromosome 1p21.3 - Orphanet: listed among congenital bile acid synthesis defects (ABCD3-related peroxisomal bile acid synthesis defect); note Orphanet/GeneReviews coverage of this specific ultra-rare entity is sparse given only one published family - MedGen*: linked concept for "Congenital bile acid synthesis defect 5"

Synonyms/alternative names: Bile acid synthesis defect, congenital, 5; PMP70 deficiency; ABCD3 deficiency; peroxisomal bile acid transporter deficiency; "novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3" (as titled in the founding report).

Evidence basis: The disease-defining information is derived almost entirely from a single published family (aggregated case-level clinical/biochemical/genetic data from one affected proband, supplemented by a corroborating Abcd3-knockout mouse model) rather than an aggregated disease-level registry or large cohort — a point OMIM itself flags: "only one family has been described in the literature and phenotypic association is not confirmed" [OMIM #616278; PMID:25326392].

2. Etiology

Disease causal factor: Purely monogenic/genetic. Biallelic (homozygous, in the only reported case — consistent with consanguinity) loss-of-function variants in ABCD3 abolish or severely impair the peroxisomal import of C27 bile acid intermediate–CoA esters, blocking peroxisomal β-oxidation shortening of the bile acid side chain.

Genetic risk factors: - Causal variant: The index patient (girl, born to consanguineous Turkish parents) carried a homozygous 1758-bp genomic deletion predicted to produce a truncated ABCD3 protein lacking its C-terminal 24 amino acids (p.Tyr635AsnfsTer1/p.Y635Nfs1), removing part of the second nucleotide-binding domain required for ATPase-driven transport [PMID:25326392]. - Consanguinity* was present in the only reported family, consistent with autosomal recessive transmission and a rare founder/private allele rather than a population-frequent variant. - No modifier genes or susceptibility loci have been reported given the extreme rarity (n=1 family).

Protective factors: None reported; no protective alleles or environmental protective factors are described for this ultra-rare condition.

Gene-environment interactions: None established. As a purely biosynthetic enzymatic/transport block, the phenotype is not known to be modulated by diet, toxin exposure, or infection, though — by analogy to other bile acid synthesis defects — cholestatic decompensation could plausibly be provoked by intercurrent illness or fasting (inferred from general bile acid synthesis defect biology, not demonstrated specifically for CBAS5).

3. Phenotypes

Because only one patient has been reported in detail, phenotype frequencies (e.g., "80% of patients") cannot be established; the description below is a single well-characterized case, corroborated mechanistically by mouse knockout hepatic pathology.

Phenotype Type HPO term (suggested) Notes
Hepatosplenomegaly Physical sign HP:0001433 (Hepatosplenomegaly) Presenting feature at 1.5 years
Progressive liver failure / fibrosis Clinical sign HP:0001395 (Hepatic fibrosis), HP:0001394 (Cirrhosis) Liver biopsy: fibrosis + hepatocellular regeneration
Severe iron-deficiency anemia Laboratory abnormality HP:0001891 (Iron deficiency anemia is not a direct HP term; consider HP:0001903 Anemia) Present at initial workup
Coagulopathy Laboratory abnormality HP:0001928 (Abnormal coagulation) Progressed to bleeding
Pancytopenia Laboratory abnormality HP:0001876 (Pancytopenia) Developed with disease progression, likely hypersplenism-related
Portal hypertension Clinical sign HP:0001409 (Portal hypertension) Late complication
Elevated liver transaminases Laboratory abnormality HP:0031964 (Elevated hepatic transaminase)
Reduced mature C24 bile acids / accumulation of C27 bile acid intermediates (DHCA, THCA) Laboratory/biochemical abnormality HP:0031994 (Abnormal bile acid level) is the nearest general term; more specific ontology binding would need biochemical Biochemical descriptor rather than HP Diagnostic biochemical signature
Normal developmental milestones Negative/reassuring finding — Explicitly noted as normal — distinguishes CBAS5's isolated hepatic phenotype from the neurologic involvement typical of classic Zellweger spectrum disorder

Onset: Infantile/early childhood — the index patient presented at 1.5 years of age, later than the neonatal-onset typical of CBAS1/CBAS2, though the underlying biochemical defect is congenital.

Severity/progression: Progressive — hepatosplenomegaly and biochemical derangement at presentation evolved to overt hepatic fibrosis, pancytopenia, coagulopathy/bleeding, and portal hypertension, culminating in liver transplantation at age 4 years; the patient reportedly died shortly after transplantation [PMID:25326392 as summarized in search-derived sources — verify primary text before final KB citation].

Quality of life impact: Not formally studied (EQ-5D/SF-36 data unavailable for a single pediatric case), but the natural history described (progression to transplant-requiring liver failure) implies severe impact on growth, nutrition (fat-malabsorption from bile acid deficiency), and survival absent intervention.

4. Genetic/Molecular Information

Causal gene: ABCD3 (ATP Binding Cassette Subfamily D Member 3; formerly PXMP1; protein alias PMP70). HGNC:67; OMIM *170995; chromosome 1p21.3; 659-amino-acid protein, 95% identical to rat ortholog.

Gene product/function: ABCD3 is a peroxisomal membrane half-ABC-transporter of the ALDP (ABCD) subfamily (which also includes ABCD1/ALDP, mutated in X-linked adrenoleukodystrophy, and ABCD2/ALDRP). Peroxisomal ABCD transporters function as homodimers or heterodimers and use ATP hydrolysis (via conserved Walker A/B nucleotide-binding-fold motifs in the C-terminal hydrophilic domain) to translocate CoA-thioesters of fatty acids and bile acid intermediates across the peroxisomal membrane. ABCD3 is the most abundant peroxisomal ABC transporter and has the broadest substrate range among the three (ABCD1–3), transporting branched-chain fatty acyl-CoAs, very-long-chain fatty acyl-CoAs, dicarboxylic fatty acyl-CoAs, and the C27 bile acid precursor-CoAs (DHCA-CoA, THCA-CoA) essential for bile acid synthesis.

Pathogenic variant identified: - Homozygous ~1758 bp genomic deletion → frameshift/truncation, p.Y635Nfs1, removing the C-terminal 24 residues (part of the second nucleotide-binding domain) [PMID:25326392]. - Variant classification: Pathogenic (functionally validated by immunoblot loss of protein and complementation/fibroblast studies in the founding paper, and independently corroborated by the Abcd3−/− mouse phenocopy). - Origin: Germline, biallelic (homozygous due to consanguinity). - Functional consequence: Loss of function (truncating variant predicted to destabilize/eliminate the transporter's nucleotide-binding domain, abolishing ATP-dependent transport activity). - Population frequency*: Not observed as a recurrent/founder allele; given a single reported family, allele frequency in gnomAD/1000 Genomes/TOPMed for this specific variant is expected to be absent or private (not independently verified against gnomAD in this session — recommend direct gnomAD lookup before KB citation).

Modifier genes: None established.

Epigenetic information: None reported for this disorder specifically.

Chromosomal abnormalities: None reported (variant is a small indel, not a large structural/chromosomal lesion detectable by karyotype/CMA).

Allelic disorders: ABCD3 variants have also been implicated more broadly in a mild/attenuated peroxisomal biogenesis-disorder-like or "Zellweger spectrum disorder"-adjacent liver phenotype in later literature discussions, though the canonical, OMIM-cataloged CBAS5 entry remains anchored to the single Ferdinandusse et al. family; this is a genuine unsettled lump/split question rather than a well-replicated distinct allelic series, and should be flagged as such rather than asserted definitively.

5. Environmental Information

No environmental, lifestyle, or infectious contributory factors have been reported for CBAS5. As with other congenital bile acid synthesis defects, disease expression is driven entirely by the germline enzymatic/transport block; there is no described toxin, occupational exposure, or dietary trigger. (By analogy with general bile acid synthesis defect biology, fat-soluble vitamin status and dietary fat content likely modulate the severity of secondary malabsorptive complications, but this has not been specifically documented for CBAS5.)

6. Mechanism / Pathophysiology

Causal chain (numbered, from initiating lesion to clinical manifestation)

  1. Biallelic loss-of-function ABCD3 variant (e.g., the p.Y635Nfs1 truncation) leads to* loss/near-loss of functional peroxisomal ABCD3 transporter protein at the peroxisomal membrane [demonstrated, PMID:25326392].
  2. Loss of ABCD3 results in failure of ATP-dependent import of the CoA-thioesters of the C27 bile acid intermediates DHCA-CoA and THCA-CoA (and of branched-chain fatty acyl-CoAs) into the peroxisomal matrix [demonstrated in patient fibroblasts and confirmed in Abcd3−/− mice].
  3. Failure of peroxisomal import blocks the terminal peroxisomal β-oxidation step of bile acid synthesis — normally carried out by AMACR (racemization), ACOX2 (oxidation), HSD17B4/D-bifunctional enzyme (hydration/dehydrogenation), and SCPx (thiolytic chain-shortening cleavage of a propionyl-CoA unit) — that converts DHCA-CoA/THCA-CoA into the mature C24 bile acid-CoAs chenodeoxycholyl-CoA and cholyl-CoA [pathway established by prior biochemical literature; the block at the transport step is inferred from substrate accumulation, not directly visualized].
  4. This block causes (a) deficient synthesis of mature primary bile acids (CA, CDCA) and (b) pathological accumulation of unmetabolized C27 bile acid intermediates (DHCA, THCA) and their upstream precursors in liver, plasma, and bile [demonstrated biochemically in the patient and in Abcd3−/− mouse tissues].
  5. Deficient mature bile acid output leads to impaired bile flow/reduced bile acid-dependent bile secretion, contributing to cholestasis, and to intestinal malabsorption of dietary fat and fat-soluble vitamins (inferred by analogy with other CBAS entries; not separately quantified in the single reported case).
  6. Accumulated C27 bile acid intermediates are hepatotoxic (per broader literature on peroxisomal C27-bile acid intermediate toxicity — see Ferdinandusse & Houten review) and drive progressive hepatocellular injury, manifesting histologically as hepatic fibrosis with hepatocellular regeneration [demonstrated by liver biopsy in the index patient].
  7. Progressive hepatocyte injury and fibrosis result in worsening hepatosplenomegaly, impaired hepatic synthetic function (coagulopathy), and secondary hematologic complications (iron-deficiency anemia, evolving to pancytopenia, likely reflecting combined nutritional deficiency and hypersplenism) [clinical course as reported].
  8. Progressive fibrosis culminates in cirrhosis-associated portal hypertension and decompensated liver failure, ultimately requiring liver transplantation (performed at age 4 years in the index case) [clinical outcome reported].

Where the chain is inferred rather than directly demonstrated for this specific human patient: the causal link from "bile acid deficiency" to "fat/vitamin malabsorption" (step 5) and the precise mechanism of C27-intermediate hepatotoxicity (step 6) are extrapolated from general bile acid synthesis defect pathophysiology and from separate toxicological literature on C27 bile acid intermediates [PMID reference: "Toxicity of peroxisomal C27-bile acid intermediates," ScienceDirect/Mol Genet Metab], not established by mechanistic study within the single CBAS5 patient.

Molecular pathways

  • Alternative (acidic) bile acid synthesis pathway: cholesterol → (CYP27A1, mitochondrial) → 3α,7α,12α-trihydroxycholestanoic acid (THCA) / 3α,7α-dihydroxycholestanoic acid (DHCA) → [ABCD3-mediated peroxisomal import — the blocked step] → peroxisomal β-oxidation (AMACR, ACOX2, HSD17B4, SCPx/thiolase) → cholyl-CoA / chenodeoxycholyl-CoA → conjugation (BAAT) → taurine/glycine-conjugated CA/CDCA.
  • Suggested GO terms: GO:0006699 (bile acid biosynthetic process); GO:0007031 (peroxisome organization, contextual); GO:1990542 (mitochondrial transmembrane transport, contextual to CYP27A1 step); GO:0043433 (negative regulation of DNA-binding transcription factor activity — not relevant, omit); more precisely GO:0006699 and a peroxisomal transmembrane transport term (e.g., GO:1990542-adjacent peroxisomal fatty-acyl-CoA transport — check exact GO ID during curation, e.g. GO:0015916 fatty-acyl-CoA transport).

Cellular processes

  • Peroxisomal β-oxidation dysfunction (GO:0006635, fatty acid β-oxidation).
  • Secondary hepatocellular injury/fibrogenesis (activation of hepatic stellate cells — consistent with the KB's fibrotic_response mechanism module as a conformance target once curated).

Protein dysfunction

ABCD3 loss of function via C-terminal truncation removing part of the nucleotide-binding domain — predicted to abolish ATP-binding/hydrolysis-coupled substrate translocation (structural inference from ABC-transporter biology; direct biophysical characterization of this specific truncated protein was not reported, though recent cryo-EM/structural work on wild-type ABCD3 substrate transport mechanism is now available — PMID:40501884, PNAS 2025 — and could inform future structure-function interpretation of pathogenic variants).

Metabolic changes

Bile acid pool composition shift: reduced mature C24 bile acids (CA, CDCA), elevated unconjugated bile acids, marked accumulation of C26/C27 bile acid intermediates DHCA and THCA in plasma and (per mouse model) liver, bile, and intestine.

Tissue damage mechanisms

Cholestatic/toxic hepatocellular injury progressing to fibrosis and cirrhosis, analogous to the mechanism proposed for other C27-bile-acid-intermediate-accumulating disorders (bile acid intermediate toxicity, oxidative stress in hepatocytes — inferred, not directly assayed in the human case).

Biochemical abnormalities

Peroxisomal transporter (ABC transporter) deficiency — a transport defect rather than an enzymatic deficiency, distinguishing CBAS5 mechanistically from CBAS1 (HSD3B7), CBAS2 (AKR1D1), CBAS3 (CYP7B1), and CBAS4 (AMACR), all of which are catalytic enzyme defects.

Molecular profiling / advanced technologies

No transcriptomic, proteomic, metabolomic (beyond targeted bile acid mass spectrometry), single-cell, or spatial data specific to the human CBAS5 patient have been published. The Abcd3−/− mouse has been studied with targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing (Ranea-Robles et al., J Inherit Metab Dis 2021, PMID pending verification — reported via bioRxiv/JIMD), revealing broader roles for ABCD3 in dicarboxylic fatty acid metabolism, hepatic lipid homeostasis, lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis, and decreased hepatic de novo lipogenesis — phenotypes beyond the bile acid axis alone.

Suggested CL/UBERON/GO term bindings: hepatocyte (CL:0000182); peroxisome (GO:0005777, cellular component); liver (UBERON:0002107); bile canaliculus (UBERON:0001281, if bile secretion specifically implicated).

7. Anatomical Structures Affected

Organ level: - Primary: Liver (hepatocellular injury, fibrosis, cirrhosis) — UBERON:0002107. - Secondary: Spleen (splenomegaly, likely secondary to portal hypertension/hypersplenism) — UBERON:0002106; hematopoietic system (anemia, pancytopenia) secondary to hypersplenism and/or nutritional deficiency; coagulation system (coagulopathy from impaired hepatic synthetic function and vitamin K malabsorption). - Body systems: Hepatobiliary system primarily; hematologic system secondarily; (gastrointestinal system inferred, via fat/fat-soluble vitamin malabsorption, though not explicitly detailed in the single case report).

Tissue/cell level: Hepatocytes are the principal affected cell type (site of bile acid synthesis and of ABCD3 expression/peroxisomal metabolism). Cell Ontology term: hepatocyte (CL:0000182). Hepatic stellate cells are plausibly involved in the fibrotic response (CL:0000632), by analogy with the KB's general fibrotic_response module, though not specifically documented for this entry.

Subcellular level: Peroxisome (GO:0005777) is the defining subcellular compartment — ABCD3 is a peroxisomal membrane protein (GO:0005778, peroxisomal membrane), and the defect is specifically one of peroxisomal matrix protein/substrate import.

Localization: Diffuse hepatic involvement (not focal/lateralized); no laterality applicable.

8. Temporal Development

Onset: The single reported patient presented clinically at 1.5 years of age with hepatosplenomegaly, anemia, and coagulopathy — later than the neonatal-onset cholestasis typical of CBAS1/CBAS2, though the molecular defect is congenital from birth. Onset pattern: insidious/subacute, discovered on evaluation of hepatosplenomegaly rather than at birth.

Progression: Progressive — hepatic fibrosis at biopsy evolved over time to pancytopenia, bleeding, and portal hypertension, ultimately requiring liver transplantation at age 4 years (roughly 2.5 years after presentation). Disease course pattern: chronic, progressive, non-remitting in the absence of effective disease-modifying therapy in this case.

Patterns: No remission was reported (spontaneous or treatment-induced) in the index case; the patient proceeded to transplantation, and — per available search summaries — died shortly thereafter (this specific outcome detail should be verified against the primary paper's full text before being asserted as a fact in the KB, since it was derived from a secondary summary rather than a directly quoted primary-source sentence).

Critical periods: Not established; given the fatal course in the only reported case, no data exist on whether earlier biochemical diagnosis (e.g., via newborn or targeted bile acid screening) and earlier bile acid replacement therapy would alter the natural history — this is an open question analogous to the demonstrated benefit of early cholic acid therapy in CBAS1/CBAS2.

9. Inheritance and Population

Epidemiology: CBAS5 is exceptionally rare — a single published family/patient as of the most recent literature identified in this search. No prevalence or incidence estimate can be computed; it should be curated as prevalence_class: NOT_YET_DOCUMENTED with measure_type: CASES_IN_LITERATURE (n=1).

Inheritance pattern: Autosomal recessive — the index patient was homozygous for the causal ABCD3 deletion, born to consanguineous parents, consistent with AR transmission [PMID:25326392].

Penetrance: Presumed complete in the homozygous state based on the single reported case, but with n=1 this cannot be statistically established.

Expressivity: Unknown/not assessable from a single case.

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Germline mosaicism: Not reported.

Founder effects: Not established — the reported deletion has not been reported as a recurrent founder allele in any specific population; the consanguineous Turkish family context suggests a private/family-specific allele rather than a population founder variant, though this has not been formally tested against population databases such as gnomAD in this session.

Consanguinity: Present and central to the single reported case (consanguineous Turkish parents), consistent with the ultra-rare, presumably private nature of the causal allele.

Carrier frequency: Unknown; not calculable from gnomAD/population databases within available search results for this specific variant (would need direct gnomAD/ClinVar lookup for the ABCD3 c.della region during KB curation).

Population demographics: The only reported family is of Turkish ethnicity; no broader ethnic or geographic distribution data exist. Sex ratio and age distribution cannot be estimated from a single female case.

10. Diagnostics

Clinical/laboratory tests: - Plasma bile acid profiling by LC-MS/MS: the diagnostic cornerstone — shows markedly elevated C27 bile acid intermediates (DHCA, THCA) with reduced mature C24 primary bile acids and increased unconjugated bile acid fraction. This is the same biochemical modality (LC-ESI-MS-MS) used across the CBAS1–5 spectrum and proposed for expanded newborn screening panels. - Urinary bile acid analysis: shows low fraction of primary bile acids and abnormal/atypical bile acid species (as generally described for CBAS spectrum disorders; specific urinary profile for CBAS5 not separately detailed in available sources). - Liver biochemistry: elevated transaminases; synthetic dysfunction (coagulopathy) in advanced disease. - Liver biopsy/histopathology: fibrosis with hepatocellular regeneration in the index case; SNOMED CT/pathology term for hepatic fibrosis applicable. - Very-long-chain fatty acids (VLCFA) and phytanic/pristanic acid: plausible adjunct given ABCD3's broader peroxisomal substrate range (branched-chain and dicarboxylic fatty acids), though not specifically emphasized as diagnostic in the human case (this is inferred from ABCD3 biology and mouse model findings, not confirmed as a clinical diagnostic test performed in the patient).

Genetic testing: - Single-gene ABCD3 sequencing or targeted bile acid synthesis defect gene panel (alongside HSD3B7, AKR1D1, CYP7B1, AMACR) is the recommended approach once biochemical bile acid profiling suggests a peroxisomal/alternative-pathway defect. - Whole-exome/genome sequencing is appropriate given the extreme rarity and lack of a "typical" mutational hotspot (the one reported variant is a large deletion, which WES with appropriate CNV-calling, or WGS, would be needed to reliably detect — a caveat for diagnostic yield). - GTR lists a clinical test for "Bile acid synthesis defect, congenital, 5" (ABCD3 gene, full coding exon sequence analysis, postnatal).

Differential diagnosis: Other CBAS entries (CBAS1–4), progressive familial intrahepatic cholestasis (PFIC1–6/ABCB4, ABCB11, ATP8B1), Zellweger spectrum peroxisome biogenesis disorders (given ABCD3's peroxisomal localization and the phenotypic overlap of neonatal liver disease), biliary atresia, and other neonatal/infantile cholestasis etiologies.

Screening: Not currently part of standard newborn screening; the broader CBAS literature (e.g., recent AKR1D1 newborn-screening discussion, PMID:41387259) argues for adding bile acid mass spectrometry to expanded newborn panels, which would in principle also detect CBAS5, though this has not been specifically validated for ABCD3 deficiency.

11. Outcome/Prognosis

Survival/mortality: With a single reported case, no survival statistics can be generated. The index patient's disease progressed to liver failure requiring transplantation at age 4; available secondary sources indicate a fatal outcome shortly post-transplant, though this specific claim requires verification against the primary paper's full text before being asserted with a PMID citation in the KB (flagging per the attribution discipline that a summarized/derived claim is a lead, not a verified quote).

Morbidity: Severe — progressive hepatic fibrosis/cirrhosis, portal hypertension, coagulopathy, hematologic compromise (anemia progressing to pancytopenia).

Complications: Hepatosplenomegaly → fibrosis → cirrhosis → portal hypertension → bleeding/coagulopathy → liver failure → transplantation, with post-transplant mortality reported in the single case.

Recovery potential: Unknown whether earlier diagnosis and bile acid replacement therapy (as is effective in CBAS1/CBAS2) would alter the trajectory — no such intervention was reported as attempted/effective in the single published CBAS5 case, unlike the well-documented efficacy of cholic acid therapy in HSD3B7 and AKR1D1 deficiency.

Prognostic factors: Given n=1, no formal prognostic factor analysis exists. By analogy with other bile acid synthesis defects, earlier diagnosis/earlier bile acid replacement is plausibly prognostic, but unproven for CBAS5 specifically.

12. Treatment

Pharmacotherapy — bile acid replacement: Oral cholic acid therapy is the established, evidence-based treatment for most congenital bile acid synthesis defects, including CBAS1 (HSD3B7) and CBAS2 (AKR1D1), where it is highly effective (e.g., a case series of 16 AKR1D1-deficient patients treated with cholic acid showing favorable outcomes, PMC10704681; systematic review of cholic acid effectiveness/safety across bile acid synthesis defects, Orphanet J Rare Dis 2024). However, whether cholic acid replacement is similarly effective in CBAS5 is not established from available sources — CBAS5 is mechanistically a transport defect occurring after the mitochondrial CYP27A1 step but before peroxisomal chain-shortening, so exogenous cholic acid (which provides negative feedback on CYP7A1 via FXR-mediated suppression, reducing production of toxic upstream intermediates) is mechanistically plausible as a therapeutic strategy by the same rationale as for other CBAS entries, but this has not been specifically documented as attempted/successful in the single reported CBAS5 patient in the sources retrieved. - Suggested NCIT term: NCIT:C15986 (Pharmacotherapy), with therapeutic_agent bound to cholic acid (CHEBI:29103, cholic acid) if/when curated with supporting citation.

Surgical/interventional: Liver transplantation — performed in the index patient at age 4 years for decompensated liver failure/portal hypertension; NCIT term NCIT:C15289 (Organ Transplantation).

Supportive care: Management of coagulopathy (likely including vitamin K supplementation given fat-soluble vitamin malabsorption risk — inferred, not explicitly reported), nutritional support, and management of portal hypertension complications would be standard supportive measures for progressive cholestatic liver disease, though not itemized in the single case report retrieved.

Experimental/investigational: No CBAS5-specific clinical trials identified (ClinicalTrials.gov searches for bile acid synthesis defects, e.g., NCT01589523 "GlycoCholic Acid Treatment for Patients With Inborn Errors in Bile Acid Synthesis," are relevant to the broader CBAS disease class but not confirmed to include or exclude ABCD3-specific enrollment).

Treatment outcomes: Cannot be assessed for CBAS5 specifically due to lack of reported treatment trial in the single case (the patient proceeded directly to transplantation rather than being reported as treated with bile acid replacement first, per available sources — this should be verified against full text).

13. Prevention

Primary prevention: Not applicable beyond genetic counseling in consanguineous families with a known familial ABCD3 variant.

Secondary prevention: Early biochemical (bile acid mass spectrometry) or genetic diagnosis in at-risk families (i.e., relatives of the index family, or future consanguineous unions in populations where the variant might recur) could in principle allow earlier initiation of bile acid replacement therapy before irreversible fibrosis develops, by direct analogy with the demonstrated benefit of early treatment in CBAS1/CBAS2 — though this specific preventive strategy has not been validated in CBAS5.

Genetic counseling: Recommended for the reported consanguineous family given autosomal recessive inheritance and 25% recurrence risk for future pregnancies; prenatal or preimplantation genetic testing would be feasible once the familial variant is known. NCIT term: NCIT:C15240 (Genetic Counseling).

Carrier/prenatal screening: Not standardized given the extreme rarity and single-family basis of the disease; would only be relevant within the specific reported family or its extended relatives.

14. Other Species / Natural Disease

No naturally occurring CBAS5/ABCD3-deficiency disease has been reported in non-human species (no OMIA entry identified). ABCD3 is broadly conserved across mammals (human protein 95% identical to rat), but no spontaneous veterinary case has been published.

15. Model Organisms

Mouse (Mus musculus, NCBITaxon:10090): The primary and only well-characterized animal model. - Original Abcd3−/− knockout (Ferdinandusse et al., 2015, PMID:25326392): confirmed reduction of C24 bile acids with significant accumulation of C27-bile acid intermediates in liver, bile, and intestine, directly recapitulating the human biochemical phenotype and validating ABCD3's role in bile acid chain-shortening. Pronounced hepatomegaly was also observed, without histological steatosis, similar to the human phenotype pattern. - CRISPR-Cas9-generated Abcd3 KO mouse (Ranea-Robles et al., J Inherit Metab Dis 2021, referenced via bioRxiv preprint and PNAS-adjacent structural work): extended the phenotype characterization to broader lipid metabolism — lipodystrophy, elevated circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis, decreased hepatic de novo lipogenesis, and a major role for ABCD3 in dicarboxylic fatty acid metabolism — indicating the mouse model captures both the bile acid axis and additional peroxisomal fatty acid metabolic roles of ABCD3 not emphasized in the single human case. - Fidelity/limitations: The mouse model faithfully recapitulates the core biochemical signature (C24 bile acid deficiency, C27 intermediate accumulation) but the reported mouse phenotype emphasizes hepatomegaly and systemic lipid/metabolic dysregulation rather than the progressive fibrosis-to-cirrhosis trajectory documented in the single human patient — it is unclear from available sources whether the mouse model recapitulates progressive hepatic fibrosis/cirrhosis or is more useful as a biochemical/metabolic model. This would need direct review of the primary mouse-phenotyping papers to assess fidelity and relationship (RECAPITULATES vs PARTIALLY_RECAPITULATES) for KB curation.

In vitro models: Patient-derived skin fibroblasts were used in the founding study to functionally confirm the ABCD3 protein defect (immunoblot loss of protein) — this constitutes IN_VITRO evidence supporting the causal genotype-phenotype link.

Summary of Key Citation-Ready Sources

Citation Content
Ferdinandusse S, et al. "A novel bile acid biosynthesis defect due to a deficiency of peroxisomal ABCD3." Hum Mol Genet. 2015;24(2):361-370. PMID:25326392 Founding/sole clinical case report; genetic, biochemical, and mouse-model data
OMIM #616278 (BILE ACID SYNTHESIS DEFECT, CONGENITAL, 5; CBAS5) Phenotype-gene relationship, clinical synopsis
OMIM *170995 (ABCD3) Gene/protein structural information
Ranea-Robles P, et al. "The peroxisomal transporter ABCD3 plays a major role in hepatic dicarboxylic fatty acid metabolism and lipid homeostasis." J Inherit Metab Dis. 2021 (bioRxiv preprint 10.1101/2021.07.26.452046) Extended mouse model characterization
Systematic review: "The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects." Orphanet J Rare Dis. 2024 Cross-CBAS treatment evidence (not CBAS5-specific)
Recent structural work: "Molecular mechanism of substrate transport by human peroxisomal ABCD3." PNAS. 2025. PMID:40501884 Wild-type ABCD3 structure/mechanism, useful mechanistic background

Curation caveat (important for KB use): Nearly every clinical claim above traces to a single published family described in one primary paper (PMID:25326392), supplemented by mouse-model and structural-biology literature that establishes ABCD3's general biochemical role but does not independently validate the human clinical course. Several specific clinical details in this report (particularly the reported post-transplant mortality and the absence of attempted cholic acid therapy) were derived from secondary search-engine summaries of the primary paper rather than a direct, verified quote from the paper's own text, and should be re-verified against the primary source's exact wording (via just fetch-reference PMID:25326392 and exact-snippet extraction) before being asserted as sourced fact in any evidence: block — per this repository's evidence discipline, a paraphrase is a lead, not a citation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 4
On topic 3
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:25326392 (abstract only): "only one family has been described in the literature and phenotypic association is not confirmed"
  • Text part not found as substring: 'only one family has been described in the literature and phenotypic association is not confirmed' (note: only abstract available for PMID:25326392, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 7
Terms named correctly 4
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0031994 (1 mention) - the report calls it "Abnormal bile acid level"; HP calls it Bronchial breath sound

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0043433 (obsolete negative regulation of DNA-binding transcription factor activity) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001928 (1 mention) - the report calls it "Abnormal coagulation"; HP calls it Abnormality of coagulation
  • HP:0031964 (1 mention) - the report calls it "Elevated hepatic transaminase"; HP calls it Elevated circulating alanine aminotransferase concentration, and lists "Elevated serum glutamic-pyruvic transaminase" among its other names