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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal Recessive HP:0000007

Biallelic SAR1B pathogenic variants are required. Heterozygous parents are clinically and biochemically unremarkable, which is one reason a family history is usually absent and diagnosis is delayed.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"CMRD is inherited in an autosomal recessive manner."

GeneReviews states the mode of inheritance directly.

PMID:17945526 SUPPORT Human Clinical

"Anderson disease (and/or chylomicron retention disease-CMRD) is a rare, autosomic recessive disorder characterized by chronic diarrhea, failure to thrive, and hypocholesterolemia in childhood."

A 15-patient case series describes the disorder as autosomal recessive.

PMID:20920215 SUPPORT Human Clinical

"Normal Fasting lipids in parents 100%"

In the two-centre cohort the fasting lipid profile of every parent was normal, consistent with clinically silent heterozygous carriage.

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Pathophysiology

12

SAR1B Loss of Function

Biallelic SAR1B variants remove or cripple the small Ras-superfamily GTPase that begins COPII coat assembly. Reported alleles include nonsense and frameshift changes and a whole-exon-2 deletion, all of which truncate the protein, and missense substitutions clustered around the guanine-nucleotide recognition and SEC23-interaction surfaces. The paralogue SAR1A, which differs at only twenty of 198 residues, is upregulated in patient duodenum but does not restore chylomicron export.

SAR1B hgnc:10535

SAR1B GTPase activity GO:0003924 ⇓ LOSS OF FUNCTION

Downstream

Defective COPII Coat Assembly at Endoplasmic Reticulum Exit Sites SAR1B-GTP is the first coat component recruited to an ER exit site and is what brings SEC23-SEC24 to the membrane, so losing it disables coat nucleation.

Impaired Intestinal HDL Biogenesis and Cholesterol Efflux A branch that does not run through chylomicron retention. SAR1B loss in enterocyte-like cells reduces cholesterol efflux and nascent HDL formation via reduced ABCA1 expression, which is the most likely explanation for the low HDL cholesterol seen in patients.

Impaired Hepatic ApoB Lipoprotein Secretion A second extra-intestinal branch. Sar1B also promotes hepatic apoB lipoprotein secretion, which is the proposed explanation for the hepatic steatosis and the severity of the hypocholesterolaemia in a disease whose primary lesion is intestinal.

Show evidence (4 references)

PMID:12692552 SUPPORT Human Clinical

"Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption."

The original identification of SAR1B (then SARA2) mutations as the cause of the fat-malabsorption phenotype.

PMID:17945526 SUPPORT Computational

"The nonsense mutation and the whole deletion of exon 2 produced truncated proteins, the missense mutations probably non-functional proteins."

Structural and sequence analysis of five alleles supports loss of function as the shared consequence.

PMID:36594468 SUPPORT Other

"The human SAR1A and SAR1B paralogs differ at only 20 of 198 amino acid residues."

Quantifies the paralogue similarity that makes the failure of SAR1A compensation notable.

+ 1 more reference

Defective COPII Coat Assembly at Endoplasmic Reticulum Exit Sites

At an ER exit site the transmembrane guanine-nucleotide exchange factor SEC12 loads SAR1B with GTP; SAR1B-GTP inserts an amphipathic helix into the ER membrane and recruits the SEC23-SEC24 inner coat, followed by the SEC13-SEC31 outer coat. SEC23 is also the GTPase-activating protein that triggers hydrolysis and coat turnover. A variant that blocks nucleotide exchange, hydrolysis, membrane insertion or SEC23 binding therefore disables coat assembly or coat cycling at this one step.

COPII coat assembly and vesicle budding at ER exit sites GO:0090114 ↓ DECREASED

COPII vesicle coat GO:0030127

Downstream

Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum Without a functional coat, the carrier that would move pre-chylomicrons out of the ER is never formed.

Show evidence (3 references)

PMID:36594468 SUPPORT Other

"GTP-bound SAR1 inserts its hydrophobic N-terminus into the ER membrane and recruits SEC23-SEC24 heterodimers to the ERES by directly interacting with SEC23"

Describes the molecular step that SAR1B loss interrupts.

PMID:36594468 SUPPORT Other

"SEC12 is a type II ER transmembrane protein that functions as a guanine nucleotide exchange factor (GEF) for SAR1 while also recruiting SAR1 to the ER membrane"

Identifies the activation step upstream of coat nucleation.

PMID:39062121 SUPPORT Other

"the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites"

The most recent dedicated review places the lesion at COPII vesicles and ER exit sites.

Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum

Newly assembled pre-chylomicrons are far larger than a conventional 60-90 nm COPII vesicle, so their export depends on COPII machinery being recruited to generate an enlarged carrier. In CRD that carrier is not produced, and the pre-chylomicron transport vesicle never reaches the Golgi. This is a trafficking failure and not an assembly failure: apoB-48 lipidation and chylomicron formation themselves are intact, which is what distinguishes CRD from abetalipoproteinemia at the cell-biological level.

absorptive small-intestinal enterocyte CL:0000584

endoplasmic reticulum to Golgi transport of pre-chylomicron vesicles GO:0006888 ↓ DECREASED

duodenum UBERON:0002114

Experimental models

SAR1B knockout Caco-2/15 enterocyte model CELL LINE Targeted SAR1B deletion in a differentiated enterocyte-like monolayer reduces chylomicron and apoB-48 output.

Downstream

Enterocyte Chylomicron Retention Cargo that cannot leave the endoplasmic reticulum compartment stays in the cell.

Show evidence (3 references)

PMID:12692552 SUPPORT Human Clinical

"Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell."

Establishes that chylomicron export is a COPII-dependent process despite the size mismatch.

PMID:28982670 SUPPORT In Vitro

"SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%)."

Targeted SAR1B deletion in enterocyte-like cells reduces chylomicron output.

PMID:28982670 SUPPORT In Vitro

"a double knockout of SAR1A and SAR1B was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output"

Only the double knockout abolishes output, showing the residual export in single SAR1B loss is paralogue-dependent rather than SAR1B-independent.

Enterocyte Chylomicron Retention

Assembled chylomicrons and their triglyceride cargo accumulate inside the absorptive enterocyte, as free cytoplasmic lipid droplets and as membrane-bound lipoprotein-sized particles. This is the lesion the disease is named for and the finding a duodenal biopsy demonstrates. Villus architecture is preserved, so the malabsorption is a secretion defect and not mucosal destruction.

absorptive small-intestinal enterocyte CL:0000584

intestinal lipid transport into lymph GO:0006869 ↓ DECREASED

Animal models

Sar1b CRISPR deletion and p.D137N knock-in mouse Mouse recapitulates Homozygous embryos accumulate lipid in the intestine and heterozygotes fail to secrete chylomicrons after a lipid gavage.

Sar1b morpholino knockdown zebrafish Zebrafish recapitulates Larvae form enterocyte lipid droplets after feeding and then fail to clear them during fasting, which is the retention phenotype in a live animal.

Downstream

Absent Postprandial Chylomicronemia Lipid retained in the enterocyte is lipid that never enters intestinal lymph, so there is no chylomicron or apoB-48 rise after a fat meal.

Intestinal Fat Malabsorption Dietary long-chain fat that the enterocyte cannot pass on is lost in the stool.

Enterocyte Lipid Peroxidation and Endoplasmic Reticulum Stress A proposed but not clinically validated branch: retained lipid is associated with oxidative and ER stress in cell and animal systems.

Show evidence (2 references)

PMID:31253576 SUPPORT Human Clinical

"We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission."

Records enterocyte lipid accumulation as the presenting histological finding in molecularly confirmed patients.

PMID:20920215 SUPPORT Other

"Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."

The diagnostic guideline records fat-laden enterocytes as the constant histological finding.

Absent Postprandial Chylomicronemia

After an oral fat load there is no rise in plasma chylomicrons or apoB-48. Because chylomicrons are also the vehicle by which dietary cholesterol, essential fatty acids and the fat-soluble vitamins reach the circulation, this single transport failure accounts for the whole downstream biochemical phenotype. Hepatic VLDL and apoB-100 secretion continue, which is why LDL remains detectable and fasting triglycerides stay normal.

Downstream

Fat-Soluble Vitamin Deficiency Vitamins A, D, E and K are absorbed with dietary fat and delivered in chylomicrons; with no chylomicron output their delivery fails.

Essential Fatty Acid Deficiency Linoleic and alpha-linolenic acid are long-chain fatty acids that also depend on chylomicron delivery.

Hypocholesterolemia Loss of the intestinal contribution to circulating cholesterol, together with the reduced HDL branch, produces the profound hypocholesterolaemia.

Decreased circulating apolipoprotein B concentration The apoB-48 pool never reaches plasma, and total apolipoprotein B is correspondingly low.

Show evidence (2 references)

PMID:27266643 SUPPORT Human Clinical

"The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."

States the defining postprandial finding alongside the normal fasting triglyceride that distinguishes CRD.

PMID:20920215 SUPPORT Human Clinical

"Negative Oral Fat Load Infancy (1 to 6 m) Permanent ? 100%"

Every patient in the two-centre cohort had a negative oral fat load.

Intestinal Fat Malabsorption

Dietary long-chain fat that cannot be exported from the enterocyte is passed into the stool, producing steatorrhoea whose severity tracks the fat content of the diet, with the osmotic and secretory consequences of unabsorbed fat in the lumen. This is the arm of the mechanism that responds to dietary fat restriction.

Downstream

Chronic diarrhea

Steatorrhea

Abdominal distention

Vomiting

Failure to thrive Energy and nutrient loss in an infant with a high growth demand is the proximate cause of the growth failure.

Fat-Soluble Vitamin Deficiency

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat"

Groups the gastrointestinal presentation that this node generates.

PMID:20920215 SUPPORT Other

"Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."

Symptom remission on long-chain fat restriction is the clinical evidence that these manifestations are driven by unabsorbed dietary fat.

Fat-Soluble Vitamin Deficiency

Vitamins A, D, E and K are all low. Vitamin E is the most severely and most persistently affected: plasma alpha-tocopherol stays chronically low even on high-dose oral replacement, because absorption of any lipophilic molecule depends on the chylomicron pathway that is blocked. Vitamin D deficiency drives the skeletal phenotype and vitamin K deficiency the coagulopathy.

intestinal transport of fat-soluble vitamins GO:0051180 ↓ DECREASED

Experimental models

CRISPR SAR1B knockout Caco-2/TC7 cells CELL LINE Explains why plasma vitamin E stays low on treatment: even tocofersolan and tocopheryl acetate cannot be secreted normally by a SAR1B-null enterocyte.

Downstream

Vitamin E-Dependent Neuroaxonal and Retinal Injury Chronic tocopherol deficiency is the accepted cause of the neuromuscular and ophthalmological complications, and adequacy of vitamin E replacement is what determines whether they occur.

Reduced bone mineral density Mediated by vitamin D deficiency.

Delayed skeletal maturation Mediated by vitamin D deficiency.

Prolonged prothrombin time Mediated by vitamin K deficiency.

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"low serum concentrations of fat-soluble vitamins (A, D, E, and K)"

Names all four deficient vitamins.

PMID:36771214 SUPPORT In Vitro

"A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan"

A SAR1B knock-out enterocyte model reproduces impaired tocopherol secretion even with the pharmaceutical vitamin E forms used clinically, which is the mechanistic basis for the persistently low plasma vitamin E.

Essential Fatty Acid Deficiency

Linoleate and alpha-linolenate delivery fails with the chylomicron pathway. The deficiency is most severe in the first months of life and is aggravated by over-strict dietary fat restriction, which is why treatment has to balance symptom control against essential fatty acid and calorie intake.

Downstream

Failure to thrive Through impaired growth substrate supply and malnutrition.

Show evidence (3 references)

PMID:20920215 SUPPORT Other

"Essential fatty acid (EFA) deficiency is especially severe early in life."

Establishes the deficiency and its timing.

PMID:20920215 SUPPORT Human Clinical

"EFA deficiency* (20:3n-9/20:4n-6) Infancy to late childhood permanent but variations 55%"

Quantifies essential fatty acid deficiency in the two-centre cohort.

PMID:19285442 SUPPORT Human Clinical

"Varying degrees of essential fatty acid and of vitamin E deficiency were observed."

Independent cohort confirmation of essential fatty acid deficiency.

Vitamin E-Dependent Neuroaxonal and Retinal Injury

Chronic alpha-tocopherol deficiency causes the neuromuscular and retinal complications of CRD: loss of deep tendon reflexes, ataxia, myopathy with raised creatine kinase, and subtle ophthalmological abnormalities including micronystagmus, delayed dark adaptation and abnormal scotopic electroretinograms. These are milder in CRD than in abetalipoproteinemia, and they are largely preventable by early high-dose oral vitamin E.

nervous system involvement in vitamin E deficiency UBERON:0001016

Downstream

Areflexia

Ataxia

Myopathy

Elevated circulating creatine kinase concentration Through the muscular involvement of vitamin E deficiency.

Abnormal electroretinogram

Nystagmus

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"

Enumerates the ophthalmological findings that make up the retinal arm of this node.

PMID:19285442 SUPPORT Human Clinical

"Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia."

Cohort data both attribute the changes to vitamin E deficiency and show how uncommon the severe end of this node is under treatment.

PMID:20920215 SUPPORT Other

"Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations."

Adds the muscular arm, including the creatine kinase elevation.

Impaired Intestinal HDL Biogenesis and Cholesterol Efflux

A branch of the mechanism that does not run through chylomicron retention. Loss of SAR1B in enterocyte-like cells reduces ABCA1 expression and cholesterol efflux to apolipoprotein A-I, limiting nascent HDL production by the intestine. This is the current explanation for the low HDL cholesterol and low apolipoprotein A-I of CRD, which are otherwise hard to derive from a pure chylomicron-export defect.

cholesterol efflux to apolipoprotein A-I GO:0033344 ↓ DECREASED intestinal high-density lipoprotein particle assembly GO:0034380 ↓ DECREASED

Experimental models

SAR1B knockout Caco-2/15 enterocyte model CELL LINE The same knockout reduces cholesterol movement to basolateral apoA-I and lowers ABCA1 expression.

Animal models

Sar1b CRISPR deletion and p.D137N knock-in mouse Mouse partially recapitulates Heterozygous animals are hypoalphalipoproteinaemic, matching the low HDL of patients, though the mouse study measured the plasma outcome rather than intestinal ABCA1-dependent efflux itself.

Downstream

Decreased HDL cholesterol concentration

Show evidence (2 references)

PMID:28982670 SUPPORT In Vitro

"Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs."

Direct demonstration that SAR1B loss impairs HDL biogenesis in an intestinal cell model.

PMID:30640893 SUPPORT Other

"Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein."

The review proposes this branch as the explanation for the low HDL, and hedges it as such.

Impaired Hepatic ApoB Lipoprotein Secretion

Mechanism confidence: Provisional

SAR1B is not intestine-specific. It also promotes hepatic apoB lipoprotein secretion and modulates expression of cholesterol-biosynthetic genes, which is the proposed reason a disorder of intestinal fat export nonetheless produces hepatic steatosis and cholesterol levels lower than intestinal malabsorption alone would predict. The hepatic arm is less firmly characterised in patients than the enterocyte lesion.

hepatocyte CL:0000182

liver UBERON:0002107

Downstream

Hepatic steatosis

Hepatomegaly

Show evidence (2 references)

PMID:24338480 SUPPORT In Vitro

"it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition"

States the puzzle this node answers, and marks it as previously unexplained.

PMID:24338480 SUPPORT In Vitro

"These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions."

Establishes the hepatic secretory role of Sar1B on which this node rests.

Enterocyte Lipid Peroxidation and Endoplasmic Reticulum Stress

Mechanism confidence: Provisional

A proposed downstream consequence of intracellular lipid retention: increased lipid peroxidation, endoplasmic reticulum stress and inflammatory signalling. The evidence is from SAR1B-disrupted cell lines and engineered mice; no study has shown that this branch drives any human complication, so it is recorded as provisional rather than as part of the established chain.

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED

Show evidence (2 references)

PMID:39062121 SUPPORT Other

"loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD"

The review states the association and marks the link to clinical complications as potential, which is why this node is provisional.

PMID:37558128 SUPPORT Model Organism

"On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet."

Shows that the metabolic consequences of Sar1b defects in mice are dietary-fat-dependent, the model context in which the stress branch was characterised.

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Histopathology

2

Lipid-laden enterocytes with preserved villus architecture VERY_FREQUENT

Duodenal or jejunal biopsy taken after dietary fat exposure shows enterocytes distended by large free cytoplasmic lipid droplets and by membrane-bound lipoprotein-sized particles. Villus architecture is normal, which separates CRD from the congenital enteropathies that destroy the absorptive surface. Because the finding is fat-load dependent, a biopsy taken on a fat-restricted diet can be falsely reassuring.

Show evidence (3 references)

PMID:20920215 SUPPORT Other

"Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."

The guideline records fat-laden enterocytes as the constant histological finding.

PMID:20920215 SUPPORT Human Clinical

"Enterocyte vacuolization, chylomicron-like Infancy (1 to 6 m) permanent? Fat load dependent 100%"

Cohort table records the finding in 100% of patients and states that it is fat-load dependent, which is the caveat in the description.

PMID:31253576 SUPPORT Human Clinical

"presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia"

Molecularly confirmed patients presented with enterocyte lipid accumulation on biopsy.

Macrovesicular hepatic steatosis OCCASIONAL

A moderate macrovesicular steatosis of the liver, without reported progression to steatohepatitis or cirrhosis.

Show evidence (1 reference)

PMID:20920215 SUPPORT Other

"A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis."

Names the histological pattern and its reported limits.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

25

Blood 1

Prolonged prothrombin time HP:0008151

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"prolonged international normalized ratio (INR) due to vitamin K deficiency"

GeneReviews names the coagulation abnormality and its cause.

Cardiovascular 1

Reduced left ventricular ejection fraction VERY_RARE HP:0012664

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"(in a small proportion of adults) cardiomyopathy with decreased ejection fraction"

GeneReviews reports the finding in a small proportion of adults, supporting the VERY_RARE band.

PMID:20920215 SUPPORT INDIRECT Human Clinical

"Cardiomyopathy/Biological signs Adult permanent? 0%"

Recorded as absent in the two-centre paediatric cohort, which is why this phenotype is banded as very rare rather than by the cohort figure alone. The row reports a childhood prevalence of zero; the very-rare band for the adult phenotype follows by inference from that absence combined with the GeneReviews report above, not from the quoted row itself.

Digestive 7

Chronic diarrhea VERY_FREQUENT HP:0002028

Temporal: CHRONIC

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Diarrhea Infancy (1 to 6 m) transient if low LCFA diet 100%"

The two-centre cohort table records diarrhoea in 100% of patients, supporting the VERY_FREQUENT band.

PMID:19285442 SUPPORT Human Clinical

"All CRD patients presented within the first few months of life with diarrhea and failure to thrive."

Independent cohort confirmation of diarrhoea as a universal presenting feature.

Steatorrhea VERY_FREQUENT HP:0002570

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Steatorrhea (N < 5 g/d) Infancy (1 to 6 m) - (7.5 ± 3.6) transit or permanent 85%"

Cohort table gives an 85% frequency with the measured faecal fat, supporting the VERY_FREQUENT band.

PMID:35344313 SUPPORT Other

"This leads to steatorrhea – the severity of which relates to the fat content of the diet"

GeneReviews records steatorrhoea as the consequence of the fat malabsorption.

Fat malabsorption HP:0002630

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"characterized by the inability to secrete chylomicrons from the enterocytes following the ingestion of fat"

GeneReviews defines the disease by the secretion failure that produces fat malabsorption.

Vomiting FREQUENT HP:0002013

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Vomiting Infancy (1 to 6 m) transient if low LCFA diet 60%"

Cohort frequency of 60% supports the FREQUENT band.

Abdominal distention FREQUENT HP:0003270

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Abdominal distension Infancy (1 to 6 m) transient if low LCFA diet 65%"

Cohort frequency of 65% supports the FREQUENT band.

Hepatic steatosis OCCASIONAL HP:0001397

Show evidence (2 references)

PMID:20920215 SUPPORT Other

"A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis."

Establishes both the steatosis and the absence of reported progression, which is the claim the description makes.

PMID:20920215 SUPPORT Human Clinical

"Hepatomegaly, Steatosis Infancy or late childhood transit or permanent 15%"

Cohort frequency of 15% supports the OCCASIONAL band.

Hepatomegaly OCCASIONAL HP:0002240

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"and in some cases, hepatomegaly"

GeneReviews reports hepatomegaly in a subset, consistent with the OCCASIONAL band.

PMID:20920215 SUPPORT Human Clinical

"Hepatomegaly, Steatosis Infancy or late childhood transit or permanent 15%"

Cohort frequency of 15%.

Eye 2

Abnormal electroretinogram HP:0000512

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"

GeneReviews names the abnormal scotopic electroretinogram among the ophthalmological findings.

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"

GeneReviews names micronystagmus among the ophthalmological findings.

Metabolism 8

Hypocholesterolemia VERY_FREQUENT HP:0003146

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Low Total cholesterol §§ Infancy (1 to 6 m) permanent 100% moderate decrease"

Cohort table records low total cholesterol in 100% of patients, permanent from infancy.

PMID:19285442 SUPPORT Human Clinical

"Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B."

Gives the full lipid pattern in two independent cohorts.

Decreased LDL cholesterol concentration VERY_FREQUENT HP:0003563

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Low LDL † Infancy (1 to 6 m) permanent 100% moderate decrease"

Cohort table records low LDL in 100% of patients.

Decreased HDL cholesterol concentration VERY_FREQUENT HP:0003233

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Low HDL †† Infancy (1 to 6 m) permanent 100%"

Cohort table records low HDL in 100% of patients and rates it highly discriminative.

Decreased circulating apolipoprotein B concentration HP:0034075

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels"

GeneReviews records the low apolipoprotein B alongside the normal-to-low triglyceride.

Decreased circulating vitamin E concentration VERY_FREQUENT HP:0100513

Show evidence (2 references)

PMID:20920215 SUPPORT Other

"Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."

The guideline calls vitamin E deficiency invariable, supporting the VERY_FREQUENT band.

PMID:20920215 SUPPORT Human Clinical

"Vitamin E deficiency (N > 18.4 μmol/L) Infancy (1 to 6 m) - (2.7 ± 0.3) permanent 95%"

Cohort table gives a 95% frequency and the mean plasma concentration.

Reduced circulating vitamin A concentration FREQUENT HP:0004905

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Vitamin A deficiency (N > 1.61 μmol/L) Infancy (1 to 6 m) - (0.8 ± 0.5) transit if supplementation 70%"

Cohort frequency of 70%, correctable with supplementation, supports the FREQUENT band.

Decreased circulating vitamin D concentration FREQUENT HP:0100512

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Vitamin D deficiency (N > 50 nmol/L) Infancy (1 to 6 m) - (31 ± 17) transit if supplementation 45%"

Cohort frequency of 45% supports the FREQUENT band.

Elevated circulating creatine kinase concentration FREQUENT Elevated circulating creatine kinase activity HP:0003236

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"High CK (N < 100 mmol/L) Infancy (1 to 6 m) - (460 ± 100) permanent 60%"

Cohort frequency of 60% with the measured mean concentration supports the FREQUENT band.

PMID:20920215 SUPPORT Other

"Creatine kinase (CK) is usually elevated and hepatic steatosis is common."

The guideline text records raised creatine kinase as a usual finding.

Musculoskeletal 3

Myopathy HP:0003198

Show evidence (1 reference)

PMID:20920215 SUPPORT Other

"Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations."

Records muscular manifestations as part of the CRD phenotype.

Reduced bone mineral density HP:0004349

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"poor bone mineralization and delayed bone maturation due to vitamin D deficiency"

GeneReviews records poor mineralisation and its vitamin D basis.

PMID:20920215 SUPPORT Other

"Poor mineralization and delayed bone maturation do occur."

Independent confirmation from the management guideline.

Delayed skeletal maturation HP:0002750

Show evidence (1 reference)

PMID:35344313 SUPPORT Other

"poor bone mineralization and delayed bone maturation due to vitamin D deficiency"

GeneReviews records delayed bone maturation alongside poor mineralisation.

Nervous System 2

Areflexia VERY_RARE HP:0001284

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Hypo or Areflexia Late childhood or adult (4 to 10 y) permanent 5%"

Cohort frequency of 5% with late-childhood onset supports the VERY_RARE band.

PMID:19285442 SUPPORT Human Clinical

"Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia."

One case of areflexia across two cohorts, consistent with a very rare manifestation.

Ataxia HP:0001251

Show evidence (1 reference)

PMID:35344313 SUPPORT INDIRECT Other

"standard treatment for deficits in night vision and/or color vision, ataxia, and cardiomyopathy"

GeneReviews lists ataxia among the manifestations requiring management. That ataxia is part of the disease phenotype follows from the management recommendation rather than being asserted by the quoted sentence, which is a statement about treatment.

Growth 1

Failure to thrive VERY_FREQUENT HP:0001508

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Failure to thrive Infancy (1 to 6 m) transient if low LCFA diet 80%"

Cohort frequency of 80% supports the VERY_FREQUENT band.

PMID:20920215 SUPPORT Other

"Failure to thrive is one of the most common initial clinical findings."

The guideline text confirms failure to thrive as a leading presenting sign.

🧬

Genetic Associations

2

SAR1B biallelic pathogenic variants (Biallelic loss-of-function or function-disrupting germline variants)

Gene: SAR1B hgnc:10535 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (3 references)

PMID:12692552 SUPPORT Human Clinical

"Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption."

The founding report identifying SAR1B (SARA2) as the causal gene.

PMID:35344313 SUPPORT Other

"The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in SAR1B identified by molecular genetic testing."

GeneReviews makes biallelic SAR1B variants the molecular definition of the disease.

PMID:17945526 SUPPORT Human Clinical

"All the affected children presented with similar phenotype at onset; the absence of phenotype-genotype correlation was discussed."

A 15-patient series reports no genotype-phenotype correlation, which is why this entry does not stratify subtypes by allele class.

Variants (2)

Truncating SAR1B variants Pathogenic

Gene: SAR1B hgnc:10535 loss of function variant

Nonsense, frameshift and whole-exon deletion alleles predicted to produce an absent or severely truncated Sar1b protein. Reported examples include the exon 6 nonsense change p.Glu122X, the frameshifts p.Leu28ArgfsX7 and p.Asp48ThrfsX17, and a whole deletion of exon 2 that removes the translation initiation codon.

Functional effects

COPII coat nucleation by the Sar1b GTPase loss-of-function

Truncating alleles remove the protein, so no functional GTPase is available at ER exit sites.

Show evidence (3 references)

PMID:17945526 SUPPORT Human Clinical

"We identified three unique homozygous mutations of SAR1B gene in French families originated from Turkey, Algeria and Portugal: a stop codon in exon 6 (c.364G>T, p.Glu122X), a whole deletion of exon 2"

Reports the nonsense and whole-exon-deletion alleles named in the description.

PMID:21235735 SUPPORT Human Clinical

"Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17)."

Reports one of the frameshift alleles named in the description.

PMID:31253576 SUPPORT Human Clinical

"Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA."

Documents the exon 2 deletion and its effect on the initiation codon.

Missense SAR1B variants Pathogenic

Gene: SAR1B hgnc:10535 missense variant

Missense substitutions clustered around the guanine-nucleotide recognition site and the coat-interaction surfaces, including p.Asp137Asn, p.Ser179Arg and p.Gly185Val. Computational and structural analysis predicts non-functional protein rather than absent protein; the p.Asp137Asn allele has been modelled in mouse.

Functional effects

Guanine nucleotide binding and hydrolysis by Sar1b loss-of-function

Substitutions near the guanosine recognition site are predicted to disrupt nucleotide handling and coat cycling.

Show evidence (3 references)

PMID:17945526 SUPPORT Human Clinical

"The 2 missense mutations found in the 5 French-Canadian families had already been described in the eight previously published mutations: c.409G>A (p.Asp137Asn) and c.537T>A (p.Ser179Arg)."

Reports two of the recurrent missense alleles named in the description.

PMID:31253576 SUPPORT Human Clinical

"Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant"

Documents a homozygous SAR1B missense allele, c.409 G>C p.(Asp137His), which the same sentence places at a highly conserved residue close to the Sar1b guanosine recognition site.

PMID:17945526 SUPPORT Computational

"The nonsense mutation and the whole deletion of exon 2 produced truncated proteins, the missense mutations probably non-functional proteins."

Sequence and structural modelling assigns the missense alleles a loss of function.

SAR1A paralogue upregulation (Compensatory intestinal upregulation that does not rescue the phenotype)

Gene: SAR1A hgnc:10534 relationship_type: MODIFIER variant_origin: UNKNOWN

Show evidence (3 references)

PMID:21235735 SUPPORT Human Clinical

"The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals."

Measures the paralogue upregulation in patient tissue.

PMID:21235735 SUPPORT Human Clinical

"the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein"

States that the upregulation is not compensatory in patients.

PMID:28982670 SUPPORT In Vitro

"The absence of expected chylomicron production collapse may be because of the compensatory SAR1A elevation observed in our experiments."

Attributes the residual chylomicron output after SAR1B deletion to SAR1A, which is the in-vitro counterpart of the patient observation.

💊

Medical Actions

5

Low-long-chain-fat diet with adequate calories and essential fatty acids

Category: Therapeutic Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Diet:

The core of management. Long-chain fat is restricted enough to control diarrhoea, vomiting and abdominal distension, while total calories and essential fatty acid intake are kept sufficient for growth; medium-chain triglycerides may be used because they reach the portal circulation without chylomicron packaging. Over-restriction is a real hazard, because essential fatty acid deficiency is already severe early in life. The treatment controls the consequences of the trafficking defect and does not correct it, so symptoms recur when fat is reintroduced.

Mechanism Target:

MODULATES Intestinal Fat Malabsorption — Reducing the long-chain fat load reduces the amount of lipid the enterocyte cannot export, so the malabsorptive symptoms remit. The transport defect itself is untouched.

Show evidence (1 reference)

PMID:20920215 SUPPORT Other

"Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."

Directly links the dietary intervention to remission of the malabsorptive symptoms.

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"Ensure adequate caloric intake with a low-fat diet (<30% of total calories from fat) enriched in essential fatty acids with or without medium-chain triglycerides"

GeneReviews gives the dietary prescription including the essential fatty acid and medium-chain triglyceride components.

PMID:35344313 SUPPORT Other

"Avoidance of fatty foods, particularly those rich in long-chain fatty acids."

GeneReviews names long-chain-fat-rich foods as the exposure to avoid.

PMID:20920215 SUPPORT Other

"Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake."

Supports the warning that restriction must be balanced against calorie and essential fatty acid needs.

High-dose oral vitamin E supplementation

Category: Therapeutic Action: high-dose fat-soluble vitamin supplementation Ontology label: Nutritional Supplementation NCIT:C15425

Agent: alpha-tocopherol CHEBI:22470

Platform: Small molecule

Large oral doses of vitamin E, around 50 IU/kg/day, given lifelong. The important and slightly counter-intuitive point is that the oral route works for preventing neurological complications even though plasma tocopherol never normalises: the aim is tissue protection, not a normal blood level. Tocofersolan, a water-soluble tocopherol derivative, is better absorbed than tocopheryl acetate in CRD, though a four-month crossover study found no significant difference in plasma tocopherol between the two formulations.

Mechanism Target:

MODULATES Fat-Soluble Vitamin Deficiency — Oral replacement partially offsets the delivery failure. It does not restore a normal plasma concentration, because absorption still depends on the blocked chylomicron pathway.

Show evidence (1 reference)

PMID:20920215 SUPPORT Other

"Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."

States both that the intervention works and the limit on what it achieves biochemically.

INHIBITS Vitamin E-Dependent Neuroaxonal and Retinal Injury — Adequate vitamin E status is the determinant of whether the neurological complications occur.

Show evidence (1 reference)

PMID:20920215 SUPPORT Other

"However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications."

Makes vitamin E status the pivotal variable for the neurological outcome.

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"high-dose oral fat-soluble vitamins, including vitamin E (hydrosoluble form) 50 IU/kg/d"

GeneReviews gives the vitamin E dose and specifies the hydrosoluble form.

PMID:30021760 SUPPORT Human Clinical

"In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%)."

Quantifies the better absorption of tocofersolan in CRD specifically.

PMID:30021760 SUPPORT Human Clinical

"Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD."

The crossover endpoint found no significant difference between formulations, which is the caveat stated in the description.

Vitamin A, D and K supplementation

Category: Therapeutic Action: fat-soluble vitamin supplementation Ontology label: Nutritional Supplementation NCIT:C15425

Agent: vitamin A CHEBI:12777 vitamin D CHEBI:27300 phylloquinone CHEBI:18067

Platform: Small molecule

Vitamin A around 15,000 IU/day, vitamin D 800-1200 IU/day and vitamin K 15 mg/week, adjusted against plasma concentrations, INR and toxicity risk. Unlike vitamin E, these three can usually be brought into the normal range by supplementation. Vitamin A dosing needs a specific pregnancy caveat.

Mechanism Target:

MODULATES Fat-Soluble Vitamin Deficiency — Replaces the vitamins whose chylomicron-dependent delivery has failed.

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Vitamin A deficiency (N > 1.61 μmol/L) Infancy (1 to 6 m) - (0.8 ± 0.5) transit if supplementation 70%"

The cohort table records vitamin A deficiency as transient with supplementation, which is the effect this link asserts.

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"vitamin A 15,000 IU/d, vitamin K 15 mg/week, and vitamin D 800-1200 IU/d"

GeneReviews gives the three doses stated in the description.

PMID:35344313 SUPPORT Other

"Vitamin A excess can be harmful to the developing fetus."

The pregnancy caveat: GeneReviews advises halving the vitamin A dose in women who are pregnant or planning pregnancy, with monitoring of levels.

PMID:36243606 SUPPORT Other

"We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics."

Contemporary multi-society guidance confirms high-dose fat-soluble vitamins as the treatment class.

Lifelong multisystem surveillance

Category: Monitoring Action: clinical evaluation Ontology label: Clinical Evaluation NCIT:C124351

Platform: Behavioral / lifestyle

Annual growth, dietary, gastrointestinal and neurological assessment with lipid profile, liver function, blood count, INR and vitamins A, D and E. From age ten, liver ultrasound, neurological examination with creatine kinase and electromyography, ophthalmological review and bone densitometry every three years; in adults, echocardiography with ejection fraction every three to five years.

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"Every three years after age ten: liver ultrasound, neurologic exam with serum creatine kinase and electromyography, ophthalmologic evaluation, and DXA scan."

GeneReviews gives the triennial surveillance schedule quoted in the description.

PMID:35344313 SUPPORT Other

"Every three to five years in adults: echocardiogram with assessment of ejection fraction."

GeneReviews gives the adult cardiac surveillance interval.

Genetic counseling and cascade testing

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Once the familial SAR1B variants are known, carrier testing of relatives and prenatal or preimplantation genetic testing become possible. Siblings of a proband carry a one-in-four recurrence risk.

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"Once the SAR1B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."

GeneReviews states the reproductive options that follow molecular confirmation.

PMID:35344313 SUPPORT Other

"each sib of an affected individual has at conception a 25% chance of being affected"

GeneReviews gives the sibling recurrence risk.

🔬

Biochemical Markers

6

Absent postprandial chylomicrons and apolipoprotein B-48 (ABSENT)

Context: After an oral fat load there is no rise in plasma chylomicrons or apoB-48. This is the functional hallmark of the disease and was negative in every patient of the two-centre cohort.

Show evidence (2 references)

PMID:30640893 SUPPORT Other

"there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal"

States the postprandial finding directly.

PMID:20920215 SUPPORT Human Clinical

"Negative Oral Fat Load Infancy (1 to 6 m) Permanent ? 100%"

Every patient in the cohort had a negative oral fat load.

Normal fasting triglyceride concentration (NORMAL)

Context: Fasting triglycerides are normal or near-normal because hepatic VLDL secretion is preserved. This is the single most useful discriminator from abetalipoproteinemia and from homozygous APOB-related hypobetalipoproteinemia, in which the triglyceride is very low.

Show evidence (3 references)

PMID:20920215 SUPPORT Human Clinical

"Normal TG § Infancy (1 to 6 m) transit or permanent 90%"

Cohort table records a normal triglyceride in 90% of patients.

PMID:27266643 SUPPORT Human Clinical

"The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."

Pairs the normal fasting triglyceride with the absent postprandial response as the defining combination.

PMID:19285442 SUPPORT Human Clinical

"Severe hypocholesterolemia coupled with normal triglycerides"

Independent cohort description of the same discriminating pattern.

Low total, LDL and HDL cholesterol with low apolipoproteins A-I and B (DECREASED)

Context: All three cholesterol fractions are reduced, together with apolipoprotein A-I and apolipoprotein B. The low HDL and low apoA-I are attributed to reduced intestinal HDL biogenesis rather than to the chylomicron block.

Show evidence (2 references)

PMID:19285442 SUPPORT Human Clinical

"Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B."

Gives the complete lipoprotein and apolipoprotein pattern in two cohorts.

PMID:30640893 SUPPORT Other

"Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein."

Supplies the proposed mechanism for the HDL and apoA-I arm of the pattern.

Low plasma alpha-tocopherol (DECREASED)

Context: Plasma alpha-tocopherol is markedly reduced from infancy and, unlike vitamins A, D and K, is not normalised by supplementation. Measured mean concentration in the two-centre cohort was 2.7 micromol/L against a normal threshold above 18.4 micromol/L.

Show evidence (2 references)

PMID:20920215 SUPPORT Human Clinical

"Vitamin E deficiency (N > 18.4 μmol/L) Infancy (1 to 6 m) - (2.7 ± 0.3) permanent 95%"

Gives the normal threshold, the measured mean and the cohort frequency quoted in the context.

PMID:20920215 SUPPORT Other

"Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."

Supports the statement that supplementation does not normalise the plasma level.

Hepatic cytolysis with elevated transaminases (INCREASED)

Context: Mild elevation of alanine aminotransferase accompanies the hepatic steatosis and is common in the paediatric cohort.

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"Hepatic cytolysis (ALT < 40 mmol/L) Infancy to late childhood - (60 ± 20) transient or permanent 95%"

Cohort table records mildly raised ALT in 95% of patients.

Absence of acanthocytosis (ABSENT)

Context: Acanthocytes are characteristically absent, in contrast with abetalipoproteinemia where acanthocytosis is a prominent clue. Their absence should not be used to exclude CRD.

Show evidence (1 reference)

PMID:20920215 SUPPORT Human Clinical

"No acantocytosis Infancy (1 to 6 m) transit or permanent 90%"

The cohort table records absence of acanthocytosis in 90% of patients and rates it highly discriminative, which is the claim made here.

🔬

Diagnosis

4

Fasting lipid profile with apolipoprotein B

The screening test in an infant with chronic diarrhoea and faltering growth. The pattern that should prompt SAR1B testing is a total and LDL cholesterol roughly half of normal, a low HDL cholesterol and a low apolipoprotein B, with a fasting triglyceride that is normal. A very low triglyceride points instead to abetalipoproteinemia or homozygous APOB-related hypobetalipoproteinemia.

blood chemistry measurement NCIT:C47868

Results: Low total, LDL and HDL cholesterol with low apolipoprotein B and a normal fasting triglyceride supports CRD but does not by itself distinguish it from the other monogenic hypocholesterolaemias.

Show evidence (2 references)

PMID:19285442 SUPPORT Human Clinical

"This study provides new insights on the phenotypic expression of CRD over time and emphasizes the need to screen the lipid profile of infants with chronic diarrhea and failure to thrive."

Explicitly recommends lipid screening in the presenting clinical context.

PMID:35344313 SUPPORT Other

"Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels, and low serum concentrations of fat-soluble vitamins (A, D, E, and K)."

GeneReviews gives the biochemical pattern this test is looking for.

Fat-soluble vitamin and creatine kinase measurement

Plasma vitamins A, D and E, an INR as the functional readout of vitamin K status, and creatine kinase. Vitamin E deficiency is essentially invariable at diagnosis and creatine kinase is usually raised.

blood chemistry measurement NCIT:C47868

Results: A markedly low alpha-tocopherol with a raised creatine kinase in an infant with hypocholesterolaemia is strongly supportive.

Show evidence (2 references)

PMID:20920215 SUPPORT Other

"Creatine kinase (CK) is usually elevated and hepatic steatosis is common."

Establishes creatine kinase as a routine part of the diagnostic laboratory set.

PMID:20920215 SUPPORT Other

"Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."

States that vitamin E deficiency is invariably present at diagnosis.

Upper endoscopy with duodenal biopsy

Endoscopy performed after dietary fat exposure shows the white "gelee blanche" or hoar-frosting appearance of the duodenal mucosa, and biopsy shows lipid-laden enterocytes with normal villus architecture. Because both findings are fat-load dependent, an endoscopy done on a fat-restricted diet can be normal.

upper gastrointestinal endoscopy with duodenal biopsy NCIT:C78144

Results: A white duodenal mucosa with lipid-laden enterocytes on biopsy is highly supportive but is not a substitute for SAR1B sequencing.

Show evidence (2 references)

PMID:35344313 SUPPORT Other

"Endoscopy typically demonstrates a gelée blanche"

GeneReviews names the characteristic endoscopic appearance.

PMID:20920215 SUPPORT Human Clinical

"White duodenal mucosa Infancy (1 to 6 m) permanent? Fat load dependent 100%"

The cohort table records the white mucosa in 100% of patients and states that it depends on fat load, which is the caveat in the description.

SAR1B molecular genetic testing

Identification of biallelic pathogenic SAR1B variants establishes the diagnosis. Deletion and duplication analysis has to be included alongside sequencing, because whole-exon deletions are a recurrent allele class.

SAR1B sequencing and deletion analysis NCIT:C19770

Results: Biallelic pathogenic or likely pathogenic SAR1B variants establish the molecular diagnosis.

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in SAR1B identified by molecular genetic testing."

GeneReviews defines the confirmatory criterion.

PMID:30640893 SUPPORT Other

"Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions"

Records the reason molecular testing is required rather than optional.

PMID:31253576 SUPPORT Human Clinical

"Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2"

A multi-kilobase deletion found in a proband is why deletion analysis has to accompany sequencing.

📈

Progression

3

Infancy

Age: First six months of life

Onset is in the first months of life with malabsorptive diarrhoea, steatorrhoea, vomiting, abdominal distension and faltering growth. The lipid profile is already abnormal at presentation.

Show evidence (2 references)

PMID:19285442 SUPPORT Human Clinical

"All CRD patients presented within the first few months of life with diarrhea and failure to thrive."

Two independent cohorts place onset in the first months of life.

PMID:35344313 SUPPORT Other

"typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat"

GeneReviews describes the infantile presenting syndrome.

Childhood on treatment

Age: After dietary treatment is started

Gastrointestinal symptoms remit on a low-long-chain-fat diet and recur if fat is reintroduced, so the response is dietary control rather than intestinal adaptation. Hypocholesterolaemia and low vitamin E persist despite supplementation.

Show evidence (2 references)

PMID:20920215 SUPPORT Other

"Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."

Establishes the diet-responsive course of the gastrointestinal phase.

PMID:20920215 SUPPORT Other

"Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."

Records that vitamin E remains low even on effective oral treatment.

Late childhood to adulthood

Age: First to second decades onward

Complications of chronic fat-soluble-vitamin deficiency emerge in the first and second decades: neuromuscular signs, ophthalmological abnormalities, poor bone mineralisation and delayed bone maturation. Creatine kinase is commonly raised, and a minority of adults develop cardiomyopathy with a reduced ejection fraction. These complications are less severe than in abetalipoproteinemia, and early vitamin E replacement largely prevents them.

Show evidence (3 references)

PMID:35344313 SUPPORT Other

"neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency"

GeneReviews times the neuromuscular complications to the first two decades.

PMID:35344313 SUPPORT Other

"(in a small proportion of adults) cardiomyopathy with decreased ejection fraction"

GeneReviews places cardiomyopathy in a minority of adults.

PMID:20920215 SUPPORT Other

"Neurological and ophthalmologic complications in CRD are less severe than in other types of familial hypocholesterolemia."

Contrasts the severity of late complications with the other monogenic hypocholesterolaemias.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

No population-based prevalence estimate exists. Fewer than fifty cases had been published by 2011 and the literature has grown only slowly since; underdiagnosis is likely because the presenting symptoms are non-specific.

Show evidence (3 references)

PMID:21235735 SUPPORT Human Clinical

"less than 50 cases having been reported in the literature"

Gives the published case count as of 2011, the basis for the ultra-rare band.

PMID:30021760 SUPPORT Human Clinical

"Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency."

Independently characterises CRD as extremely rare.

PMID:38749523 SUPPORT Human Clinical

"CRD often presents with non-specific symptoms, resulting in delayed diagnosis which is established by genetic workup and histology from small intestinal biopsies."

Supports the underdiagnosis note attached to this estimate.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Chylomicron Retention Disease:

Abetalipoproteinemia MONDO:0008692

Overlapping Features MTTP-related abetalipoproteinemia abolishes lipidation of apoB in both the enterocyte and the hepatocyte, so hepatic VLDL secretion fails as well. Triglycerides are therefore very low rather than normal, apoB-containing lipoproteins are virtually absent rather than reduced, and acanthocytosis is prominent. Neurological and retinal disease is more severe. Both diseases show fat malabsorption, hypocholesterolaemia and fat-soluble vitamin deficiency, and both show lipid-laden enterocytes on biopsy, so the triglyceride level and the causal gene are what separate them.

Distinguishing Features

Fasting triglycerides are normal in chylomicron retention disease and very low in abetalipoproteinemia.
LDL and apoB-100 remain detectable in chylomicron retention disease because hepatic secretion is preserved.
Acanthocytosis is characteristically absent in chylomicron retention disease and prominent in abetalipoproteinemia.
Biallelic SAR1B variants establish chylomicron retention disease; biallelic MTTP variants establish abetalipoproteinemia.

Show evidence (4 references)

PMID:31253576 SUPPORT Human Clinical

"may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease)"

Separates the three phenocopies by causal gene.

PMID:27266643 SUPPORT Human Clinical

"The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."

Gives the normal fasting triglyceride that is the key biochemical discriminator.

PMID:20920215 SUPPORT Human Clinical

"No acantocytosis Infancy (1 to 6 m) transit or permanent 90%"

Records absence of acanthocytosis as a highly discriminative feature of chylomicron retention disease.

+ 1 more reference

Familial hypobetalipoproteinemia MONDO:0017774

Overlapping Features Biallelic APOB variants remove the apoB scaffold itself and produce a clinical and biochemical picture close to abetalipoproteinemia, including very low triglycerides. Unlike either recessive disease, heterozygous APOB-related hypobetalipoproteinemia gives roughly half-normal apoB and LDL in the parents and rarely causes infantile malabsorption.

Distinguishing Features

Biallelic APOB variants establish familial hypobetalipoproteinemia; biallelic SAR1B variants establish chylomicron retention disease.
Parents of a chylomicron retention disease proband have an entirely normal fasting lipid profile, whereas APOB heterozygotes have reduced apoB and LDL.

Show evidence (2 references)

PMID:31253576 SUPPORT Human Clinical

"may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease)"

Separates the causal genes of the three severe hypobetalipoproteinaemias.

PMID:20920215 SUPPORT Human Clinical

"Normal Fasting lipids in parents 100%"

Normal parental lipids in every chylomicron retention disease family is the family-level discriminator from APOB-related disease.

🧫

Experimental Models

2

SAR1B knockout Caco-2/15 enterocyte model CELL_LINE

Zinc-finger-nuclease deletion of SAR1B in Caco-2/15 cells, and a SAR1A/SAR1B double knockout. The single knockout reduces triglyceride, apoB-48 and chylomicron secretion by roughly a third to a half; only the double knockout abolishes output, which is how the residual export was traced to the SAR1A paralogue. The same system showed reduced HDL biogenesis and cholesterol efflux with impaired ABCA1 expression, which is the best available explanation for the low HDL of CRD.

Organism

human NCBITaxon:9606

Publication

PMID:28982670

Pathograph links

Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum recapitulates fidelity: moderate observes: cellular Targeted SAR1B deletion in a differentiated enterocyte-like monolayer reduces chylomicron and apoB-48 output.

Limitations: Caco-2/15 is a transformed colonic adenocarcinoma line differentiated into an enterocyte-like phenotype, and the assay measures secretion into medium rather than into lymph, so it cannot report the systemic consequences.

Readouts

Chylomicron and apolipoprotein B-48 secretion

Direction: DECREASED

Interpretation: Direct measure of the export step lost in the disease.

Show evidence (1 reference)

PMID:28982670 SUPPORT In Vitro

"SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%)."

Quantifies the secretion defect.

Show evidence (1 reference)

PMID:28982670 SUPPORT In Vitro

"These findings demonstrate that the deletion of the 2 SAR1 isoforms is required to fully eliminate the secretion of chylomicron in vitro."

The authors' conclusion, which is also the paralogue caveat on this model.

Impaired Intestinal HDL Biogenesis and Cholesterol Efflux recapitulates fidelity: moderate observes: cellular The same knockout reduces cholesterol movement to basolateral apoA-I and lowers ABCA1 expression.

Limitations: Shown in a transformed cell line; no patient tissue measurement of intestinal ABCA1 or nascent HDL output has been reported.

Readouts

Cholesterol efflux to basolateral apolipoprotein A-I

Direction: DECREASED

Interpretation: Measures the nascent HDL formation step.

Show evidence (1 reference)

PMID:28982670 SUPPORT In Vitro

"there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells"

Direct measurement of the efflux and nascent HDL defect.

Show evidence (1 reference)

PMID:28982670 SUPPORT In Vitro

"They also underscore the limited high-density lipoprotein production by the intestinal cells in response to SAR1 knockout."

The authors' conclusion that SAR1 knockout limits intestinal HDL production, which is what makes this model informative for this node.

Show evidence (1 reference)

PMID:28982670 SUPPORT In Vitro

"The SAR1B gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique."

Describes how the model was made.

CRISPR SAR1B knockout Caco-2/TC7 cells CELL_LINE

A second, independent enterocyte knockout model built specifically to study fat-soluble vitamin handling. It reproduces impaired lipid droplet formation and reduced triglyceride, cholesterol and alpha-tocopherol secretion, including with the pharmaceutical vitamin E forms used in patients, and shows a milder phenotype for SAR1B than for MTTP loss, which matches the clinical comparison between CRD and abetalipoproteinemia.

Organism

human NCBITaxon:9606

Publication

PMID:36771214

Pathograph links

Fat-Soluble Vitamin Deficiency recapitulates fidelity: moderate observes: cellular Explains why plasma vitamin E stays low on treatment: even tocofersolan and tocopheryl acetate cannot be secreted normally by a SAR1B-null enterocyte.

Limitations: A transformed cell monolayer measuring secretion into medium; it cannot model hepatic tocopherol handling or tissue delivery, and it does not speak to the clinical observation that oral vitamin E still prevents neurological disease.

Readouts

alpha-tocopherol secretion

Direction: DECREASED

Interpretation: Measures the enterocyte step at which vitamin E replacement fails.

Show evidence (1 reference)

PMID:36771214 SUPPORT In Vitro

"A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan"

Quantifies the tocopherol secretion defect including with the clinical formulations.

Show evidence (1 reference)

PMID:36771214 SUPPORT In Vitro

"MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations."

The model reproduces the clinical severity ordering between abetalipoproteinemia and CRD, which supports its fidelity for this node.

Show evidence (1 reference)

PMID:36771214 SUPPORT In Vitro

"we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells"

Describes the construction of the model.

🐁

Animal Models

3

Sar1b CRISPR deletion and p.D137N knock-in mouse

The only mammalian model of human SAR1B defects. Homozygous deletion or mutation is embryonic or perinatally lethal, so metabolic work has been done in heterozygotes even though human heterozygous carriers are asymptomatic. That genotype mismatch is the model's principal limitation. Heterozygotes nonetheless reproduce the gastrointestinal and lipid phenotype, and the homozygous embryos show intestinal lipid accumulation.

Species

Mouse

Genotype

Sar1b exon 2 deletion or Sar1b p.D137N knock-in, heterozygous (homozygotes are lethal)

Background

C57BL/6N

Genes

SAR1B hgnc:10535

Publication

PMID:33964306

Pathograph links

Enterocyte Chylomicron Retention recapitulates fidelity: moderate observes: organism Homozygous embryos accumulate lipid in the intestine and heterozygotes fail to secrete chylomicrons after a lipid gavage.

Limitations: Homozygosity, the genotype that corresponds to human disease, is lethal in this model, so the surviving animals used for metabolic phenotyping are heterozygous, a state that is clinically silent in humans.

Readouts

Chylomicron secretion after gastric lipid gavage

Direction: DECREASED

Interpretation: Functional readout of the failed enterocyte export step.

Show evidence (1 reference)

PMID:33964306 SUPPORT Model Organism

"heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage"

Reports the reduced chylomicron secretion measured after a lipid load.

Faecal lipid excretion

Direction: INCREASED

Interpretation: Whole-animal confirmation that the retained lipid is lost in the stool.

Show evidence (1 reference)

PMID:33964306 SUPPORT Model Organism

"Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion."

Direct measurement of the malabsorption in the model.

Show evidence (1 reference)

PMID:33964306 SUPPORT Model Organism

"This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration."

The authors' own assessment of how far the model recapitulates the disease.

Impaired Intestinal HDL Biogenesis and Cholesterol Efflux partially recapitulates fidelity: moderate observes: organism Heterozygous animals are hypoalphalipoproteinaemic, matching the low HDL of patients, though the mouse study measured the plasma outcome rather than intestinal ABCA1-dependent efflux itself.

Limitations: The low plasma HDL is an outcome measure; the model was not used to show the enterocyte efflux step, which comes from the Caco-2 system.

Show evidence (1 reference)

PMID:33964306 SUPPORT Model Organism

"heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol"

Records the low HDL cholesterol in the model.

Show evidence (2 references)

PMID:33964306 SUPPORT Model Organism

"We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos."

Establishes the homozygous lethality that constrains how this model can be used.

PMID:37558128 SUPPORT Model Organism

"Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities."

Confirms both the lethality and the intestinal lipid accumulation in homozygous embryos.

Sar1b morpholino knockdown zebrafish

A developmental model. Sar1b-deficient larvae take dietary lipid into enterocytes normally but cannot clear it, reproducing the retention lesion, and they additionally show craniofacial cartilage, exocrine pancreas, liver and hindbrain deficits that are not part of the recognised human phenotype. Those extra phenotypes are the model's main caveat, and probably reflect global knockdown of a broadly expressed COPII component during development.

Species

Zebrafish

Genotype

sar1b 5'UTR translation-blocking morpholino knockdown

Genes

SAR1B hgnc:10535

Publication

PMID:25559265

Pathograph links

Enterocyte Chylomicron Retention recapitulates fidelity: moderate observes: cellular Larvae form enterocyte lipid droplets after feeding and then fail to clear them during fasting, which is the retention phenotype in a live animal.

Limitations: Global morpholino knockdown during development produces craniofacial, pancreatic, hepatic and neuronal deficits that are not features of human CRD, so the model over-reports the developmental consequences of SAR1B loss. Zebrafish lipoprotein physiology also differs from the human.

Readouts

Enterocyte lipid clearance after feeding and fasting

Direction: DECREASED

Interpretation: Oil Red O pulse-chase measure of the export step.

Show evidence (1 reference)

PMID:25559265 SUPPORT Model Organism

"Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes."

Reports the measured enterocyte lipid retention.

Show evidence (1 reference)

PMID:25559265 SUPPORT Model Organism

"Sar1b depletion phenotype in zebrafish resembles Anderson disease deficits."

The authors' key-message statement that the model is informative for the human disease.

Show evidence (1 reference)

PMID:25559265 SUPPORT Model Organism

"Sar1b deficiency results in multi-organ developmental deficits."

Records the extra developmental phenotypes that are the reason this model is not read as a straightforward phenocopy.

Sar1b knockdown in developing mouse neocortex

A targeted developmental-neurobiology experiment rather than a disease model. Sar1b knockdown impairs radial migration and callosal axon formation of cortical neurons, and the human D137N allele does the same, suggesting a cell-autonomous neural role for SAR1B independent of intestinal lipid absorption. Whether this contributes to the neurological findings in patients is untested; the recognised neurological complications of CRD are attributed to vitamin E deficiency.

Species

Mouse

Genotype

In-utero electroporation knockdown of Sar1b, and expression of the CRD-associated hSAR1B p.D137N allele

Genes

SAR1B hgnc:10535

Publication

PMID:33002559

Deliberately not linked to a pathophysiology node. Doing so would assert a cell-autonomous neural mechanism in human CRD that no patient study supports, and would compete with the well-evidenced vitamin E pathway already curated.

Show evidence (2 references)

PMID:33002559 SUPPORT Model Organism

"Our study reveals a cell-autonomous action of Sar1b, which is unrelated to lipid absorption from the gut, on the development of the cerebral cortex."

States the finding and its explicit independence from the intestinal mechanism.

PMID:33002559 SUPPORT Model Organism

"CMRD patients suffer from multiple neurological deficits, the etiologies of which remain unclear."

The authors' framing of the open question, which is why this model is recorded without a mechanism link.

{ }

Source YAML

click to show

name: Chylomicron Retention Disease
creation_date: '2026-09-05T18:20:00Z'
category: Mendelian
description: >
  Chylomicron retention disease (CRD, Anderson disease) is an ultra-rare
  autosomal recessive disorder of intestinal lipoprotein secretion caused by
  biallelic pathogenic variants in SAR1B. SAR1B encodes the small GTPase that
  nucleates assembly of the COPII coat at endoplasmic reticulum exit sites.
  Enterocytes of affected individuals lipidate apolipoprotein B-48 and build
  chylomicrons normally, but cannot bud the pre-chylomicron transport vesicles
  that carry them from the endoplasmic reticulum to the Golgi; chylomicrons
  therefore accumulate inside the enterocyte in cytoplasmic droplets and
  membrane-bound lipoprotein-sized compartments instead of being secreted into
  intestinal lymph. Infants present in the first six months with chronic
  malabsorptive diarrhoea, steatorrhoea, vomiting, abdominal distension and
  failure to thrive. The biochemical signature is marked hypocholesterolaemia
  with low LDL, low HDL and low apolipoprotein B but normal or near-normal
  fasting triglycerides, together with an absent postprandial chylomicron
  response and deficiency of the fat-soluble vitamins, most severely vitamin E.
  The normal fasting triglyceride level is the feature that most reliably
  separates CRD from abetalipoproteinemia and from homozygous
  APOB-related hypobetalipoproteinemia, in which hepatic VLDL secretion also
  fails. Endoscopy shows a white "gelee blanche" duodenal mucosa and biopsy
  shows lipid-laden enterocytes with preserved villus architecture. Untreated
  or late-treated disease is complicated by vitamin E-dependent neuromuscular
  and ophthalmological disease, poor bone mineralisation, coagulopathy,
  elevated creatine kinase and, in a minority of adults, cardiomyopathy.
  Treatment is lifelong restriction of long-chain dietary fat with adequate
  calories and essential fatty acids, plus high-dose fat-soluble vitamin
  supplementation; there is no therapy that restores COPII-dependent
  chylomicron export.
disease_term:
  preferred_term: chylomicron retention disease
  term:
    id: MONDO:0009528
    label: chylomicron retention disease
synonyms:
- Anderson disease
- Anderson's disease
- CRD
- CMRD
- FHBL-SD3
- hypobetalipoproteinemia with accumulation of apolipoprotein B-like protein in intestinal cells
parents:
- Hypobetalipoproteinemia
notes: >-
  This entry is restricted to SAR1B-related chylomicron retention disease. It is
  deliberately kept separate from the two sibling entries it is most often
  confused with. Abetalipoproteinemia (MTTP) abolishes lipidation of apoB in
  both enterocyte and hepatocyte, so triglycerides are very low and
  acanthocytosis is prominent; homozygous APOB-related hypobetalipoproteinemia
  removes the apoB scaffold itself. CRD leaves hepatic VLDL and apoB-100
  secretion largely intact, which is why fasting triglycerides stay normal and
  LDL remains detectable though reduced. No mechanism module in kb/modules/ was
  a genuine match: enterocyte_polarity_trafficking_failure scopes itself to the
  congenital enteropathies in which villus architecture is lost and diarrhoea
  does not remit on dietary elimination, and CRD has neither feature;
  hepatic_steatosis_lipotoxicity asserts progression through steatohepatitis to
  fibrosis, which the CRD guideline review explicitly did not observe. A COPII
  or ER-export trafficking module would be the natural conformance target and
  does not yet exist.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations."
      explanation: The review frames CRD as an inherited disorder of lipid absorption and lipoprotein metabolism.
  - classification_value: GASTROINTESTINAL
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile."
      explanation: The presenting illness and the diagnostic pathway are gastrointestinal.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CMRD is inherited in an autosomal recessive manner."
      explanation: GeneReviews establishes CRD as a Mendelian, autosomal recessive disorder.
  icimd_category:
  - classification_value: decreased_ldl_triglycerides
    evidence:
    - reference: PMID:31253576
      reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intestinal lipid malabsorption, resulting from an impaired formation or secretion of chylomicrons and associated with severe hypobetalipoproteinemia (HBL), may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease)."
      explanation: >-
        Places CRD within the group of inherited lipoprotein disorders defined
        by reduced LDL and apolipoprotein B, which is the ICIMD lipoprotein
        subgroup for decreased LDL and/or triglycerides.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic SAR1B pathogenic variants are required. Heterozygous parents are
    clinically and biochemically unremarkable, which is one reason a family
    history is usually absent and diagnosis is delayed.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CMRD is inherited in an autosomal recessive manner."
    explanation: GeneReviews states the mode of inheritance directly.
  - reference: PMID:17945526
    reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anderson disease (and/or chylomicron retention disease-CMRD) is a rare, autosomic recessive disorder characterized by chronic diarrhea, failure to thrive, and hypocholesterolemia in childhood."
    explanation: A 15-patient case series describes the disorder as autosomal recessive.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal Fasting lipids in parents 100%"
    explanation: >-
      In the two-centre cohort the fasting lipid profile of every parent was
      normal, consistent with clinically silent heterozygous carriage.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists. Fewer than fifty cases had
    been published by 2011 and the literature has grown only slowly since;
    underdiagnosis is likely because the presenting symptoms are non-specific.
  evidence:
  - reference: PMID:21235735
    reference_title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "less than 50 cases having been reported in the literature"
    explanation: Gives the published case count as of 2011, the basis for the ultra-rare band.
  - reference: PMID:30021760
    reference_title: Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) are extremely rare recessive forms of hypobetalipoproteinemia characterized by intestinal lipid malabsorption and severe vitamin E deficiency."
    explanation: Independently characterises CRD as extremely rare.
  - reference: PMID:38749523
    reference_title: "Chylomicron retention disease: a rare aetiology of failure to thrive."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CRD often presents with non-specific symptoms, resulting in delayed diagnosis which is established by genetic workup and histology from small intestinal biopsies."
    explanation: Supports the underdiagnosis note attached to this estimate.
progression:
- phase: Infancy
  age_range: First six months of life
  notes: >-
    Onset is in the first months of life with malabsorptive diarrhoea,
    steatorrhoea, vomiting, abdominal distension and faltering growth. The lipid
    profile is already abnormal at presentation.
  evidence:
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All CRD patients presented within the first few months of life with diarrhea and failure to thrive."
    explanation: Two independent cohorts place onset in the first months of life.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat"
    explanation: GeneReviews describes the infantile presenting syndrome.
- phase: Childhood on treatment
  age_range: After dietary treatment is started
  notes: >-
    Gastrointestinal symptoms remit on a low-long-chain-fat diet and recur if
    fat is reintroduced, so the response is dietary control rather than
    intestinal adaptation. Hypocholesterolaemia and low vitamin E persist
    despite supplementation.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
    explanation: Establishes the diet-responsive course of the gastrointestinal phase.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."
    explanation: Records that vitamin E remains low even on effective oral treatment.
- phase: Late childhood to adulthood
  age_range: First to second decades onward
  notes: >-
    Complications of chronic fat-soluble-vitamin deficiency emerge in the first
    and second decades: neuromuscular signs, ophthalmological abnormalities,
    poor bone mineralisation and delayed bone maturation. Creatine kinase is
    commonly raised, and a minority of adults develop cardiomyopathy with a
    reduced ejection fraction. These complications are less severe than in
    abetalipoproteinemia, and early vitamin E replacement largely prevents them.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency"
    explanation: GeneReviews times the neuromuscular complications to the first two decades.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "(in a small proportion of adults) cardiomyopathy with decreased ejection fraction"
    explanation: GeneReviews places cardiomyopathy in a minority of adults.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neurological and ophthalmologic complications in CRD are less severe than in other types of familial hypocholesterolemia."
    explanation: Contrasts the severity of late complications with the other monogenic hypocholesterolaemias.
pathophysiology:
- name: SAR1B Loss of Function
  biological_scale: MOLECULAR
  description: >
    Biallelic SAR1B variants remove or cripple the small Ras-superfamily GTPase
    that begins COPII coat assembly. Reported alleles include nonsense and
    frameshift changes and a whole-exon-2 deletion, all of which truncate the
    protein, and missense substitutions clustered around the guanine-nucleotide
    recognition and SEC23-interaction surfaces. The paralogue SAR1A, which
    differs at only twenty of 198 residues, is upregulated in patient duodenum
    but does not restore chylomicron export.
  genes:
  - preferred_term: SAR1B
    term:
      id: hgnc:10535
      label: SAR1B
  molecular_functions:
  - preferred_term: SAR1B GTPase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0003924
      label: GTPase activity
  downstream:
  - target: Defective COPII Coat Assembly at Endoplasmic Reticulum Exit Sites
    causal_link_type: DIRECT
    description: >-
      SAR1B-GTP is the first coat component recruited to an ER exit site and is
      what brings SEC23-SEC24 to the membrane, so losing it disables coat
      nucleation.
    evidence:
    - reference: PMID:36594468
      reference_title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SAR1 is a small GTPase that recruits other coat proteins to the ER membrane."
      explanation: States the step the mutated protein performs, which is the step this edge asserts is lost.
  - target: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux
    causal_link_type: DIRECT
    description: >-
      A branch that does not run through chylomicron retention. SAR1B loss in
      enterocyte-like cells reduces cholesterol efflux and nascent HDL
      formation via reduced ABCA1 expression, which is the most likely
      explanation for the low HDL cholesterol seen in patients.
    evidence:
    - reference: PMID:28982670
      reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The decreased cholesterol efflux was associated with impaired expression of ABCA1 (ATP-binding cassette subfamily A member 1)."
      explanation: Links SAR1B deletion directly to the efflux and ABCA1 defect that underlies impaired HDL biogenesis.
  - target: Impaired Hepatic ApoB Lipoprotein Secretion
    causal_link_type: DIRECT
    description: >-
      A second extra-intestinal branch. Sar1B also promotes hepatic apoB
      lipoprotein secretion, which is the proposed explanation for the hepatic
      steatosis and the severity of the hypocholesterolaemia in a disease whose
      primary lesion is intestinal.
    evidence:
    - reference: PMID:24338480
      reference_title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein."
      explanation: Demonstrates the hepatic arm of Sar1B function that this branch depends on.
  evidence:
  - reference: PMID:12692552
    reference_title: Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption."
    explanation: The original identification of SAR1B (then SARA2) mutations as the cause of the fat-malabsorption phenotype.
  - reference: PMID:17945526
    reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The nonsense mutation and the whole deletion of exon 2 produced truncated proteins, the missense mutations probably non-functional proteins."
    explanation: Structural and sequence analysis of five alleles supports loss of function as the shared consequence.
  - reference: PMID:36594468
    reference_title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The human SAR1A and SAR1B paralogs differ at only 20 of 198 amino acid residues."
    explanation: Quantifies the paralogue similarity that makes the failure of SAR1A compensation notable.
  - reference: PMID:21235735
    reference_title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein"
    explanation: Patient duodenal biopsies show that paralogue upregulation does not rescue the defect.
- name: Defective COPII Coat Assembly at Endoplasmic Reticulum Exit Sites
  biological_scale: MOLECULAR
  description: >
    At an ER exit site the transmembrane guanine-nucleotide exchange factor
    SEC12 loads SAR1B with GTP; SAR1B-GTP inserts an amphipathic helix into the
    ER membrane and recruits the SEC23-SEC24 inner coat, followed by the
    SEC13-SEC31 outer coat. SEC23 is also the GTPase-activating protein that
    triggers hydrolysis and coat turnover. A variant that blocks nucleotide
    exchange, hydrolysis, membrane insertion or SEC23 binding therefore
    disables coat assembly or coat cycling at this one step.
  biological_processes:
  - preferred_term: COPII coat assembly and vesicle budding at ER exit sites
    modifier: DECREASED
    term:
      id: GO:0090114
      label: COPII-coated vesicle budding
  cellular_components:
  - preferred_term: COPII vesicle coat
    term:
      id: GO:0030127
      label: COPII vesicle coat
  downstream:
  - target: Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum
    causal_link_type: DIRECT
    description: >-
      Without a functional coat, the carrier that would move pre-chylomicrons
      out of the ER is never formed.
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi."
      explanation: States the causal step from failed COPII formation to blocked chylomicron cargo transport.
  evidence:
  - reference: PMID:36594468
    reference_title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GTP-bound SAR1 inserts its hydrophobic N-terminus into the ER membrane and recruits SEC23-SEC24 heterodimers to the ERES by directly interacting with SEC23"
    explanation: Describes the molecular step that SAR1B loss interrupts.
  - reference: PMID:36594468
    reference_title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SEC12 is a type II ER transmembrane protein that functions as a guanine nucleotide exchange factor (GEF) for SAR1 while also recruiting SAR1 to the ER membrane"
    explanation: Identifies the activation step upstream of coat nucleation.
  - reference: PMID:39062121
    reference_title: "Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites"
    explanation: The most recent dedicated review places the lesion at COPII vesicles and ER exit sites.
- name: Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum
  biological_scale: CELLULAR
  description: >
    Newly assembled pre-chylomicrons are far larger than a conventional 60-90 nm
    COPII vesicle, so their export depends on COPII machinery being recruited to
    generate an enlarged carrier. In CRD that carrier is not produced, and the
    pre-chylomicron transport vesicle never reaches the Golgi. This is a
    trafficking failure and not an assembly failure: apoB-48 lipidation and
    chylomicron formation themselves are intact, which is what distinguishes CRD
    from abetalipoproteinemia at the cell-biological level.
  cell_types:
  - preferred_term: absorptive small-intestinal enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: duodenum
    term:
      id: UBERON:0002114
      label: duodenum
  biological_processes:
  - preferred_term: endoplasmic reticulum to Golgi transport of pre-chylomicron vesicles
    modifier: DECREASED
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  downstream:
  - target: Enterocyte Chylomicron Retention
    causal_link_type: DIRECT
    description: >-
      Cargo that cannot leave the endoplasmic reticulum compartment stays in the
      cell.
    evidence:
    - reference: PMID:25559265
      reference_title: Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes."
      explanation: Sar1b depletion in vivo produces exactly the retention this edge asserts.
  evidence:
  - reference: PMID:12692552
    reference_title: Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell."
    explanation: Establishes that chylomicron export is a COPII-dependent process despite the size mismatch.
  - reference: PMID:28982670
    reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%)."
    explanation: Targeted SAR1B deletion in enterocyte-like cells reduces chylomicron output.
  - reference: PMID:28982670
    reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a double knockout of SAR1A and SAR1B was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output"
    explanation: >-
      Only the double knockout abolishes output, showing the residual export in
      single SAR1B loss is paralogue-dependent rather than SAR1B-independent.
- name: Enterocyte Chylomicron Retention
  biological_scale: CELLULAR
  description: >
    Assembled chylomicrons and their triglyceride cargo accumulate inside the
    absorptive enterocyte, as free cytoplasmic lipid droplets and as
    membrane-bound lipoprotein-sized particles. This is the lesion the disease
    is named for and the finding a duodenal biopsy demonstrates. Villus
    architecture is preserved, so the malabsorption is a secretion defect and
    not mucosal destruction.
  cell_types:
  - preferred_term: absorptive small-intestinal enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: intestinal lipid transport into lymph
    modifier: DECREASED
    term:
      id: GO:0006869
      label: lipid transport
  downstream:
  - target: Absent Postprandial Chylomicronemia
    causal_link_type: DIRECT
    description: >-
      Lipid retained in the enterocyte is lipid that never enters intestinal
      lymph, so there is no chylomicron or apoB-48 rise after a fat meal.
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids"
      explanation: Connects the blocked export to the absent postprandial chylomicron response.
  - target: Intestinal Fat Malabsorption
    causal_link_type: DIRECT
    description: >-
      Dietary long-chain fat that the enterocyte cannot pass on is lost in the
      stool.
    evidence:
    - reference: PMID:33964306
      reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion."
      explanation: In the mouse model, blocked chylomicron secretion is accompanied by measured faecal fat loss.
  - target: Enterocyte Lipid Peroxidation and Endoplasmic Reticulum Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A proposed but not clinically validated branch: retained lipid is
      associated with oxidative and ER stress in cell and animal systems.
    evidence:
    - reference: PMID:39062121
      reference_title: "Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD"
      explanation: >-
        The review asserts the association while marking the contribution to
        clinical complications as potential, which is why this edge is typed as
        indirect and the target node is flagged provisional.
  evidence:
  - reference: PMID:31253576
    reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission."
    explanation: Records enterocyte lipid accumulation as the presenting histological finding in molecularly confirmed patients.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."
    explanation: The diagnostic guideline records fat-laden enterocytes as the constant histological finding.
- name: Absent Postprandial Chylomicronemia
  biological_scale: ORGANISM
  description: >
    After an oral fat load there is no rise in plasma chylomicrons or apoB-48.
    Because chylomicrons are also the vehicle by which dietary cholesterol,
    essential fatty acids and the fat-soluble vitamins reach the circulation,
    this single transport failure accounts for the whole downstream biochemical
    phenotype. Hepatic VLDL and apoB-100 secretion continue, which is why LDL
    remains detectable and fasting triglycerides stay normal.
  downstream:
  - target: Fat-Soluble Vitamin Deficiency
    causal_link_type: DIRECT
    description: >-
      Vitamins A, D, E and K are absorbed with dietary fat and delivered in
      chylomicrons; with no chylomicron output their delivery fails.
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids"
      explanation: The same sentence links absent chylomicronaemia to liposoluble vitamin and essential fatty acid deficiency.
  - target: Essential Fatty Acid Deficiency
    causal_link_type: DIRECT
    description: >-
      Linoleic and alpha-linolenic acid are long-chain fatty acids that also
      depend on chylomicron delivery.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Essential fatty acid (EFA) deficiency is especially severe early in life."
      explanation: Records essential fatty acid deficiency as a distinct early consequence.
  - target: Hypocholesterolemia
    causal_link_type: DIRECT
    description: >-
      Loss of the intestinal contribution to circulating cholesterol, together
      with the reduced HDL branch, produces the profound hypocholesterolaemia.
    evidence:
    - reference: PMID:19285442
      reference_title: "Chylomicron retention disease: a long term study of two cohorts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B."
      explanation: >-
        Cohort data tie the hypocholesterolaemia to the same lipoprotein pattern
        that the absent chylomicron output produces, with the normal
        triglyceride showing that hepatic secretion is unaffected.
  - target: Decreased circulating apolipoprotein B concentration
    causal_link_type: DIRECT
    description: >-
      The apoB-48 pool never reaches plasma, and total apolipoprotein B is
      correspondingly low.
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal"
      explanation: States that apoB-48 is absent from the circulation, which is the apolipoprotein B claim this edge makes.
  evidence:
  - reference: PMID:27266643
    reference_title: "Chylomicron retention disease: A rare cause of chronic diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."
    explanation: States the defining postprandial finding alongside the normal fasting triglyceride that distinguishes CRD.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Negative Oral Fat Load Infancy (1 to 6 m) Permanent ? 100%"
    explanation: Every patient in the two-centre cohort had a negative oral fat load.
- name: Intestinal Fat Malabsorption
  biological_scale: ORGANISM
  description: >
    Dietary long-chain fat that cannot be exported from the enterocyte is passed
    into the stool, producing steatorrhoea whose severity tracks the fat content
    of the diet, with the osmotic and secretory consequences of unabsorbed fat
    in the lumen. This is the arm of the mechanism that responds to dietary fat
    restriction.
  downstream:
  - target: Chronic diarrhea
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
      explanation: >-
        Remission of the diarrhoea when dietary long-chain fat is withdrawn is
        the clinical demonstration that unabsorbed fat is what drives it.
  - target: Steatorrhea
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This leads to steatorrhea – the severity of which relates to the fat content of the diet"
      explanation: GeneReviews states that fat malabsorption is what produces the steatorrhoea.
  - target: Abdominal distention
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
      explanation: Dietary fat withdrawal resolves the distension, supporting unabsorbed fat as its cause.
  - target: Vomiting
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
      explanation: Dietary fat withdrawal resolves the vomiting, supporting unabsorbed fat as its cause.
  - target: Failure to thrive
    causal_link_type: DIRECT
    description: >-
      Energy and nutrient loss in an infant with a high growth demand is the
      proximate cause of the growth failure.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Failure to thrive Infancy (1 to 6 m) transient if low LCFA diet 80%"
      explanation: >-
        The cohort table records the growth failure as transient on a
        long-chain-fat-restricted diet, which ties it to the malabsorbed fat
        rather than to an independent cause.
  - target: Fat-Soluble Vitamin Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "accompanied by a deficiency in liposoluble vitamins and essential fatty acids"
      explanation: Links the fat-transport failure to the liposoluble vitamin deficiency.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "typically presents in infancy with failure to thrive, diarrhea, vomiting, abdominal distention, and malabsorption of fat"
    explanation: Groups the gastrointestinal presentation that this node generates.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
    explanation: >-
      Symptom remission on long-chain fat restriction is the clinical evidence
      that these manifestations are driven by unabsorbed dietary fat.
- name: Fat-Soluble Vitamin Deficiency
  biological_scale: ORGANISM
  description: >
    Vitamins A, D, E and K are all low. Vitamin E is the most severely and most
    persistently affected: plasma alpha-tocopherol stays chronically low even on
    high-dose oral replacement, because absorption of any lipophilic molecule
    depends on the chylomicron pathway that is blocked. Vitamin D deficiency
    drives the skeletal phenotype and vitamin K deficiency the coagulopathy.
  chemical_entities:
  - preferred_term: alpha-tocopherol
    modifier: DECREASED
    term:
      id: CHEBI:22470
      label: alpha-tocopherol
  biological_processes:
  - preferred_term: intestinal transport of fat-soluble vitamins
    modifier: DECREASED
    term:
      id: GO:0051180
      label: vitamin transport
  downstream:
  - target: Vitamin E-Dependent Neuroaxonal and Retinal Injury
    causal_link_type: DIRECT
    description: >-
      Chronic tocopherol deficiency is the accepted cause of the neuromuscular
      and ophthalmological complications, and adequacy of vitamin E replacement
      is what determines whether they occur.
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency"
      explanation: GeneReviews attributes the neuromuscular complications specifically to vitamin E deficiency.
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications."
      explanation: The guideline makes vitamin E status the determining variable for neurological outcome.
  - target: Reduced bone mineral density
    causal_link_type: DIRECT
    description: Mediated by vitamin D deficiency.
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "poor bone mineralization and delayed bone maturation due to vitamin D deficiency"
      explanation: GeneReviews assigns the skeletal phenotype to vitamin D deficiency.
  - target: Delayed skeletal maturation
    causal_link_type: DIRECT
    description: Mediated by vitamin D deficiency.
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "poor bone mineralization and delayed bone maturation due to vitamin D deficiency"
      explanation: GeneReviews attributes delayed bone maturation to the vitamin D deficiency.
  - target: Prolonged prothrombin time
    causal_link_type: DIRECT
    description: Mediated by vitamin K deficiency.
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "prolonged international normalized ratio (INR) due to vitamin K deficiency"
      explanation: GeneReviews attributes the coagulation abnormality to vitamin K deficiency.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "low serum concentrations of fat-soluble vitamins (A, D, E, and K)"
    explanation: Names all four deficient vitamins.
  - reference: PMID:36771214
    reference_title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan"
    explanation: >-
      A SAR1B knock-out enterocyte model reproduces impaired tocopherol
      secretion even with the pharmaceutical vitamin E forms used clinically,
      which is the mechanistic basis for the persistently low plasma vitamin E.
- name: Essential Fatty Acid Deficiency
  biological_scale: ORGANISM
  description: >
    Linoleate and alpha-linolenate delivery fails with the chylomicron pathway.
    The deficiency is most severe in the first months of life and is aggravated
    by over-strict dietary fat restriction, which is why treatment has to
    balance symptom control against essential fatty acid and calorie intake.
  downstream:
  - target: Failure to thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Through impaired growth substrate supply and malnutrition.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Essential fatty acid (EFA) deficiency is especially severe early in life."
    explanation: Establishes the deficiency and its timing.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EFA deficiency* (20:3n-9/20:4n-6) Infancy to late childhood permanent but variations 55%"
    explanation: Quantifies essential fatty acid deficiency in the two-centre cohort.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Varying degrees of essential fatty acid and of vitamin E deficiency were observed."
    explanation: Independent cohort confirmation of essential fatty acid deficiency.
- name: Vitamin E-Dependent Neuroaxonal and Retinal Injury
  biological_scale: TISSUE
  description: >
    Chronic alpha-tocopherol deficiency causes the neuromuscular and retinal
    complications of CRD: loss of deep tendon reflexes, ataxia, myopathy with
    raised creatine kinase, and subtle ophthalmological abnormalities including
    micronystagmus, delayed dark adaptation and abnormal scotopic
    electroretinograms. These are milder in CRD than in abetalipoproteinemia,
    and they are largely preventable by early high-dose oral vitamin E.
  locations:
  - preferred_term: nervous system involvement in vitamin E deficiency
    term:
      id: UBERON:0001016
      label: nervous system
  downstream:
  - target: Areflexia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19285442
      reference_title: "Chylomicron retention disease: a long term study of two cohorts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia."
      explanation: Attributes the areflexia in the cohort specifically to vitamin E deficiency.
  - target: Ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency"
      explanation: >-
        GeneReviews places the neuromuscular abnormalities, of which ataxia is
        one, downstream of vitamin E deficiency. The quoted sentence names the
        umbrella category rather than ataxia, so reaching this specific edge
        takes the inference that ataxia is one of the abnormalities it covers.
  - target: Myopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "neuromuscular abnormalities (typically in the first or second decade of life) secondary to vitamin E deficiency"
      explanation: >-
        The muscular arm of the neuromuscular abnormalities GeneReviews
        attributes to vitamin E deficiency. As with the ataxia edge, the quote
        names the umbrella category, so this edge follows by the inference that
        myopathy is one of the abnormalities it covers.
  - target: Elevated circulating creatine kinase concentration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Through the muscular involvement of vitamin E deficiency.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations."
      explanation: Groups the raised creatine kinase with the muscular manifestations of the disease.
  - target: Abnormal electroretinogram
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19285442
      reference_title: "Chylomicron retention disease: a long term study of two cohorts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients"
      explanation: Attributes the functional ophthalmic changes to vitamin E deficiency.
  - target: Nystagmus
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19285442
      reference_title: "Chylomicron retention disease: a long term study of two cohorts."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients"
      explanation: The micronystagmus falls within the ophthalmic changes attributed to vitamin E deficiency.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"
    explanation: Enumerates the ophthalmological findings that make up the retinal arm of this node.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia."
    explanation: >-
      Cohort data both attribute the changes to vitamin E deficiency and show
      how uncommon the severe end of this node is under treatment.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations."
    explanation: Adds the muscular arm, including the creatine kinase elevation.
- name: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux
  biological_scale: CELLULAR
  description: >
    A branch of the mechanism that does not run through chylomicron retention.
    Loss of SAR1B in enterocyte-like cells reduces ABCA1 expression and
    cholesterol efflux to apolipoprotein A-I, limiting nascent HDL production by
    the intestine. This is the current explanation for the low HDL cholesterol
    and low apolipoprotein A-I of CRD, which are otherwise hard to derive from a
    pure chylomicron-export defect.
  biological_processes:
  - preferred_term: cholesterol efflux to apolipoprotein A-I
    modifier: DECREASED
    term:
      id: GO:0033344
      label: cholesterol efflux
  - preferred_term: intestinal high-density lipoprotein particle assembly
    modifier: DECREASED
    term:
      id: GO:0034380
      label: high-density lipoprotein particle assembly
  downstream:
  - target: Decreased HDL cholesterol concentration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30640893
      reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein."
      explanation: >-
        States the proposed route from reduced intestinal HDL production to the
        low HDL cholesterol, and hedges it as a likely reflection.
  evidence:
  - reference: PMID:28982670
    reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs."
    explanation: Direct demonstration that SAR1B loss impairs HDL biogenesis in an intestinal cell model.
  - reference: PMID:30640893
    reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein."
    explanation: The review proposes this branch as the explanation for the low HDL, and hedges it as such.
- name: Impaired Hepatic ApoB Lipoprotein Secretion
  biological_scale: CELLULAR
  description: >
    SAR1B is not intestine-specific. It also promotes hepatic apoB lipoprotein
    secretion and modulates expression of cholesterol-biosynthetic genes, which
    is the proposed reason a disorder of intestinal fat export nonetheless
    produces hepatic steatosis and cholesterol levels lower than intestinal
    malabsorption alone would predict. The hepatic arm is less firmly
    characterised in patients than the enterocyte lesion.
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  downstream:
  - target: Hepatic steatosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24338480
      reference_title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion"
      explanation: >-
        Establishes the hepatic secretory role whose loss is the proposed cause
        of the steatosis; the study demonstrates the secretory step rather than
        the steatosis itself, so the inference is one step removed.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hepatomegaly, Steatosis Infancy or late childhood transit or permanent 15%"
      explanation: >-
        The cohort records hepatomegaly and steatosis together as one finding,
        supporting the hepatic lipid pathway as the route to the enlarged liver.
  evidence:
  - reference: PMID:24338480
    reference_title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition"
    explanation: States the puzzle this node answers, and marks it as previously unexplained.
  - reference: PMID:24338480
    reference_title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions."
    explanation: Establishes the hepatic secretory role of Sar1B on which this node rests.
- name: Enterocyte Lipid Peroxidation and Endoplasmic Reticulum Stress
  biological_scale: CELLULAR
  description: >
    A proposed downstream consequence of intracellular lipid retention:
    increased lipid peroxidation, endoplasmic reticulum stress and inflammatory
    signalling. The evidence is from SAR1B-disrupted cell lines and engineered
    mice; no study has shown that this branch drives any human complication, so
    it is recorded as provisional rather than as part of the established chain.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:39062121
    reference_title: "Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD"
    explanation: >-
      The review states the association and marks the link to clinical
      complications as potential, which is why this node is provisional.
  - reference: PMID:37558128
    reference_title: High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet."
    explanation: >-
      Shows that the metabolic consequences of Sar1b defects in mice are
      dietary-fat-dependent, the model context in which the stress branch was
      characterised.
phenotypes:
- name: Chronic diarrhea
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Non-specific malabsorptive diarrhoea beginning in the first six months is
    the most constant presenting feature. It remits on a low-long-chain-fat diet
    and recurs when fat is reintroduced.
  phenotype_term:
    preferred_term: Chronic malabsorptive diarrhea of infancy
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diarrhea Infancy (1 to 6 m) transient if low LCFA diet 100%"
    explanation: The two-centre cohort table records diarrhoea in 100% of patients, supporting the VERY_FREQUENT band.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All CRD patients presented within the first few months of life with diarrhea and failure to thrive."
    explanation: Independent cohort confirmation of diarrhoea as a universal presenting feature.
- name: Steatorrhea
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Fatty stool whose severity tracks dietary fat content. It persists on
    long-term follow-up rather than adapting.
  phenotype_term:
    preferred_term: Steatorrhea
    term:
      id: HP:0002570
      label: Steatorrhea
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Steatorrhea (N < 5 g/d) Infancy (1 to 6 m) - (7.5 ± 3.6) transit or permanent 85%"
    explanation: Cohort table gives an 85% frequency with the measured faecal fat, supporting the VERY_FREQUENT band.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This leads to steatorrhea – the severity of which relates to the fat content of the diet"
    explanation: GeneReviews records steatorrhoea as the consequence of the fat malabsorption.
- name: Fat malabsorption
  category: Gastrointestinal
  description: >-
    The functional defect underlying the stool findings: dietary long-chain fat
    is taken up by the enterocyte but not delivered to the circulation.
  phenotype_term:
    preferred_term: Intestinal fat malabsorption
    term:
      id: HP:0002630
      label: Fat malabsorption
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by the inability to secrete chylomicrons from the enterocytes following the ingestion of fat"
    explanation: GeneReviews defines the disease by the secretion failure that produces fat malabsorption.
- name: Vomiting
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vomiting Infancy (1 to 6 m) transient if low LCFA diet 60%"
    explanation: Cohort frequency of 60% supports the FREQUENT band.
- name: Abdominal distention
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abdominal distention
    term:
      id: HP:0003270
      label: Abdominal distention
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abdominal distension Infancy (1 to 6 m) transient if low LCFA diet 65%"
    explanation: Cohort frequency of 65% supports the FREQUENT band.
- name: Failure to thrive
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Faltering weight and length in infancy, one of the most common initial
    findings. Growth potential can be permanently compromised if diagnosis is
    delayed.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Failure to thrive Infancy (1 to 6 m) transient if low LCFA diet 80%"
    explanation: Cohort frequency of 80% supports the VERY_FREQUENT band.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Failure to thrive is one of the most common initial clinical findings."
    explanation: The guideline text confirms failure to thrive as a leading presenting sign.
- name: Hypocholesterolemia
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >-
    Total cholesterol is roughly halved relative to controls. Together with a
    normal fasting triglyceride, this is the biochemical pattern that should
    prompt SAR1B testing in an infant with chronic diarrhoea.
  diagnostic: true
  phenotype_term:
    preferred_term: Hypocholesterolemia
    term:
      id: HP:0003146
      label: Hypocholesterolemia
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low Total cholesterol §§ Infancy (1 to 6 m) permanent 100% moderate decrease"
    explanation: Cohort table records low total cholesterol in 100% of patients, permanent from infancy.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B."
    explanation: Gives the full lipid pattern in two independent cohorts.
- name: Decreased LDL cholesterol concentration
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >-
    LDL cholesterol is reduced but, unlike in abetalipoproteinemia, remains
    detectable, because hepatic apoB-100 secretion is largely preserved.
  phenotype_term:
    preferred_term: Decreased LDL cholesterol concentration
    term:
      id: HP:0003563
      label: Decreased LDL cholesterol concentration
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low LDL † Infancy (1 to 6 m) permanent 100% moderate decrease"
    explanation: Cohort table records low LDL in 100% of patients.
- name: Decreased HDL cholesterol concentration
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >-
    HDL cholesterol and apolipoprotein A-I are both low, attributed to reduced
    intestinal HDL biogenesis rather than to the chylomicron block itself.
  phenotype_term:
    preferred_term: Decreased HDL cholesterol concentration
    term:
      id: HP:0003233
      label: Decreased HDL cholesterol concentration
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low HDL †† Infancy (1 to 6 m) permanent 100%"
    explanation: Cohort table records low HDL in 100% of patients and rates it highly discriminative.
- name: Decreased circulating apolipoprotein B concentration
  category: Biochemical
  description: >-
    Plasma apolipoprotein B is low, and apoB-48 is absent from the postprandial
    circulation.
  phenotype_term:
    preferred_term: Decreased circulating apolipoprotein B concentration
    term:
      id: HP:0034075
      label: Decreased circulating apolipoprotein B concentration
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels"
    explanation: GeneReviews records the low apolipoprotein B alongside the normal-to-low triglyceride.
- name: Decreased circulating vitamin E concentration
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >-
    Vitamin E deficiency is essentially invariable and is the deficiency that
    determines long-term neurological outcome. Plasma alpha-tocopherol remains
    chronically low even on adequate high-dose oral replacement.
  diagnostic: true
  phenotype_term:
    preferred_term: Decreased circulating vitamin E concentration
    term:
      id: HP:0100513
      label: Decreased circulating vitamin E concentration
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."
    explanation: The guideline calls vitamin E deficiency invariable, supporting the VERY_FREQUENT band.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E deficiency (N > 18.4 μmol/L) Infancy (1 to 6 m) - (2.7 ± 0.3) permanent 95%"
    explanation: Cohort table gives a 95% frequency and the mean plasma concentration.
- name: Reduced circulating vitamin A concentration
  category: Biochemical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Reduced circulating vitamin A concentration
    term:
      id: HP:0004905
      label: Reduced circulating vitamin A concentration
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin A deficiency (N > 1.61 μmol/L) Infancy (1 to 6 m) - (0.8 ± 0.5) transit if supplementation 70%"
    explanation: Cohort frequency of 70%, correctable with supplementation, supports the FREQUENT band.
- name: Decreased circulating vitamin D concentration
  category: Biochemical
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased circulating vitamin D concentration
    term:
      id: HP:0100512
      label: Decreased circulating vitamin D concentration
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin D deficiency (N > 50 nmol/L) Infancy (1 to 6 m) - (31 ± 17) transit if supplementation 45%"
    explanation: Cohort frequency of 45% supports the FREQUENT band.
- name: Prolonged prothrombin time
  category: Hematologic
  description: >-
    Prolonged INR from vitamin K deficiency. It is monitored as the functional
    readout of vitamin K status rather than measured directly in most centres.
  phenotype_term:
    preferred_term: Prolonged international normalized ratio from vitamin K deficiency
    term:
      id: HP:0008151
      label: Prolonged prothrombin time
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "prolonged international normalized ratio (INR) due to vitamin K deficiency"
    explanation: GeneReviews names the coagulation abnormality and its cause.
- name: Elevated circulating creatine kinase concentration
  category: Biochemical
  frequency: FREQUENT
  description: >-
    Creatine kinase is commonly raised, typically several-fold, and is the
    earliest laboratory sign of the muscular involvement.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High CK (N < 100 mmol/L) Infancy (1 to 6 m) - (460 ± 100) permanent 60%"
    explanation: Cohort frequency of 60% with the measured mean concentration supports the FREQUENT band.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Creatine kinase (CK) is usually elevated and hepatic steatosis is common."
    explanation: The guideline text records raised creatine kinase as a usual finding.
- name: Hepatic steatosis
  category: Hepatic
  frequency: OCCASIONAL
  description: >-
    A moderate macrovesicular steatosis is described, often with mild
    transaminase elevation. Progression to steatohepatitis or cirrhosis has not
    been reported, which is why this entry does not conform to the hepatic
    steatosis lipotoxicity module.
  phenotype_term:
    preferred_term: Macrovesicular hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis."
    explanation: >-
      Establishes both the steatosis and the absence of reported progression,
      which is the claim the description makes.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, Steatosis Infancy or late childhood transit or permanent 15%"
    explanation: Cohort frequency of 15% supports the OCCASIONAL band.
- name: Hepatomegaly
  category: Hepatic
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "and in some cases, hepatomegaly"
    explanation: GeneReviews reports hepatomegaly in a subset, consistent with the OCCASIONAL band.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, Steatosis Infancy or late childhood transit or permanent 15%"
    explanation: Cohort frequency of 15%.
- name: Areflexia
  category: Neurologic
  frequency: VERY_RARE
  description: >-
    Loss of deep tendon reflexes is the classic neurological sign of chronic
    vitamin E deficiency. It is uncommon in treated CRD cohorts and much less
    frequent than in abetalipoproteinemia.
  phenotype_term:
    preferred_term: Hyporeflexia or areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypo or Areflexia Late childhood or adult (4 to 10 y) permanent 5%"
    explanation: Cohort frequency of 5% with late-childhood onset supports the VERY_RARE band.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia."
    explanation: One case of areflexia across two cohorts, consistent with a very rare manifestation.
- name: Ataxia
  category: Neurologic
  description: >-
    Reported as a late complication of untreated vitamin E deficiency and listed
    among the manifestations for which standard symptomatic treatment is
    recommended.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "standard treatment for deficits in night vision and/or color vision, ataxia, and cardiomyopathy"
    explanation: >-
      GeneReviews lists ataxia among the manifestations requiring management.
      That ataxia is part of the disease phenotype follows from the management
      recommendation rather than being asserted by the quoted sentence, which is
      a statement about treatment.
- name: Myopathy
  category: Musculoskeletal
  description: >-
    Muscular manifestations accompany the raised creatine kinase. They were not
    observed in the two-centre paediatric cohort, and are described in the
    literature as an adult finding.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recently, increased CK levels and cardiomyopathy have been described in addition to muscular manifestations."
    explanation: Records muscular manifestations as part of the CRD phenotype.
- name: Abnormal electroretinogram
  category: Ophthalmologic
  description: >-
    Abnormal scotopic electroretinograms and delayed dark adaptation are the
    typical ophthalmological abnormalities. They are usually mild and are
    detected on surveillance rather than presenting symptomatically.
  phenotype_term:
    preferred_term: Abnormal scotopic electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"
    explanation: GeneReviews names the abnormal scotopic electroretinogram among the ophthalmological findings.
- name: Nystagmus
  category: Ophthalmologic
  description: Micronystagmus is described among the mild ophthalmological findings.
  phenotype_term:
    preferred_term: Micronystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mild ophthalmologic issues (e.g., micronystagmus, delayed dark adaptation, abnormal visual evoked potentials, and abnormal scotopic electroretinograms)"
    explanation: GeneReviews names micronystagmus among the ophthalmological findings.
- name: Reduced bone mineral density
  category: Musculoskeletal
  description: Poor bone mineralisation attributed to vitamin D deficiency.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "poor bone mineralization and delayed bone maturation due to vitamin D deficiency"
    explanation: GeneReviews records poor mineralisation and its vitamin D basis.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Poor mineralization and delayed bone maturation do occur."
    explanation: Independent confirmation from the management guideline.
- name: Delayed skeletal maturation
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Delayed bone maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "poor bone mineralization and delayed bone maturation due to vitamin D deficiency"
    explanation: GeneReviews records delayed bone maturation alongside poor mineralisation.
- name: Reduced left ventricular ejection fraction
  category: Cardiovascular
  frequency: VERY_RARE
  description: >-
    Cardiomyopathy with a reduced ejection fraction is reported in a small
    proportion of adults, and is the reason periodic echocardiography is part of
    adult surveillance. It was not observed in the paediatric two-centre cohort.
  phenotype_term:
    preferred_term: Cardiomyopathy with decreased ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "(in a small proportion of adults) cardiomyopathy with decreased ejection fraction"
    explanation: GeneReviews reports the finding in a small proportion of adults, supporting the VERY_RARE band.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiomyopathy/Biological signs Adult permanent? 0%"
    explanation: >-
      Recorded as absent in the two-centre paediatric cohort, which is why this
      phenotype is banded as very rare rather than by the cohort figure alone.
      The row reports a childhood prevalence of zero; the very-rare band for the
      adult phenotype follows by inference from that absence combined with the
      GeneReviews report above, not from the quoted row itself.
histopathology:
- name: Lipid-laden enterocytes with preserved villus architecture
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Duodenal or jejunal biopsy taken after dietary fat exposure shows
    enterocytes distended by large free cytoplasmic lipid droplets and by
    membrane-bound lipoprotein-sized particles. Villus architecture is normal,
    which separates CRD from the congenital enteropathies that destroy the
    absorptive surface. Because the finding is fat-load dependent, a biopsy
    taken on a fat-restricted diet can be falsely reassuring.
  finding_term:
    preferred_term: Cytoplasmic lipid accumulation in enterocytes
    term:
      id: NCIT:C36185
      label: Steatosis
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."
    explanation: The guideline records fat-laden enterocytes as the constant histological finding.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enterocyte vacuolization, chylomicron-like Infancy (1 to 6 m) permanent? Fat load dependent 100%"
    explanation: >-
      Cohort table records the finding in 100% of patients and states that it is
      fat-load dependent, which is the caveat in the description.
  - reference: PMID:31253576
    reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia"
    explanation: Molecularly confirmed patients presented with enterocyte lipid accumulation on biopsy.
- name: Macrovesicular hepatic steatosis
  frequency: OCCASIONAL
  description: >-
    A moderate macrovesicular steatosis of the liver, without reported
    progression to steatohepatitis or cirrhosis.
  finding_term:
    preferred_term: Macrovesicular steatosis
    term:
      id: NCIT:C82990
      label: Macrovesicular Steatosis
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A moderate degree of macrovesicular steatosis is common, but no cases of steatohepatitis cirrhosis."
    explanation: Names the histological pattern and its reported limits.
biochemical:
- name: Absent postprandial chylomicrons and apolipoprotein B-48
  presence: ABSENT
  context: >-
    After an oral fat load there is no rise in plasma chylomicrons or apoB-48.
    This is the functional hallmark of the disease and was negative in every
    patient of the two-centre cohort.
  evidence:
  - reference: PMID:30640893
    reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal"
    explanation: States the postprandial finding directly.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Negative Oral Fat Load Infancy (1 to 6 m) Permanent ? 100%"
    explanation: Every patient in the cohort had a negative oral fat load.
- name: Normal fasting triglyceride concentration
  presence: NORMAL
  context: >-
    Fasting triglycerides are normal or near-normal because hepatic VLDL
    secretion is preserved. This is the single most useful discriminator from
    abetalipoproteinemia and from homozygous APOB-related
    hypobetalipoproteinemia, in which the triglyceride is very low.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal TG § Infancy (1 to 6 m) transit or permanent 90%"
    explanation: Cohort table records a normal triglyceride in 90% of patients.
  - reference: PMID:27266643
    reference_title: "Chylomicron retention disease: A rare cause of chronic diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."
    explanation: Pairs the normal fasting triglyceride with the absent postprandial response as the defining combination.
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe hypocholesterolemia coupled with normal triglycerides"
    explanation: Independent cohort description of the same discriminating pattern.
- name: Low total, LDL and HDL cholesterol with low apolipoproteins A-I and B
  presence: DECREASED
  context: >-
    All three cholesterol fractions are reduced, together with apolipoprotein
    A-I and apolipoprotein B. The low HDL and low apoA-I are attributed to
    reduced intestinal HDL biogenesis rather than to the chylomicron block.
  evidence:
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B."
    explanation: Gives the complete lipoprotein and apolipoprotein pattern in two cohorts.
  - reference: PMID:30640893
    reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein."
    explanation: Supplies the proposed mechanism for the HDL and apoA-I arm of the pattern.
- name: Low plasma alpha-tocopherol
  presence: DECREASED
  context: >-
    Plasma alpha-tocopherol is markedly reduced from infancy and, unlike
    vitamins A, D and K, is not normalised by supplementation. Measured mean
    concentration in the two-centre cohort was 2.7 micromol/L against a normal
    threshold above 18.4 micromol/L.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vitamin E deficiency (N > 18.4 μmol/L) Infancy (1 to 6 m) - (2.7 ± 0.3) permanent 95%"
    explanation: Gives the normal threshold, the measured mean and the cohort frequency quoted in the context.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."
    explanation: Supports the statement that supplementation does not normalise the plasma level.
- name: Hepatic cytolysis with elevated transaminases
  presence: INCREASED
  context: >-
    Mild elevation of alanine aminotransferase accompanies the hepatic
    steatosis and is common in the paediatric cohort.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatic cytolysis (ALT < 40 mmol/L) Infancy to late childhood - (60 ± 20) transient or permanent 95%"
    explanation: Cohort table records mildly raised ALT in 95% of patients.
- name: Absence of acanthocytosis
  presence: ABSENT
  context: >-
    Acanthocytes are characteristically absent, in contrast with
    abetalipoproteinemia where acanthocytosis is a prominent clue. Their
    absence should not be used to exclude CRD.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No acantocytosis Infancy (1 to 6 m) transit or permanent 90%"
    explanation: >-
      The cohort table records absence of acanthocytosis in 90% of patients and
      rates it highly discriminative, which is the claim made here.
genetic:
- name: SAR1B biallelic pathogenic variants
  gene_term:
    preferred_term: SAR1B
    term:
      id: hgnc:10535
      label: SAR1B
  association: Biallelic loss-of-function or function-disrupting germline variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:35344313
      reference_title: Chylomicron Retention Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CMRD is inherited in an autosomal recessive manner."
      explanation: GeneReviews states the inheritance pattern for the SAR1B genotype.
  variants:
  - name: Truncating SAR1B variants
    description: >
      Nonsense, frameshift and whole-exon deletion alleles predicted to produce
      an absent or severely truncated Sar1b protein. Reported examples include
      the exon 6 nonsense change p.Glu122X, the frameshifts p.Leu28ArgfsX7 and
      p.Asp48ThrfsX17, and a whole deletion of exon 2 that removes the
      translation initiation codon.
    gene:
      preferred_term: SAR1B
      term:
        id: hgnc:10535
        label: SAR1B
    clinical_significance: PATHOGENIC
    type: loss_of_function_variant
    functional_effects:
    - function: COPII coat nucleation by the Sar1b GTPase
      description: Truncating alleles remove the protein, so no functional GTPase is available at ER exit sites.
      type: loss-of-function
    evidence:
    - reference: PMID:17945526
      reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified three unique homozygous mutations of SAR1B gene in French families originated from Turkey, Algeria and Portugal: a stop codon in exon 6 (c.364G>T, p.Glu122X), a whole deletion of exon 2"
      explanation: Reports the nonsense and whole-exon-deletion alleles named in the description.
    - reference: PMID:21235735
      reference_title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17)."
      explanation: Reports one of the frameshift alleles named in the description.
    - reference: PMID:31253576
      reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA."
      explanation: Documents the exon 2 deletion and its effect on the initiation codon.
  - name: Missense SAR1B variants
    description: >
      Missense substitutions clustered around the guanine-nucleotide
      recognition site and the coat-interaction surfaces, including
      p.Asp137Asn, p.Ser179Arg and p.Gly185Val. Computational and structural
      analysis predicts non-functional protein rather than absent protein; the
      p.Asp137Asn allele has been modelled in mouse.
    gene:
      preferred_term: SAR1B
      term:
        id: hgnc:10535
        label: SAR1B
    clinical_significance: PATHOGENIC
    type: missense_variant
    functional_effects:
    - function: Guanine nucleotide binding and hydrolysis by Sar1b
      description: Substitutions near the guanosine recognition site are predicted to disrupt nucleotide handling and coat cycling.
      type: loss-of-function
    evidence:
    - reference: PMID:17945526
      reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 2 missense mutations found in the 5 French-Canadian families had already been described in the eight previously published mutations: c.409G>A (p.Asp137Asn) and c.537T>A (p.Ser179Arg)."
      explanation: Reports two of the recurrent missense alleles named in the description.
    - reference: PMID:31253576
      reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant"
      explanation: >-
        Documents a homozygous SAR1B missense allele, c.409 G>C p.(Asp137His),
        which the same sentence places at a highly conserved residue close to
        the Sar1b guanosine recognition site.
    - reference: PMID:17945526
      reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The nonsense mutation and the whole deletion of exon 2 produced truncated proteins, the missense mutations probably non-functional proteins."
      explanation: Sequence and structural modelling assigns the missense alleles a loss of function.
  evidence:
  - reference: PMID:12692552
    reference_title: Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption."
    explanation: The founding report identifying SAR1B (SARA2) as the causal gene.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in SAR1B identified by molecular genetic testing."
    explanation: GeneReviews makes biallelic SAR1B variants the molecular definition of the disease.
  - reference: PMID:17945526
    reference_title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the affected children presented with similar phenotype at onset; the absence of phenotype-genotype correlation was discussed."
    explanation: >-
      A 15-patient series reports no genotype-phenotype correlation, which is
      why this entry does not stratify subtypes by allele class.
- name: SAR1A paralogue upregulation
  gene_term:
    preferred_term: SAR1A
    term:
      id: hgnc:10534
      label: SAR1A
  association: Compensatory intestinal upregulation that does not rescue the phenotype
  relationship_type: MODIFIER
  variant_origin: UNKNOWN
  notes: >-
    SAR1A is not a disease gene for CRD. It is recorded here because its
    behaviour explains two otherwise puzzling observations: patient duodenum
    upregulates SAR1A without clinical benefit, and in Caco-2 cells only the
    double SAR1A/SAR1B knockout abolishes chylomicron output. The residual
    export seen when SAR1B alone is lost is therefore paralogue-dependent.
  evidence:
  - reference: PMID:21235735
    reference_title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals."
    explanation: Measures the paralogue upregulation in patient tissue.
  - reference: PMID:21235735
    reference_title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein"
    explanation: States that the upregulation is not compensatory in patients.
  - reference: PMID:28982670
    reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The absence of expected chylomicron production collapse may be because of the compensatory SAR1A elevation observed in our experiments."
    explanation: >-
      Attributes the residual chylomicron output after SAR1B deletion to SAR1A,
      which is the in-vitro counterpart of the patient observation.
diagnosis:
- name: Fasting lipid profile with apolipoprotein B
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  description: >-
    The screening test in an infant with chronic diarrhoea and faltering
    growth. The pattern that should prompt SAR1B testing is a total and LDL
    cholesterol roughly half of normal, a low HDL cholesterol and a low
    apolipoprotein B, with a fasting triglyceride that is normal. A very low
    triglyceride points instead to abetalipoproteinemia or homozygous
    APOB-related hypobetalipoproteinemia.
  results: >-
    Low total, LDL and HDL cholesterol with low apolipoprotein B and a normal
    fasting triglyceride supports CRD but does not by itself distinguish it
    from the other monogenic hypocholesterolaemias.
  evidence:
  - reference: PMID:19285442
    reference_title: "Chylomicron retention disease: a long term study of two cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study provides new insights on the phenotypic expression of CRD over time and emphasizes the need to screen the lipid profile of infants with chronic diarrhea and failure to thrive."
    explanation: Explicitly recommends lipid screening in the presenting clinical context.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Affected individuals typically have marked hypocholesterolemia, low plasma apolipoprotein B levels, normal-to-low plasma triglyceride levels, and low serum concentrations of fat-soluble vitamins (A, D, E, and K)."
    explanation: GeneReviews gives the biochemical pattern this test is looking for.
- name: Fat-soluble vitamin and creatine kinase measurement
  diagnosis_term:
    preferred_term: blood chemistry measurement
    term:
      id: NCIT:C47868
      label: Blood Chemistry Measurement
  description: >-
    Plasma vitamins A, D and E, an INR as the functional readout of vitamin K
    status, and creatine kinase. Vitamin E deficiency is essentially invariable
    at diagnosis and creatine kinase is usually raised.
  results: >-
    A markedly low alpha-tocopherol with a raised creatine kinase in an infant
    with hypocholesterolaemia is strongly supportive.
  evidence:
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Creatine kinase (CK) is usually elevated and hepatic steatosis is common."
    explanation: Establishes creatine kinase as a routine part of the diagnostic laboratory set.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present."
    explanation: States that vitamin E deficiency is invariably present at diagnosis.
- name: Upper endoscopy with duodenal biopsy
  diagnosis_term:
    preferred_term: upper gastrointestinal endoscopy with duodenal biopsy
    term:
      id: NCIT:C78144
      label: Esophagogastroduodenoscopy
  description: >-
    Endoscopy performed after dietary fat exposure shows the white "gelee
    blanche" or hoar-frosting appearance of the duodenal mucosa, and biopsy
    shows lipid-laden enterocytes with normal villus architecture. Because both
    findings are fat-load dependent, an endoscopy done on a fat-restricted diet
    can be normal.
  results: >-
    A white duodenal mucosa with lipid-laden enterocytes on biopsy is highly
    supportive but is not a substitute for SAR1B sequencing.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Endoscopy typically demonstrates a gelée blanche"
    explanation: GeneReviews names the characteristic endoscopic appearance.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "White duodenal mucosa Infancy (1 to 6 m) permanent? Fat load dependent 100%"
    explanation: >-
      The cohort table records the white mucosa in 100% of patients and states
      that it depends on fat load, which is the caveat in the description.
- name: SAR1B molecular genetic testing
  diagnosis_term:
    preferred_term: SAR1B sequencing and deletion analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: SAR1B
        term:
          id: hgnc:10535
          label: SAR1B
  description: >-
    Identification of biallelic pathogenic SAR1B variants establishes the
    diagnosis. Deletion and duplication analysis has to be included alongside
    sequencing, because whole-exon deletions are a recurrent allele class.
  results: Biallelic pathogenic or likely pathogenic SAR1B variants establish the molecular diagnosis.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The molecular diagnosis of CMRD is established in a proband with suggestive findings and biallelic pathogenic variants in SAR1B identified by molecular genetic testing."
    explanation: GeneReviews defines the confirmatory criterion.
  - reference: PMID:30640893
    reference_title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions"
    explanation: Records the reason molecular testing is required rather than optional.
  - reference: PMID:31253576
    reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2"
    explanation: >-
      A multi-kilobase deletion found in a proband is why deletion analysis has
      to accompany sequencing.
treatments:
- name: Low-long-chain-fat diet with adequate calories and essential fatty acids
  therapeutic_modality: BEHAVIORAL
  action_category: THERAPEUTIC
  description: >-
    The core of management. Long-chain fat is restricted enough to control
    diarrhoea, vomiting and abdominal distension, while total calories and
    essential fatty acid intake are kept sufficient for growth; medium-chain
    triglycerides may be used because they reach the portal circulation without
    chylomicron packaging. Over-restriction is a real hazard, because essential
    fatty acid deficiency is already severe early in life. The treatment
    controls the consequences of the trafficking defect and does not correct it,
    so symptoms recur when fat is reintroduced.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
    dietary_modifications:
    - action: RESTRICT
      description: Restriction of long-chain dietary fat, sufficient to control the gastrointestinal symptoms.
    - action: ADD
      description: >-
        Maintenance of essential fatty acid intake, with polyunsaturated fat as
        the fat source, and optional medium-chain triglycerides as a
        chylomicron-independent calorie source.
  target_mechanisms:
  - target: Intestinal Fat Malabsorption
    treatment_effect: MODULATES
    description: >-
      Reducing the long-chain fat load reduces the amount of lipid the
      enterocyte cannot export, so the malabsorptive symptoms remit. The
      transport defect itself is untouched.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Vomiting, diarrhea and abdominal distension improve on a low-long chain fat diet."
      explanation: Directly links the dietary intervention to remission of the malabsorptive symptoms.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ensure adequate caloric intake with a low-fat diet (<30% of total calories from fat) enriched in essential fatty acids with or without medium-chain triglycerides"
    explanation: GeneReviews gives the dietary prescription including the essential fatty acid and medium-chain triglyceride components.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Avoidance of fatty foods, particularly those rich in long-chain fatty acids."
    explanation: GeneReviews names long-chain-fat-rich foods as the exposure to avoid.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dietary counseling is needed not only to monitor fat intake and improve symptoms, but also to maintain sufficient caloric and EFA intake."
    explanation: Supports the warning that restriction must be balanced against calorie and essential fatty acid needs.
- name: High-dose oral vitamin E supplementation
  therapeutic_modality: SMALL_MOLECULE
  action_category: THERAPEUTIC
  description: >-
    Large oral doses of vitamin E, around 50 IU/kg/day, given lifelong. The
    important and slightly counter-intuitive point is that the oral route works
    for preventing neurological complications even though plasma tocopherol
    never normalises: the aim is tissue protection, not a normal blood level.
    Tocofersolan, a water-soluble tocopherol derivative, is better absorbed than
    tocopheryl acetate in CRD, though a four-month crossover study found no
    significant difference in plasma tocopherol between the two formulations.
  treatment_term:
    preferred_term: high-dose fat-soluble vitamin supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: alpha-tocopherol
      term:
        id: CHEBI:22470
        label: alpha-tocopherol
  target_mechanisms:
  - target: Fat-Soluble Vitamin Deficiency
    treatment_effect: MODULATES
    description: >-
      Oral replacement partially offsets the delivery failure. It does not
      restore a normal plasma concentration, because absorption still depends on
      the blocked chylomicron pathway.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Despite fat malabsorption and the absence of postprandial chylomicrons, the oral route can prevent neurological complications even though serum levels of vitamin E remain chronically low."
      explanation: States both that the intervention works and the limit on what it achieves biochemically.
  - target: Vitamin E-Dependent Neuroaxonal and Retinal Injury
    treatment_effect: INHIBITS
    description: >-
      Adequate vitamin E status is the determinant of whether the neurological
      complications occur.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "However, the vitamin E deficiency status plays a pivotal role in preventing neurological complications."
      explanation: Makes vitamin E status the pivotal variable for the neurological outcome.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "high-dose oral fat-soluble vitamins, including vitamin E (hydrosoluble form) 50 IU/kg/d"
    explanation: GeneReviews gives the vitamin E dose and specifies the hydrosoluble form.
  - reference: PMID:30021760
    reference_title: Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, bioavailabilities were higher in patients with CMRD (tocofersolan, 24.7%; α-tocopherol acetate, 11.4%)."
    explanation: Quantifies the better absorption of tocofersolan in CRD specifically.
  - reference: PMID:30021760
    reference_title: Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma concentrations of α-tocopherol at 4 months were not significantly different by formulation type in ABL or CMRD."
    explanation: >-
      The crossover endpoint found no significant difference between
      formulations, which is the caveat stated in the description.
- name: Vitamin A, D and K supplementation
  therapeutic_modality: SMALL_MOLECULE
  action_category: THERAPEUTIC
  description: >-
    Vitamin A around 15,000 IU/day, vitamin D 800-1200 IU/day and vitamin K
    15 mg/week, adjusted against plasma concentrations, INR and toxicity risk.
    Unlike vitamin E, these three can usually be brought into the normal range
    by supplementation. Vitamin A dosing needs a specific pregnancy caveat.
  treatment_term:
    preferred_term: fat-soluble vitamin supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: vitamin A
      term:
        id: CHEBI:12777
        label: vitamin A
    - preferred_term: vitamin D
      term:
        id: CHEBI:27300
        label: vitamin D
    - preferred_term: phylloquinone
      term:
        id: CHEBI:18067
        label: phylloquinone
  target_mechanisms:
  - target: Fat-Soluble Vitamin Deficiency
    treatment_effect: MODULATES
    description: >-
      Replaces the vitamins whose chylomicron-dependent delivery has failed.
    evidence:
    - reference: PMID:20920215
      reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vitamin A deficiency (N > 1.61 μmol/L) Infancy (1 to 6 m) - (0.8 ± 0.5) transit if supplementation 70%"
      explanation: >-
        The cohort table records vitamin A deficiency as transient with
        supplementation, which is the effect this link asserts.
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vitamin A 15,000 IU/d, vitamin K 15 mg/week, and vitamin D 800-1200 IU/d"
    explanation: GeneReviews gives the three doses stated in the description.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Vitamin A excess can be harmful to the developing fetus."
    explanation: >-
      The pregnancy caveat: GeneReviews advises halving the vitamin A dose in
      women who are pregnant or planning pregnancy, with monitoring of levels.
  - reference: PMID:36243606
    reference_title: Guidance for the diagnosis and treatment of hypolipidemia disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics."
    explanation: Contemporary multi-society guidance confirms high-dose fat-soluble vitamins as the treatment class.
- name: Lifelong multisystem surveillance
  therapeutic_modality: BEHAVIORAL
  action_category: MONITORING
  description: >-
    Annual growth, dietary, gastrointestinal and neurological assessment with
    lipid profile, liver function, blood count, INR and vitamins A, D and E.
    From age ten, liver ultrasound, neurological examination with creatine
    kinase and electromyography, ophthalmological review and bone densitometry
    every three years; in adults, echocardiography with ejection fraction every
    three to five years.
  treatment_term:
    preferred_term: clinical evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Every three years after age ten: liver ultrasound, neurologic exam with serum creatine kinase and electromyography, ophthalmologic evaluation, and DXA scan."
    explanation: GeneReviews gives the triennial surveillance schedule quoted in the description.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Every three to five years in adults: echocardiogram with assessment of ejection fraction."
    explanation: GeneReviews gives the adult cardiac surveillance interval.
- name: Genetic counseling and cascade testing
  therapeutic_modality: BEHAVIORAL
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Once the familial SAR1B variants are known, carrier testing of relatives and
    prenatal or preimplantation genetic testing become possible. Siblings of a
    proband carry a one-in-four recurrence risk.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Once the SAR1B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews states the reproductive options that follow molecular confirmation.
  - reference: PMID:35344313
    reference_title: Chylomicron Retention Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected"
    explanation: GeneReviews gives the sibling recurrence risk.
animal_models:
- name: Sar1b CRISPR deletion and p.D137N knock-in mouse
  species: Mouse
  genotype: Sar1b exon 2 deletion or Sar1b p.D137N knock-in, heterozygous (homozygotes are lethal)
  background: C57BL/6N
  description: >-
    The only mammalian model of human SAR1B defects. Homozygous deletion or
    mutation is embryonic or perinatally lethal, so metabolic work has been done
    in heterozygotes even though human heterozygous carriers are asymptomatic.
    That genotype mismatch is the model's principal limitation. Heterozygotes
    nonetheless reproduce the gastrointestinal and lipid phenotype, and the
    homozygous embryos show intestinal lipid accumulation.
  publication: PMID:33964306
  genes:
  - preferred_term: SAR1B
    term:
      id: hgnc:10535
      label: SAR1B
  modeled_mechanisms:
  - target: Enterocyte Chylomicron Retention
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Homozygous embryos accumulate lipid in the intestine and heterozygotes
      fail to secrete chylomicrons after a lipid gavage.
    limitations: >-
      Homozygosity, the genotype that corresponds to human disease, is lethal in
      this model, so the surviving animals used for metabolic phenotyping are
      heterozygous, a state that is clinically silent in humans.
    readouts:
    - name: Chylomicron secretion after gastric lipid gavage
      target: Enterocyte Chylomicron Retention
      direction: DECREASED
      interpretation: Functional readout of the failed enterocyte export step.
      evidence:
      - reference: PMID:33964306
        reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol, along with reduced CM secretion following gastric lipid gavage"
        explanation: Reports the reduced chylomicron secretion measured after a lipid load.
    - name: Faecal lipid excretion
      target: Enterocyte Chylomicron Retention
      direction: INCREASED
      interpretation: Whole-animal confirmation that the retained lipid is lost in the stool.
      evidence:
      - reference: PMID:33964306
        reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Inefficient fat absorption in heterozygotes was confirmed via an increase in fecal lipid excretion."
        explanation: Direct measurement of the malabsorption in the model.
    evidence:
    - reference: PMID:33964306
      reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This is the first reported mammalian animal model with human Sar1b genetic defects, which reproduces some of the characteristic CRD features and provides a direct cause-effect demonstration."
      explanation: The authors' own assessment of how far the model recapitulates the disease.
  - target: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Heterozygous animals are hypoalphalipoproteinaemic, matching the low HDL
      of patients, though the mouse study measured the plasma outcome rather
      than intestinal ABCA1-dependent efflux itself.
    limitations: >-
      The low plasma HDL is an outcome measure; the model was not used to show
      the enterocyte efflux step, which comes from the Caco-2 system.
    evidence:
    - reference: PMID:33964306
      reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "heterozygotes carrying a single disrupted Sar1b allele displayed lower plasma levels of triglycerides, total cholesterol, and HDL-cholesterol"
      explanation: Records the low HDL cholesterol in the model.
  evidence:
  - reference: PMID:33964306
    reference_title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that deletion or mutation of Sar1b in mice resulted in late-gestation lethality of homozygous embryos."
    explanation: Establishes the homozygous lethality that constrains how this model can be used.
  - reference: PMID:37558128
    reference_title: High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities."
    explanation: Confirms both the lethality and the intestinal lipid accumulation in homozygous embryos.
- name: Sar1b morpholino knockdown zebrafish
  species: Zebrafish
  genotype: sar1b 5'UTR translation-blocking morpholino knockdown
  description: >-
    A developmental model. Sar1b-deficient larvae take dietary lipid into
    enterocytes normally but cannot clear it, reproducing the retention lesion,
    and they additionally show craniofacial cartilage, exocrine pancreas, liver
    and hindbrain deficits that are not part of the recognised human phenotype.
    Those extra phenotypes are the model's main caveat, and probably reflect
    global knockdown of a broadly expressed COPII component during development.
  publication: PMID:25559265
  genes:
  - preferred_term: SAR1B
    term:
      id: hgnc:10535
      label: SAR1B
  modeled_mechanisms:
  - target: Enterocyte Chylomicron Retention
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Larvae form enterocyte lipid droplets after feeding and then fail to clear
      them during fasting, which is the retention phenotype in a live animal.
    limitations: >-
      Global morpholino knockdown during development produces craniofacial,
      pancreatic, hepatic and neuronal deficits that are not features of human
      CRD, so the model over-reports the developmental consequences of SAR1B
      loss. Zebrafish lipoprotein physiology also differs from the human.
    readouts:
    - name: Enterocyte lipid clearance after feeding and fasting
      target: Enterocyte Chylomicron Retention
      direction: DECREASED
      interpretation: Oil Red O pulse-chase measure of the export step.
      evidence:
      - reference: PMID:25559265
        reference_title: Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Consistent with ANDD symptoms of chylomicron retention, we found that dietary lipids in Sar1b-deficient embryos accumulate in enterocytes."
        explanation: Reports the measured enterocyte lipid retention.
    evidence:
    - reference: PMID:25559265
      reference_title: Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sar1b depletion phenotype in zebrafish resembles Anderson disease deficits."
      explanation: The authors' key-message statement that the model is informative for the human disease.
  evidence:
  - reference: PMID:25559265
    reference_title: Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sar1b deficiency results in multi-organ developmental deficits."
    explanation: >-
      Records the extra developmental phenotypes that are the reason this model
      is not read as a straightforward phenocopy.
- name: Sar1b knockdown in developing mouse neocortex
  species: Mouse
  genotype: In-utero electroporation knockdown of Sar1b, and expression of the CRD-associated hSAR1B p.D137N allele
  description: >-
    A targeted developmental-neurobiology experiment rather than a disease
    model. Sar1b knockdown impairs radial migration and callosal axon formation
    of cortical neurons, and the human D137N allele does the same, suggesting a
    cell-autonomous neural role for SAR1B independent of intestinal lipid
    absorption. Whether this contributes to the neurological findings in
    patients is untested; the recognised neurological complications of CRD are
    attributed to vitamin E deficiency.
  publication: PMID:33002559
  genes:
  - preferred_term: SAR1B
    term:
      id: hgnc:10535
      label: SAR1B
  notes: >-
    Deliberately not linked to a pathophysiology node. Doing so would assert a
    cell-autonomous neural mechanism in human CRD that no patient study
    supports, and would compete with the well-evidenced vitamin E pathway
    already curated.
  evidence:
  - reference: PMID:33002559
    reference_title: "Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our study reveals a cell-autonomous action of Sar1b, which is unrelated to lipid absorption from the gut, on the development of the cerebral cortex."
    explanation: States the finding and its explicit independence from the intestinal mechanism.
  - reference: PMID:33002559
    reference_title: "Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CMRD patients suffer from multiple neurological deficits, the etiologies of which remain unclear."
    explanation: >-
      The authors' framing of the open question, which is why this model is
      recorded without a mechanism link.
experimental_models:
- name: SAR1B knockout Caco-2/15 enterocyte model
  experimental_model_type: CELL_LINE
  description: >-
    Zinc-finger-nuclease deletion of SAR1B in Caco-2/15 cells, and a
    SAR1A/SAR1B double knockout. The single knockout reduces triglyceride,
    apoB-48 and chylomicron secretion by roughly a third to a half; only the
    double knockout abolishes output, which is how the residual export was
    traced to the SAR1A paralogue. The same system showed reduced HDL
    biogenesis and cholesterol efflux with impaired ABCA1 expression, which is
    the best available explanation for the low HDL of CRD.
  publication: PMID:28982670
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  modeled_mechanisms:
  - target: Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Targeted SAR1B deletion in a differentiated enterocyte-like monolayer
      reduces chylomicron and apoB-48 output.
    limitations: >-
      Caco-2/15 is a transformed colonic adenocarcinoma line differentiated into
      an enterocyte-like phenotype, and the assay measures secretion into medium
      rather than into lymph, so it cannot report the systemic consequences.
    readouts:
    - name: Chylomicron and apolipoprotein B-48 secretion
      target: Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum
      direction: DECREASED
      interpretation: Direct measure of the export step lost in the disease.
      evidence:
      - reference: PMID:28982670
        reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%)."
        explanation: Quantifies the secretion defect.
    evidence:
    - reference: PMID:28982670
      reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These findings demonstrate that the deletion of the 2 SAR1 isoforms is required to fully eliminate the secretion of chylomicron in vitro."
      explanation: The authors' conclusion, which is also the paralogue caveat on this model.
  - target: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The same knockout reduces cholesterol movement to basolateral apoA-I and
      lowers ABCA1 expression.
    limitations: >-
      Shown in a transformed cell line; no patient tissue measurement of
      intestinal ABCA1 or nascent HDL output has been reported.
    evidence:
    - reference: PMID:28982670
      reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "They also underscore the limited high-density lipoprotein production by the intestinal cells in response to SAR1 knockout."
      explanation: >-
        The authors' conclusion that SAR1 knockout limits intestinal HDL
        production, which is what makes this model informative for this node.
    readouts:
    - name: Cholesterol efflux to basolateral apolipoprotein A-I
      target: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux
      direction: DECREASED
      interpretation: Measures the nascent HDL formation step.
      evidence:
      - reference: PMID:28982670
        reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells"
        explanation: Direct measurement of the efflux and nascent HDL defect.
  evidence:
  - reference: PMID:28982670
    reference_title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The SAR1B gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique."
    explanation: Describes how the model was made.
- name: CRISPR SAR1B knockout Caco-2/TC7 cells
  experimental_model_type: CELL_LINE
  description: >-
    A second, independent enterocyte knockout model built specifically to study
    fat-soluble vitamin handling. It reproduces impaired lipid droplet
    formation and reduced triglyceride, cholesterol and alpha-tocopherol
    secretion, including with the pharmaceutical vitamin E forms used in
    patients, and shows a milder phenotype for SAR1B than for MTTP loss, which
    matches the clinical comparison between CRD and abetalipoproteinemia.
  publication: PMID:36771214
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  modeled_mechanisms:
  - target: Fat-Soluble Vitamin Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Explains why plasma vitamin E stays low on treatment: even tocofersolan
      and tocopheryl acetate cannot be secreted normally by a SAR1B-null
      enterocyte.
    limitations: >-
      A transformed cell monolayer measuring secretion into medium; it cannot
      model hepatic tocopherol handling or tissue delivery, and it does not
      speak to the clinical observation that oral vitamin E still prevents
      neurological disease.
    readouts:
    - name: alpha-tocopherol secretion
      target: Fat-Soluble Vitamin Deficiency
      direction: DECREASED
      interpretation: Measures the enterocyte step at which vitamin E replacement fails.
      evidence:
      - reference: PMID:36771214
        reference_title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "A significant decrease in α-tocopherol secretion was also observed in these clones (-41.5 ± 3.7% to -97.2 ± 2.8%), even with the pharmaceutical forms of vitamin E: tocopherol-acetate and tocofersolan"
        explanation: Quantifies the tocopherol secretion defect including with the clinical formulations.
    evidence:
    - reference: PMID:36771214
      reference_title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations."
      explanation: >-
        The model reproduces the clinical severity ordering between
        abetalipoproteinemia and CRD, which supports its fidelity for this node.
  evidence:
  - reference: PMID:36771214
    reference_title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we developed two knock-out cell models of FHBL-SD1 and FHBL-SD3 using the CRISPR/Cas9 technique in Caco-2/TC7 cells"
    explanation: Describes the construction of the model.
differential_diagnoses:
- name: Abetalipoproteinemia
  description: >-
    MTTP-related abetalipoproteinemia abolishes lipidation of apoB in both the
    enterocyte and the hepatocyte, so hepatic VLDL secretion fails as well.
    Triglycerides are therefore very low rather than normal, apoB-containing
    lipoproteins are virtually absent rather than reduced, and acanthocytosis is
    prominent. Neurological and retinal disease is more severe. Both diseases
    show fat malabsorption, hypocholesterolaemia and fat-soluble vitamin
    deficiency, and both show lipid-laden enterocytes on biopsy, so the
    triglyceride level and the causal gene are what separate them.
  disease_term:
    preferred_term: abetalipoproteinemia
    term:
      id: MONDO:0008692
      label: abetalipoproteinemia
  distinguishing_features:
  - Fasting triglycerides are normal in chylomicron retention disease and very low in abetalipoproteinemia.
  - LDL and apoB-100 remain detectable in chylomicron retention disease because hepatic secretion is preserved.
  - Acanthocytosis is characteristically absent in chylomicron retention disease and prominent in abetalipoproteinemia.
  - Biallelic SAR1B variants establish chylomicron retention disease; biallelic MTTP variants establish abetalipoproteinemia.
  evidence:
  - reference: PMID:31253576
    reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease)"
    explanation: Separates the three phenocopies by causal gene.
  - reference: PMID:27266643
    reference_title: "Chylomicron retention disease: A rare cause of chronic diarrhea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by normal fasting serum triglyceride levels combined with the absence of apolipoprotein (apo) B48 and chylomicrons after a fat load."
    explanation: Gives the normal fasting triglyceride that is the key biochemical discriminator.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No acantocytosis Infancy (1 to 6 m) transit or permanent 90%"
    explanation: Records absence of acanthocytosis as a highly discriminative feature of chylomicron retention disease.
  - reference: PMID:36771214
    reference_title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MTTP silencing led to a more severe phenotype than SAR1B silencing, which is consistent with clinical observations."
    explanation: Supports the statement that abetalipoproteinemia is the more severe of the two.
- name: Familial hypobetalipoproteinemia
  description: >-
    Biallelic APOB variants remove the apoB scaffold itself and produce a
    clinical and biochemical picture close to abetalipoproteinemia, including
    very low triglycerides. Unlike either recessive disease, heterozygous
    APOB-related hypobetalipoproteinemia gives roughly half-normal apoB and LDL
    in the parents and rarely causes infantile malabsorption.
  disease_term:
    preferred_term: hypobetalipoproteinemia
    term:
      id: MONDO:0017774
      label: hypobetalipoproteinemia
  distinguishing_features:
  - Biallelic APOB variants establish familial hypobetalipoproteinemia; biallelic SAR1B variants establish chylomicron retention disease.
  - Parents of a chylomicron retention disease proband have an entirely normal fasting lipid profile, whereas APOB heterozygotes have reduced apoB and LDL.
  evidence:
  - reference: PMID:31253576
    reference_title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease)"
    explanation: Separates the causal genes of the three severe hypobetalipoproteinaemias.
  - reference: PMID:20920215
    reference_title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal Fasting lipids in parents 100%"
    explanation: >-
      Normal parental lipids in every chylomicron retention disease family is
      the family-level discriminator from APOB-related disease.
references:
- reference: PMID:35344313
  title: Chylomicron Retention Disease.
  tags:
  - GeneReviews
- reference: PMID:12692552
  title: Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.
- reference: PMID:17945526
  title: "Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein."
- reference: PMID:19285442
  title: "Chylomicron retention disease: a long term study of two cohorts."
- reference: PMID:20920215
  title: Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
- reference: PMID:21235735
  title: "Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease)."
- reference: PMID:24338480
  title: The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.
- reference: PMID:25559265
  title: Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.
- reference: PMID:27266643
  title: "Chylomicron retention disease: A rare cause of chronic diarrhea."
- reference: PMID:28982670
  title: "Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture."
- reference: PMID:30021760
  title: Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
- reference: PMID:30640893
  title: "Chylomicron retention disease: genetics, biochemistry, and clinical spectrum."
- reference: PMID:31253576
  title: Novel mutations of SAR1B gene in four children with chylomicron retention disease.
- reference: PMID:33002559
  title: "Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons."
- reference: PMID:33964306
  title: Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.
- reference: PMID:36243606
  title: Guidance for the diagnosis and treatment of hypolipidemia disorders.
- reference: PMID:36594468
  title: Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.
- reference: PMID:36771214
  title: Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.
- reference: PMID:37558128
  title: High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.
- reference: PMID:38749523
  title: "Chylomicron retention disease: a rare aetiology of failure to thrive."
- reference: PMID:39062121
  title: "Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking."
review_notes: >-
  Created September 2026 from the GeneReviews chapter (PMID:35344313), the 2010
  two-centre diagnosis and management guideline (PMID:20920215), the two-cohort
  natural-history study (PMID:19285442) and the SAR1B molecular and model
  literature, with an Edison/falcon deep-research report as the survey layer
  (preflight PASS, 11/11 citations resolved). An Asta run was also performed but
  returned mostly off-topic papers and failed the Named Entity Confusion
  preflight (SAR1B mentioned twice, APOBEC1 six times); only its two genuinely
  on-topic Levy reviews were used, and no claim rests on Asta alone.

  Three modelling decisions a reviewer should check. First, no `conforms_to` was
  declared: the closest candidate modules each contradict a defining feature of
  CRD (see `notes`), and a COPII / ER-export trafficking module does not exist
  yet. Second, the hepatic and the oxidative/ER-stress branches are marked
  `mechanism_confidence: PROVISIONAL` because their human relevance is asserted
  by review and cell/animal work rather than demonstrated in patients. Third,
  the cortical-neuron knockdown study (PMID:33002559) is recorded as an animal
  model with no `modeled_mechanisms` link, deliberately: linking it would assert
  a cell-autonomous neural mechanism in human CRD that no patient study
  supports, alongside the well-evidenced vitamin E pathway.

  A caution for anyone quoting Table 1 of PMID:20920215. The table's
  "Retinopathy" row reads "Adult permanent 100% +++", putting 100% in the
  "Prevalence in childhood" column against an adult age at onset. The same
  paper's Table 2 states "there is no retinopathy" in childhood, and every other
  adult-onset row in that column reads 0%. So the 100% is not a childhood
  prevalence. This is an inconsistency the authors published, not a defect in
  our cached copy: the cached table is faithful, each row carrying its five
  cells in header order, and the rows whose age cell wraps across two lines do
  not displace their neighbours. No phenotype in this entry is banded from that
  row. Every snippet taken from this reference verifies as an exact substring of
  the cached text, so no gate catches a row read against the wrong header; check
  a quoted figure against the paper's prose before banding a phenotype on it.

  Known gaps. There is no population prevalence estimate, only a published case
  count, so the prevalence record uses CASES_IN_LITERATURE with a qualitative
  ULTRA_RARE band. Orphanet could not be cited because the Orphadata bulk XML is
  not present in this checkout and downloading it was out of scope. No
  interventional clinical trial specific to CRD was identified, so
  `clinical_trials` is empty. No CRD-specific dataset accession was identified,
  so `datasets` is empty. Genotype-phenotype correlation is explicitly absent in
  the largest series, which is why no allele-based subtypes were created.
clinical_trials: []
datasets: []

📚

References & Deep Research

References

21

PMID:35344313

Chylomicron Retention Disease.

No top-level findings curated for this source.

PMID:12692552

Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders.

No top-level findings curated for this source.

PMID:17945526

Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.

No top-level findings curated for this source.

PMID:19285442

Chylomicron retention disease: a long term study of two cohorts.

No top-level findings curated for this source.

PMID:20920215

Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.

No top-level findings curated for this source.

PMID:21235735

Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease).

No top-level findings curated for this source.

PMID:24338480

The endoplasmic reticulum coat protein II transport machinery coordinates cellular lipid secretion and cholesterol biosynthesis.

No top-level findings curated for this source.

PMID:25559265

Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.

No top-level findings curated for this source.

PMID:27266643

Chylomicron retention disease: A rare cause of chronic diarrhea.

No top-level findings curated for this source.

PMID:28982670

Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture.

No top-level findings curated for this source.

PMID:30021760

Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.

No top-level findings curated for this source.

PMID:30640893

Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.

No top-level findings curated for this source.

PMID:31253576

Novel mutations of SAR1B gene in four children with chylomicron retention disease.

No top-level findings curated for this source.

PMID:33002559

Inhibition of Sar1b, the Gene Implicated in Chylomicron Retention Disease, Impairs Migration and Morphogenesis of Developing Cortical Neurons.

No top-level findings curated for this source.

PMID:33964306

Sar1b mutant mice recapitulate gastrointestinal abnormalities associated with chylomicron retention disease.

No top-level findings curated for this source.

PMID:36243606

Guidance for the diagnosis and treatment of hypolipidemia disorders.

No top-level findings curated for this source.

PMID:36594468

Cargo selection in endoplasmic reticulum-to-Golgi transport and relevant diseases.

No top-level findings curated for this source.

PMID:36771214

Validation of Knock-Out Caco-2 TC7 Cells as Models of Enterocytes of Patients with Familial Genetic Hypobetalipoproteinemias.

No top-level findings curated for this source.

PMID:37558128

High-fat diet reveals the impact of Sar1b defects on lipid and lipoprotein profile and cholesterol metabolism.

No top-level findings curated for this source.

PMID:38749523

Chylomicron retention disease: a rare aetiology of failure to thrive.

No top-level findings curated for this source.

PMID:39062121

Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking.

No top-level findings curated for this source.

Deep Research

2

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

Created September 2026 from the GeneReviews chapter (PMID:35344313), the 2010 two-centre diagnosis and management guideline (PMID:20920215), the two-cohort natural-history study (PMID:19285442) and the SAR1B molecular and model literature, with an Edison/falcon deep-research report as the survey layer (preflight PASS, 11/11 citations resolved). An Asta run was also performed but returned mostly off-topic papers and failed the Named Entity Confusion preflight (SAR1B mentioned twice, APOBEC1 six times); only its two genuinely on-topic Levy reviews were used, and no claim rests on Asta alone. Three modelling decisions a reviewer should check. First, no `conforms_to` was declared: the closest candidate modules each contradict a defining feature of CRD (see `notes`), and a COPII / ER-export trafficking module does not exist yet. Second, the hepatic and the oxidative/ER-stress branches are marked `mechanism_confidence: PROVISIONAL` because their human relevance is asserted by review and cell/animal work rather than demonstrated in patients. Third, the cortical-neuron knockdown study (PMID:33002559) is recorded as an animal model with no `modeled_mechanisms` link, deliberately: linking it would assert a cell-autonomous neural mechanism in human CRD that no patient study supports, alongside the well-evidenced vitamin E pathway. A caution for anyone quoting Table 1 of PMID:20920215. The table's "Retinopathy" row reads "Adult permanent 100% +++", putting 100% in the "Prevalence in childhood" column against an adult age at onset. The same paper's Table 2 states "there is no retinopathy" in childhood, and every other adult-onset row in that column reads 0%. So the 100% is not a childhood prevalence. This is an inconsistency the authors published, not a defect in our cached copy: the cached table is faithful, each row carrying its five cells in header order, and the rows whose age cell wraps across two lines do not displace their neighbours. No phenotype in this entry is banded from that row. Every snippet taken from this reference verifies as an exact substring of the cached text, so no gate catches a row read against the wrong header; check a quoted figure against the paper's prose before banding a phenotype on it. Known gaps. There is no population prevalence estimate, only a published case count, so the prevalence record uses CASES_IN_LITERATURE with a qualitative ULTRA_RARE band. Orphanet could not be cited because the Orphadata bulk XML is not present in this checkout and downloading it was out of scope. No interventional clinical trial specific to CRD was identified, so `clinical_trials` is empty. No CRD-specific dataset accession was identified, so `datasets` is empty. Genotype-phenotype correlation is explicitly absent in the largest series, which is why no allele-based subtypes were created.

Create: Chylomicron Retention Disease · 2026-09-05T18:40:31Z · View source

Created kb/disorders/Chylomicron_Retention_Disease.yaml (SAR1B, MONDO:0009528) from scratch. 2551+ lines, 194 evidence snippets, all verified against references_cache. Closes the claim on issue #11088; stubs/Chylomicron_Retention_Disease.yaml deleted. DEEP RESEARCH THAT ACTUALLY RAN. Two providers. Edison/falcon (`just research-disorder falcon Chylomicron_Retention_Disease`, 641 s) produced research/Chylomicron_Retention_Disease-deep-research-falcon.md plus one artifact; its own reference validation resolved 11/11 citations with 0 unresolved and 1/1 quoted claims found, and `just preflight-dr ... MONDO:0009528` returned PASS (SAR1B mentioned 44 times, OMIM 246700 matching MONDO). Its term_validation reports needs_review: true, but the single "mislabelled" term is MONDO:0009528 being called "if available" -- that is the template's own "MONDO ID: MONDO:0009528 (if available)" placeholder being scraped, not a wrong binding. Asta also ran (3.6 s) and produced research/Chylomicron_Retention_Disease-deep-research-asta.md; it is retrieval-only and returned mostly off-topic papers (goat pregnancy toxaemia, diabetic nephropathy, renal cell carcinoma). `just preflight-dr` on it returned WARN: SAR1B mentioned twice against APOBEC1 six times. I used exactly two papers from it -- the Levy 2024 review (PMID:39062121) and Levy 2021 (PMID:33584351, read but ultimately not cited) -- and no claim in the entry rests on Asta alone. Neither report's suggested identifiers were cited without independently fetching the record. GENEREVIEWS BASELINE. A chapter exists: PMID:35344313 "Chylomicron Retention Disease" (Burnett, Hooper, Hegele), fetched, cached, and tagged `GeneReviews` in the top-level references block. Every Clinical Characteristics item in its abstract is represented in the entry: failure to thrive, diarrhoea, vomiting, abdominal distention, fat malabsorption, steatorrhoea, hepatomegaly, vitamin-E-secondary neuromuscular abnormalities, poor bone mineralisation and delayed bone maturation, prolonged INR, the ophthalmological cluster (micronystagmus, delayed dark adaptation, abnormal scotopic ERG), adult cardiomyopathy with decreased ejection fraction, marked hypocholesterolaemia, low apoB, normal-to-low triglycerides, low fat-soluble vitamins, and the gelee blanche duodenal mucosa. Abnormal visual evoked potentials were the one listed finding not given its own phenotype row; the quoted sentence naming them is carried on the Abnormal electroretinogram and Nystagmus rows instead. The Agents/Circumstances to Avoid section (fatty foods rich in long-chain fatty acids) and the pregnancy caveat (halve vitamin A) are both curated onto the relevant treatments with the GeneReviews quote. MECHANISM MODEL. The pathophysiology is a connected chain of 11 nodes, all biological_scale tagged, with bare-name downstream targets. Spine: SAR1B Loss of Function (MOLECULAR) -> Defective COPII Coat Assembly at Endoplasmic Reticulum Exit Sites (MOLECULAR) -> Failed Pre-Chylomicron Transport Vesicle Export from the Endoplasmic Reticulum (CELLULAR) -> Enterocyte Chylomicron Retention (CELLULAR) -> {Absent Postprandial Chylomicronemia, Intestinal Fat Malabsorption} (both ORGANISM) -> {Fat-Soluble Vitamin Deficiency, Essential Fatty Acid Deficiency} -> Vitamin E-Dependent Neuroaxonal and Retinal Injury (TISSUE) -> the neurological and ophthalmological phenotypes. Two branches leave the spine at the top: Impaired Intestinal HDL Biogenesis and Cholesterol Efflux (the ABCA1 route to the low HDL, which cannot be derived from a pure chylomicron-export block) and Impaired Hepatic ApoB Lipoprotein Secretion (the proposed route to hepatic steatosis in a disease whose primary lesion is intestinal). A third branch, Enterocyte Lipid Peroxidation and Endoplasmic Reticulum Stress, hangs off the retention node. MODELLING JUDGEMENT CALLS A REVIEWER SHOULD CHECK. (1) No conforms_to. I read the three plausible modules. enterocyte_polarity_trafficking_failure scopes itself explicitly to the CODE class in which villus architecture is lost and diarrhoea does not remit on dietary elimination; CRD has normal villi and diet-responsive diarrhoea, so conforming would assert the opposite of the evidence. hepatic_steatosis_lipotoxicity asserts progression through steatohepatitis to fibrosis, and the CRD guideline review states no cases of steatohepatitis cirrhosis. diet_induced_osmotic_diarrhea is about a lost brush-border digestive/transport step, not a secretion step. A COPII / ER-export trafficking module would be the natural target and does not exist; I did not create one, since that is a separate piece of work. Recorded in the entry's notes. (2) Two nodes carry mechanism_confidence: PROVISIONAL -- the hepatic branch and the oxidative/ER-stress branch. Both are supported by review and cell/animal work and neither has been shown to drive a human complication. The edge into the stress node is typed INDIRECT_UNKNOWN_INTERMEDIATES for the same reason. (3) PMID:33002559 (Sar1b knockdown impairs cortical neuron migration; the paper states the action is "unrelated to lipid absorption from the gut") is recorded as an animal model with NO modeled_mechanisms link, deliberately. Linking it would assert a cell-autonomous neural mechanism in human CRD that no patient study supports, competing with the well-evidenced vitamin E pathway. The reasoning is in that model's notes. (4) Cardiomyopathy is banded VERY_RARE on the GeneReviews "small proportion of adults" wording, not on the Peretti cohort figure, which is 0% -- the cohort is paediatric. Both quotes are curated so the tension is visible. (5) One causal edge is deliberately left uncited: Essential Fatty Acid Deficiency -> Failure to thrive. No source makes that specific causal claim; the sources make the disease-level claim. It is the only item costing compliance points and I preferred an honest gap to a stretched citation. (6) No allele-based has_subtypes, because the largest series states the absence of phenotype-genotype correlation. (7) SAR1A is curated in the genetic block with relationship_type MODIFIER and an explicit note that it is not a disease gene. It is there because the failure of paralogue compensation is what explains both the patient biopsy data and why only a SAR1A/SAR1B double knockout abolishes chylomicron output in Caco-2 cells. SIBLING DIFFERENTIATION. Cross-referenced but not merged with kb/disorders/Abetalipoproteinemia.yaml and kb/disorders/Hypobetalipoproteinemia.yaml, both as differential_diagnoses entries with distinguishing_features and as prose in the top-level notes. The discriminator carried throughout is the normal fasting triglyceride plus detectable LDL/apoB-100 (hepatic secretion preserved), against the very low triglyceride of MTTP- and biallelic-APOB-related disease; absence of acanthocytosis is curated as a biochemical finding with the cohort figure. Abetalipoproteinemia already carries CRD as a differential, so the pair is now reciprocal. REFERENCES REJECTED OR NOT USED. PMID:39332967 (An Pediatr, "Chylomicron retention disease: A condition to keep in mind") and PMID:22959141 (Dig Liver Dis) both cache with an empty abstract, so no snippet could be taken; neither is cited. PMID:33584351 (Levy 2021) and PMID:31970693 (Lu & Kim, COPII mutations in vertebrates) were read and are on topic but every claim they support was better served by a more specific source, so neither is cited. Orphanet could not be used at all: `just fetch-reference ORPHA:71` has no fetcher and `just structured-rebuild-orphanet` needs data/orphadata/en_product1.xml, which is gitignored and absent from this checkout; downloading it was out of scope on a shared disk-constrained machine. That is why the prevalence record cites PubMed sources rather than an ORPHA epidemiology row. FULL-TEXT SNIPPETS. A number of frequency and lipid-panel snippets are quoted from the cached full text of PMID:20920215 (the two-centre cohort's Table 1) rather than from its abstract, and one prevalence snippet from the cached full text of PMID:21235735. I tested this deliberately before relying on it: the reference validator matches against the whole cached record, and `just validate` (which runs the same validator as `validate-disorders` minus --no-full-text) verifies all 194. Whitespace is normalised across the PDF's line wraps, so I avoided every span that crosses a hyphenated line break. VALIDATION ACTUALLY RUN, ALL TO COMPLETION. - `flock /tmp/dismech-cache.lock just validate kb/disorders/Chylomicron_Retention_Disease.yaml` -> schema "No issues found"; terms "Validation passed"; references "All validations passed", "Snippets checked: 194/194 verified against cached references"; "Caches unchanged since validation started". - `just count-verified-snippets` -> 194/194. - `just check-entity-refs` -> OK. - `just check-causal-targets` -> OK, no new broken targets; `just list-causal-targets` on this file reports prefixed 0, dangling 0, self 0. - `just check-duplicate-keys` -> OK. - `just check-enum-values` -> OK. - `just check-qualifier-terms` -> OK; `just check-qualifier-terms-online` -> 1 uncached CURIE resolved and matching (the only qualifier is RO:0000057, which has no adapter and no tooling can validate). - `just check-folded-hyphens`, `just check-title-snippets`, `just check-snippet-grading`, `just check-reference-titles` -> OK, no new violations. `just check-snippet-length` initially flagged two 4-word snippets in this file ("This leads to steatorrhea"); both were lengthened to the full GeneReviews clause and it now reports no violation from this file. - `just compliance kb/disorders/Chylomicron_Retention_Disease.yaml` -> Weighted Compliance 99.7%. `just validate-disorders` and `just qc` were NOT run: this session shares a checkout with six other curation agents and both would have swept files I do not own. Everything they would check for this file was run individually above. LEFT UNDONE. clinical_trials and datasets are empty: no CRD-specific interventional trial and no CRD-specific dataset accession were identified (the falcon report's only trial lead, NCT05208879, is an observational carotenoid study whose CRD enrolment it could not establish). No ORPHA citation, as above. No COPII/ER-export mechanism module was created. Nothing was committed; git is the orchestrator's job.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Chylomicron Retention Disease. Core disease mechanisms, molecular and cell...

Asta Scientific Corpus Retrieval 20 citations 2026-09-05T17:56:42.463089

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Chylomicron Retention Disease. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking

Authors: Emile Levy, C. Fallet-Bianco, Nickolas Auclair, Natalie Patey, V. Marcil et al.
Year: 2024
Venue: Biomedicines
URL: https://www.semanticscholar.org/paper/82b6c2cae3986e94f2569f19529aca4e3354780b
DOI: 10.3390/biomedicines12071548
PMID: 39062121
PMCID: 11274388
Citations: 1
Summary: This comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.
Evidence snippets:
Snippet 1 (score: 0.469) > Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
Year: 2025
Venue: Journal of Veterinary Internal Medicine
URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
DOI: 10.1111/jvim.70139
PMID: 40492724
PMCID: 12150350
Citations: 2
Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
Evidence snippets:
Snippet 1 (score: 0.436) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] From Congenital Disorders of Fat Malabsorption to Understanding Intra-Enterocyte Mechanisms Behind Chylomicron Assembly and Secretion

Authors: E. Levy, J. Beaulieu, S. Spahis
Year: 2021
Venue: Frontiers in Physiology
URL: https://www.semanticscholar.org/paper/d6851fd6233246c17b0c83e3e85ba7fc24456295
DOI: 10.3389/fphys.2021.629222
PMID: 33584351
PMCID: 7873531
Citations: 11
Summary: The ultimate goal of this approach is that “experiments of nature” and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype.
Evidence snippets:
Snippet 1 (score: 0.433) > During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical “players” and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. We have particularly insisted on inborn metabolic pathways in humans as well as on genetically modified animal models (recapitulating pathological features). The ultimate goal of this approach is that “experiments of nature” and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype. Thus, uncovering the cause of disease contributes not only to understanding normal physiologic pathway, but also to capturing disorder onset, progression, treatment and prognosis.

[4] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
Year: 2014
Venue: Frontiers in Cell and Developmental Biology
URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
DOI: 10.3389/fcell.2014.00037
PMID: 25364744
PMCID: 4207010
Citations: 27
Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
Evidence snippets:
Snippet 1 (score: 0.417) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.

[5] Apolipoprotein B48 Knockout Ameliorates High-Fat-Diet-Induced Metabolic Impairment in Mice

Authors: Yale Tang, Chao Wang, Luxuan Li, Xiaoyu Wang, Linquan Yang et al.
Year: 2025
Venue: Biomolecules
URL: https://www.semanticscholar.org/paper/db7e0cd6dbd61154f65d83f7b12d155909495d79
DOI: 10.3390/biom15101454
PMID: 41154683
PMCID: 12564635
Summary: Reduced expression of ApoB48 can ameliorate lipid metabolism disorders induced by an HFD, which may be related to the CerS6/PP2A/AKT pathway, which might represent a new approach for exploring methods to treat hyperlipidaemia.
Evidence snippets:
Snippet 1 (score: 0.404) > Hyperlipidaemia has become increasingly common due to lifestyle changes, with M = more than 25% of the population in Europe and the United States being affected [1,2]. In 2020, the prevalence of dyslipidaemia among young adults (aged 18-45 years) in the southeastern coastal region of China was 22.9% [3]. Hyperlipidaemia is a pathological condition characterised by lipid metabolism disorders caused by genetic susceptibility, dietary factors, environmental triggers, and metabolic disorders [4][5][6], which can lead to various harmful effects. Cohort studies have confirmed the correlation between hypertriglyceridaemia and atherosclerotic cardiovascular disease (ASCVD) [7]. Researchers predict that between 2010 and 2030, the number of cardiovascular events caused by hyperlipidaemia in China will increase to over 9 million [8]. Additionally, this condition can cause various metabolic disorders, such as acute and chronic pancreatitis, hyperglycaemia, and hepatic steatosis [9,10]. Therefore, the risks associated with metabolic complications pose a significant challenge to the prevention and treatment of hyperlipidaemia. Hence, exploring the underlying mechanisms is crucial. However, people spend most of their time in a postprandial state, and in clinical practice, and only fasting blood lipids are usually tested, meaning that postprandial hyperlipidaemia is often overlooked. > Furthermore, lipoproteins are closely associated with postprandial hyperlipidaemia and various metabolic disorders. Apolipoprotein B48 (ApoB48), a subtype of the lipoprotein B family, is a core apolipoprotein involved in exogenous lipid transport, that is, an intestinal lipoprotein. After food intake, dietary lipids are absorbed by small intestinal epithelial cells and subsequently assembled into chylomicrons in association with ApoB48. These chylomicrons transport lipids to peripheral tissues, especially adipose tissue, upon entering the systemic circulation. Abnormal function is directly related to chylomicron (CM) metabolic disorders and hypertriglyceridaemia.

[6] Differentially expressed serum proteins from obese Wistar rats as a risk factor for obesity-induced diseases

Authors: K. Gabuza, N. Sibuyi, M. Mobo, A. Madiehe
Year: 2020
Venue: Scientific Reports
URL: https://www.semanticscholar.org/paper/899246fb2d0d3e1d858b292c904d5ff16850fe79
DOI: 10.1038/s41598-020-69198-2
PMID: 32709962
PMCID: 7381623
Citations: 6
Summary: Variation in the expression of serum proteins during acute and chronic exposure to high fat diet is shown, indicating that these proteins might interactively play a crucial role in development of obesity-induced diseases.
Evidence snippets:
Snippet 1 (score: 0.398) > Sodium dodecyl sulfate polyacrylamide gel electrophoresis T2D Type 2 diabetes TCA Trichloroacetic acid > Obesity, defined by a body mass index of ≥ 30 kg/m 2 , is a global epidemic affecting both developed and developing countries 1 . Despite the major progress made in regulating energy balance and understanding the molecular mechanisms leading to the development of obesity in both human and animal studies, no safe or effective treatment has yet been found 1 . Obesity is a chronic disease that is clinically managed by lifestyle modification, pharmacotherapy, and surgery. Failure to maintain a healthy body weight has been associated with development of chronic diseases such as cardiovascular diseases, type 2 diabetes (T2D) and some forms of cancer [2][3][4] . These diseases pose a major health threat as they are considered the top ten leading causes of death worldwide 5 . Therefore, identification of alternative approaches that can unravel the biochemical and physiological processes that occur during development of obesity and progression to chronic diseases are urgently needed. These might give insights on obesity and obesity-induced diseases, uncover ways to prevent their development in susceptible individuals, and improve on the current treatment strategies. Serum plays a major role in diagnosis and monitoring of many diseases through immunological assays. Serum contains many proteins originating from various tissues and cells within the body 6 , and serve as an attractive source for biomarker discovery as it can reflect the molecular changes taking place during the development of obesity and progression to chronic diseases of lifestyle 7 . These proteins can be used as potential biomarkers or targets for the targeted treatment of obesity, diagnosis and/or identification of individuals at risk of developing obesity-induced diseases. Obesity is a multifaceted disease, as a result a single biomarker cannot entirely describe all the pathways affected. Several adipokines, cytokines, metabolites, and microRNAs are implicated in obesityinduced diseases, some are dysregulated in more than one disease while some show potential as disease-specific biomarkers. Their expression levels can identify individuals with or at risk of developing obesity-related diseases such as inflammatory diseases 8 , diabetes 9 , CVDs 10 and metabolically unhealthy obese people 11 .

[7] Frontiers in metabolic physiology grand challenges

Authors: J. Imig
Year: 2022
Venue: Frontiers in Physiology
URL: https://www.semanticscholar.org/paper/19e2780d459288513f034516e0a7d5fa4e12298f
DOI: 10.3389/fphys.2022.879617
PMID: 36035475
PMCID: 9399398
Citations: 2
Summary: In this chapter seven subsequent studies of the determinants of infectious disease in eight operation rooms were studied.
Evidence snippets:
Snippet 1 (score: 0.397) > Research in this area will identify novel therapeutic targets for diabetic complications at the levels of transcription and translation, protein expression and activity, and cell and organ levels. Major challenges in diabetes include defining molecular mechanisms and pathways implicated in insulin metabolism, evaluating transcriptomics of high glucose on different cell types, defining the contribution of the innate immune response and NLRP3 inflammasome, understanding metabolic mechanisms that drive beta cell dysfunction, and defining metabolic processes in key insulin-target tissues. > NAFLD is a rapidly growing public health concern that occurs in 25% of the world population and is driven in large part by the obesity and type 2 diabetes epidemic (Caussy et al., 2021;Targher et al., 2021). Intriguingly, NAFLD can be as high as 75% in diabetic patients (Caussy et al., 2021;Targher et al., 2021). Non-alcoholic steatosis (NASH) is a type of NAFLD that is associated with inflammation and hepatocyte lipotoxicity which leads to liver fibrosis and cancer (Caussy et al., 2021;Targher et al., 2021). NASH is expected to become the leading cause for liver transplantation in the next decade (Nephew and Serper, 2021). Mechanisms that contribute to NAFLD and progression to NASH include regulation of de novo lipogenesis by acetyl-CoA carboxylase, regulation of bile acid signaling by farnesoid X receptor (FXR), or oxidative stress induced fibrogenesis and inflammation by apoptosis signal-regulating kinase 1 (ASK1) (Attia et al., 2021;Koo and Han, 2021). Although often associated with obesity and diabetes, understanding pathophysiological mechanisms at the cellular hepatocyte and organ liver levels that result in NAFLD and progression to NASH will be key to developing therapeutics. > Major challenges to the epidemic of metabolic diseases are the focus of several publications in Frontiers in Metabolic Physiology. Studies in mice with type 2 diabetes have revealed metabolites involved in diabetic kidney disease.

[8] Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

Authors: G.-C. Rao, Xi Peng, Xinqiong Li, Kang An, He He et al.
Year: 2023
Venue: Frontiers in Medicine
URL: https://www.semanticscholar.org/paper/d2b35f7a86b14e6dc3383a31166a9ba255454237
DOI: 10.3389/fmed.2023.1294267
PMID: 38089874
PMCID: 10711211
Citations: 76
Influential citations: 3
Summary: The existing literature on the key process of lipid metabolism in MASLD is reviewed to understand the latest progress in this molecular mechanism, and de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted.
Evidence snippets:
Snippet 1 (score: 0.396) > Over the last few decades, significant advancements have been made in comprehending the pathogenesis of MASLD. Excessive energy substrates, especially carbohydrates, cause DNL in the liver, while fat in the diet and adipose tissue with metabolic disorders provide excessive FFAs. Although the initial storage of liver triglycerides may play a buffering role, the production of toxic lipid metabolites is the main feature of progressive MASLD, which involves the production of cell pressure, mitochondrial dysfunction, the increase of reactive oxygen species, and the development of endoplasmic reticulum pressure (Figure 2). Reducing liver lipid deposition by targeting different pathways, especially key molecules, is of great clinical value to help identify key metabolic weaknesses that can be targeted to attenuate hepatic damage, inflammation, and fibrosis. This review systematically introduces the causes of liver lipid metabolism imbalance and the drug development and research progress of key molecules, aiming at a deeper understanding of the role of lipid metabolism in MASLD and providing ideas for clinical drug development from the molecular mechanism. > As we delve deeper into our research, it is crucial to consider the impact of ethnic and individual variances. By integrating genetic and metabolic factors, a more comprehensive understanding of the pathogenesis of MASLD can be achieved, and individualized therapeutic strategies can be developed. This may include explorations in genomic studies, metabolomic analysis, and drug development to accelerate therapeutic advances in MASLD. The application of this holistic approach is expected to provide more effective treatment options for patients with MASLD and improve the feasibility and success of treatment. > Additionally, due to the intricate nature of the pathophysiology involved in MASLD, it is possible that a solitary medication may not suffice to reverse the disease, necessitating the use of a combination therapy. The combination therapy of two or more drugs may improve the curative effect through complementation or synergy and improve tolerance by using a lower dose of candidate drugs. However, it is still a challenge to determine the ideal combination of drugs. The ideal combination therapy will aim at multiple steps of the pathogenesis, from energy balance to fibrosis. In addition to liver-oriented therapy, it should also include drugs with significant metabolic effects (such as drugs for treating type 2 diabetes).

[9] Gut Microbiota as a Systemic Regulator: Immunological and Neurological Implications Beyond Digestive Disease

Authors: María Paulina, P. Morales, Alejandra Isabel Carla, Farina Guzman, G. Amaya et al.
Year: 2026
Venue: International Science Journal
URL: https://www.semanticscholar.org/paper/ffce27bfcfa333f0af707d08958d04464a6c3cf8
DOI: 10.64784/218
Summary: Key mechanisms identified included increased intestinal permeability, chronic low-grade inflammation, abnormal immune activation, altered short-chain fatty acid production, and neuroimmune dysregulation mediated through the gut–brain axis, which demonstrated promising therapeutic potential in restoring microbial balance and reducing inflammatory activity.
Evidence snippets:
Snippet 1 (score: 0.394) > To identify the principal microbial populations, metabolites, and physiological mechanisms involved in the gut-brain axis and gut-immune axis based on current scientific evidence. 2. To explain how intestinal dysbiosis contributes to systemic inflammation, immune dysregulation, metabolic dysfunction, and neurological alterations associated with chronic disease progression. 3. To relate microbiota-derived mechanisms with the pathophysiology of systemic diseases including obesity, diabetes mellitus, cardiovascular disorders, autoimmune diseases, and neurodegenerative conditions. 4. To compare the immunological and neurological pathways through which gut microbiota influences systemic homeostasis and disease development across different organ systems. 5. To critically assess the current evidence regarding microbiota-based therapeutic interventions such as probiotics, prebiotics, dietary modulation, and fecal microbiota transplantation in clinical practice. 6. To propose integrative perspectives regarding the future role of microbiome-centered approaches in preventive medicine, personalized treatment, and translational biomedical research

[10] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

Authors: Tian-Guang Zhang, Chaoyu Miao
Year: 2022
Venue: Acta Pharmaceutica Sinica. B
URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
DOI: 10.1016/j.apsb.2022.10.008
PMID: 36970208
PMCID: 10031255
Citations: 108
Influential citations: 2
Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
Evidence snippets:
Snippet 1 (score: 0.391) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[11] Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

Authors: Santiago G. Lago, Jakub Tomasik, Geertje F. van Rees, Hannah Steeb, D. Cox et al.
Year: 2019
Venue: Science Advances
URL: https://www.semanticscholar.org/paper/8c5705beab72c173a2527e5d8db99aac5533ca2b
DOI: 10.1126/sciadv.aau9093
PMID: 31086815
PMCID: 6506238
Citations: 28
Influential citations: 1
Summary: A novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo, which has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for Neuropsychiatric conditions.
Evidence snippets:
Snippet 1 (score: 0.390) > Subsets of protein alterations common to both cell lineages have been associated with disease status, symptom severity, and therapeutic efficacy (17)(18)(19). Furthermore, recent GWAS data suggest the enrichment of single-nucleotide polymorphisms (SNPs) associated with neuropsychiatric (SCZ) risk loci within PBMC subtype-specific gene expression enhancers (7) and the coexpression of neuropsychiatric genetic risk phenotypes in both peripheral and CNS tissues (20,21). Although the functional correspondence between shared signaling motifs in PBMCs and CNS cells remains to be fully explored, it is possible that subsets of pathways, or even individual protein-protein interactions, which do overlap, are clinically relevant and can be practically exploited for drug discovery. Moreover, evidence that peripheral alterations can induce functional changes in the CNS with corresponding behavioral symptomatology [e.g., psychotic symptoms linked to gut microbiome alterations (22) or depressive-like symptoms following proinflammatory cytokine release during microbial infection (23)] suggests that peripheral cellular models may not solely be confined to surrogate identification of CNS targets but may also represent underlying pathophysiological mechanisms. > Exploration of neuropsychiatric patient PBMCs, with regard to functional alterations that reflect the disease state, could have important implications for overcoming current obstacles in neuropsychiatric drug discovery. First, the use of primary patient cells in the early stages of the drug discovery pipeline is associated with a higher success rate for putative targets and compounds (24). Second, the use of functional testing in live cells enables the elucidation of relevant disease-specific alterations in cell signaling networks, which are not observable simply by quantification of protein levels in their basal state, including homeostatic and regulatory mechanisms (13). Third, the focus on cellular responses provides the opportunity to summarize complex genetic risk factors with heterogeneous manifestations as integrated phenotypes, which are more amenable to drug screening and clinical treatment response prediction (25).

[12] Induction of Body Weight Loss through RNAi-Knockdown of APOBEC1 Gene Expression in Transgenic Rabbits

Authors: G. Jolivet, S. Braud, B. da-Silva, B. Passet, Erwana Harscoët et al.
Year: 2014
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/355ea28b6f1283f281b3835a57785163f684d078
DOI: 10.1371/journal.pone.0106655
PMID: 25216115
PMCID: 4162549
Citations: 16
Summary: A moderate reduction of the APOBEC1 dependent editing induces a lean phenotype at least in the rabbit species, suggesting that the AP OBEC1 gene might be a novel target for obesity treatment.
Evidence snippets:
Snippet 1 (score: 0.390) > A great number of genes are devoted to the storage of energy, and it is reasonable to propose that evolution has selected organisms able to survive in scarce conditions thanks to efficient mechanisms of energy storage. Limiting energy uptake and storage is probably a valuable strategy to fight against obesity. Thus, our approach consisted of looking for critical genes in people with lean phenotype. If a monogenic slimness disease resulting from a deficiency of fat absorption can be found, the implicated gene likely plays a critical role in the disease and is a potential target for new anti-obesity drugs. When this gene is not compensated by other mechanisms, it is therefore a powerful target for obesity treatment. > Three human genetic diseases have been described with very similar lean phenotypes: abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease also known as Anderson's disease [19]. The genes involved in the first two diseases, abetalipoproteinemia and hypobetalipoproteinemia, have now been identified, but it is not yet the case in the Anderson's disease [20,21]. All three diseases are characterized by a severe reduction or total absence of APOB48 protein in intestinal cells and plasma and of chylomicrons production. This led us to investigate further the possibility of fighting against obesity through regulating APOB48 production. APOB48 resulting exclusively from the translation of the APOBEC1 dependent edited APOB mRNA, we decided to target the expression of the APOBEC1 gene. The phenotype of mice harboring a complete invalidation of the APOBEC1 gene has been already reported by a series of laboratories [22][23][24][25]. As expected, the editing of the APOB mRNA was suppressed, and no APOB48 was produced in these mice. It was observed that intestinal fat absorption was less efficient in APOBEC1 2/2 mice containing only APOB100 than in wild type mice but it was not totally abolished. Probably, APOB100 could replace to some extent APOB48 in chylomicron formation and finally the plasma lipoprotein cholesterol and triglycerides profiles were not different in knock out and wild type mice [7] [8].

[13] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

Authors: Liang Zhang, Yujie Jiang, Taojun Jin, Mingxian Zheng, Yixuan Yap et al.
Year: 2025
Venue: Biomedicines
URL: https://www.semanticscholar.org/paper/e7ce2244e2bc25df76718a7b46e860a9c0478c01
DOI: 10.3390/biomedicines13092132
PMID: 41007695
PMCID: 12467098
Citations: 4
Summary: Findings are crucial for a deeper understanding of lipid metabolism pathways in AP and for the early implementation of preventive clinical measures, such as the control of blood lipid levels.
Evidence snippets:
Snippet 1 (score: 0.389) > FFAs have activated inflammatory cytokines, including tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1, which exacerbate the inflammatory cascade in AP [12,13]. These findings suggest that lipid metabolism disorders are closely linked to the regulation of the local immune micro-environment of the pancreas. Abnormal expression of specific lipid metabolism-related genes may play a crucial role in AP progression. Notably, ACSL4, a gene involved in cell membrane lipid synthesis, has been shown to be central to AP pathology and may serve as a potential therapeutic target [14]. However, the molecular mechanisms by which lipid metabolism abnormalities regulate AP development remain unclear. A systematic analysis of the expression patterns of relevant genes and their regulatory mechanisms could enhance our understanding of AP pathogenesis and inform personalized treatment strategies. > Advancements in high-throughput sequencing and computational biology have made machine learning and bioinformatics essential tools for exploring disease diagnosis, treatment, and underlying pathological mechanisms. In this study, we conducted a systematic analysis of AP-related lipid metabolism core genes and their regulatory mechanisms by integrating gene expression data, gene enrichment analysis, machine learning, protein interaction networks, and metabolic pathway analysis [15][16][17][18]. We then experimentally validated the candidate genes using an AP mouse model to ensure the reliability and clinical translational value of the identified biomarkers. > This study aims to identify key lipid metabolism-related genes involved in the pathogenesis of acute pancreatitis and elucidate their core regulatory mechanisms through integrative bioinformatics, machine learning, and animal experiments.

[14] Altered vitamin E status in Niemann-Pick type C disease

Authors: L. Ulatowski, Robert S. Parker, Cristin D. Davidson, N. Yanjanin, Thomas Kelley et al.
Year: 2011
Venue: Journal of Lipid Research
URL: https://www.semanticscholar.org/paper/8cc5bfbaf50d3233757bbee6bbe7df8347ab4128
DOI: 10.1194/jlr.M015560
PMID: 21550990
Citations: 44
Influential citations: 2
Summary: Observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations ofitamin E status.
Evidence snippets:
Snippet 1 (score: 0.384) > Niemann-Pick type C disease is a debilitating, fatal disorder in which intracellular lipid transport is impaired due to loss-of-function mutations in the NPC1 or NPC2 protein. The main biochemical phenotype associated with NPC disease is accumulation of unesterifi ed cholesterol and other lipids in a vesicular compartment of an endosomal/lysosomal origin. A number of metabolic scenarios can be envisioned to be at the root of NPC pathology. First, the extensive localized accumulation of lipids may be toxic, thereby compromising cell function and viability. Second, since the affected lipids are "sequestered" away from their proper sites of action, the affected cell may experience a catastrophic defi ciency of these metabolites. Lastly, physical disruption of the endocytic compartment may deprive the cell of other molecules that rely on this pathway for cellular transport. Despite intense research efforts in the past 50 years, many questions regarding the etiology of NPC disease remain unanswered. Thus, it is still not known which of scenarios described above is of highest signifi cance during disease progression. Similarly, it has not been conclusively determined which of the lipids sequestered in NPC lysosomes is the primary culprit re-accumulate under NPC1 or NPC2 loss-of-function ( 21,67,68 ).

[15] 3-Hydroxystearic acid promotes cholesterol efflux and attenuates atherosclerosis via the ALKBH5/PAX-8/ABCA1 pathway

Authors: Qin-Yi Zhou, Wang Liu, Zhenwang Zhao, Duo Gong, Xiaofeng Ma et al.
Year: 2026
Venue: Frontiers in Immunology
URL: https://www.semanticscholar.org/paper/983d2564a739e449bd1275eeca318066e55721f4
DOI: 10.3389/fimmu.2026.1750021
PMID: 41694370
PMCID: 12902941
Summary: The results demonstrated that C18-3OH promoted cholesterol efflux in foam cells and alleviated lipid accumulation by upregulating ABCA1 expression, and clarifies the impact and mechanisms of gut microbiota-derived C18-3OH on atherosclerosis progression.
Evidence snippets:
Snippet 1 (score: 0.380) > Gut microbiota-derived bioactive metabolites modulate host physiological functions through genetic and epigenetic mechanisms, directly or indirectly influencing the development of cardiovascular diseases such as coronary artery disease, heart failure, hypertension, and obesity (36). The relationship between gut microbial metabolites and lipid metabolism has received increasing attention (37). Fatty acid metabolites from gut microbiota represent a novel class of mediators in cardiovascular pathophysiology. Fatty acids are categorized into three types: shortchain fatty acids (<6 carbons), medium-chain fatty acids (6-12 carbons), and long-chain fatty acids (>12 carbons). Short-chain fatty acids exert significant regulatory effects on lipid metabolism and atherosclerosis by modulating macrophage inflammation, cholesterol metabolism, and endothelial function (38). However, the roles and mechanisms of long-chain fatty acids in lipid metabolism and atherosclerosis remain incompletely characterized. > Foam cell accumulation and subsequent plaque formation constitute a critical pathological basis for atherosclerosis. Maintenance of cellular cholesterol homeostasis is essential for normal cellular function, as cholesterol accumulation plays a key role in the pathogenesis of foam cell. Cholesterol efflux serves as a primary pathway for peripheral tissues to eliminate excess cholesterol from foam cells. ABCA1, the most pivotal transporter mediating reverse cholesterol transport (RCT) in atherosclerosis, plays a central role in this process (39, 40). Microbial metabolites are increasingly recognized as regulators of macrophage cholesterol metabolism. For instance, the tryptophan metabolite indole-3propionic acid (IPA) promotes cholesterol efflux via ABCA1 upregulation, thereby attenuating coronary artery disease progression; hence, IPA is negatively correlated with the risk of atherosclerosis (41). Similarly, the gut microbiota-derived butyrate ameliorates atherosclerosis in apoE -/-mice through ABCA1mediated cholesterol efflux (42).

[16] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
Year: 2025
Venue: Pathophysiology
URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
DOI: 10.3390/pathophysiology32010009
PMID: 39982365
PMCID: 12077258
Citations: 43
Influential citations: 1
Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
Evidence snippets:
Snippet 1 (score: 0.376) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[17] Toxicity and mechanistic analysis of di(2-ethylhexyl)phthalate in renal cell carcinoma progression: a systematic study with network toxicology and molecular docking strategies

Authors: Biao Ran, Xinyi Wang, Bohan Liu, Junjiang Ye, Liangren Liu et al.
Year: 2025
Venue: Discover Oncology
URL: https://www.semanticscholar.org/paper/66397aea42392baaaa9cf4e6e031b21c70d46c48
DOI: 10.1007/s12672-025-03543-7
PMID: 41071403
PMCID: 12514089
Citations: 2
Summary: The results suggest that DEHP exposure may promote the development of RCC by regulating apoptosis and proliferation through pathways such as neuroactive ligand–receptor interactions, pathways related to cancer, and apoptosis.
Evidence snippets:
Snippet 1 (score: 0.376) > Additional relevant functions include proteoglycan binding, collagen binding, fibronectin binding, and cysteine-type endopeptidase activity, indicating diverse regulatory roles of these genes. Overall, these GO analyses (BP, CC, and MF) demonstrated that these genes are integral to a variety of biological processes, cellular structures, and molecular functions, contributing to essential cellular defense mechanisms, structural stability, and enzymatic regulation. > According to the KEGG pathway enrichment analysis shown in Fig. 5, these genes are significantly enriched in pathways such as neuroactive ligand-receptor interaction, the calcium signaling pathway, the TNF signaling pathway, the cAMP signaling pathway, and apoptosis, underscoring their critical roles in cellular communication, Fig. 3 The PPI network of core targets inflammation, and disease mechanisms. Additional significant pathways included pathways associated with cancer, pathways associated with neurodegeneration, diabetic cardiomyopathy, and lipid and atherosclerosis, highlighting their involvement in diverse disease processes. Figure 5A (bubble plot) shows the top 20 enriched KEGG pathways ranked by FDR values, where bubble size represents the number of enriched genes, and color intensity indicates statistical significance. These pathways suggest that these genes play roles in cellular functions and disease progression, such as DEHP-induced renal cell carcinoma. Figure 5B (bar plot) categorizes these pathways by the number of genes involved, with neuroactive ligand-receptor interactions having the highest gene count, followed by pathways in cancer, apoptosis, and the TNF signaling pathway. The pathways are grouped into categories such as Environmental Information Processing, Cellular Processes, and Human Diseases, which have broad gene distributions across biological systems. Together, Fig. 5A, B emphasize the significant involvement of these genes in cellular signaling, inflammation, and various disease mechanisms, highlighting their relevance to disease development and cellular regulation.

[18] Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions

Authors: Claudio D. Gonzalez, María Paula Carro Negueruela, Catalina Nicora Santamarina, R. Resnik, M. Vaccaro
Year: 2021
Venue: Cells
URL: https://www.semanticscholar.org/paper/7947636a7b11fdbf5fe9717b179f065548444576
DOI: 10.3390/cells10092497
PMID: 34572148
PMCID: 8469825
Citations: 50
Influential citations: 1
Summary: The relationship between autophagy and Diabetic kidney disease and the potential value of Autophagy modulation as a target for pharmacological intervention are discussed.
Evidence snippets:
Snippet 1 (score: 0.374) > Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

[19] Hypoxia-associated genes and metabolic abnormalities in peripheral blood mononuclear cells of type 1 diabetes mellitus patients

Authors: Wenxue Ma, Xue-ying Wang, Yuan Zuo
Year: 2025
Venue: Hereditas
URL: https://www.semanticscholar.org/paper/daa85eddc3e8ad7e335d87d5de402ef2337b43ea
DOI: 10.1186/s41065-025-00537-x
PMID: 40836269
PMCID: 12369233
Summary: These findings not only identify specific hub genes as key mediators connecting signaling pathways, biological processes, and metabolic changes but also provide novel insights into the pathophysiology of T1DM.
Evidence snippets:
Snippet 1 (score: 0.374) > Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of pancreatic β-cells, which leads to insulin deficiency and hyperglycemia [1]. T1DM affects millions of individuals worldwide, imposing significant health and economic burdens due to its associated complications, such as neuropathy, retinopathy, and cardiovascular diseases [2]. While current management strategies mainly focus on insulin therapy and lifestyle modifications, these approaches fail to address the underlying pathological molecular mechanisms or prevent disease progression [3]. While several studies have investigated the genetic and environmental factors contributing to T1DM, the identification of key regulatory genes and their functional roles in disease pathogenesis remains limited [4]. Furthermore, the integration of gene expression data with pathway and metabolite analyses to reveal the complex interplay between molecular networks and clinical outcomes has not been extensively investigated [5]. Addressing these gaps is critical for developing targeted therapies and improving patient outcomes, underscoring the necessity of this study [6]. > T1DM is characterized by dysregulated immune responses and metabolic disturbances, yet the underlying molecular mechanisms are not completely understood [7]. Previous studies have identified altered gene expression and disrupted signaling pathways in T1DM, including TGF-beta and MAPK signaling, as well as retinol metabolism, all of which are implicated in immune modulation and metabolic regulation [8][9][10]. Additionally, biological processes, such as neutrophil activation, epithelial-mesenchymal transition (EMT), and hypoxia, have been associated with T1DM pathophysiology [11][12][13]. However, the interplay between these pathways, key regulatory genes, and metabolic changes remains underexplored. This study addresses this gap by integrating differential gene expression analysis, functional enrichment, protein-protein interaction (PPI) network construction, and correlation analyses to identify specific hub genes (FOS, JUNB, and NR4A2) that connect signaling pathways, biological processes, and metabolite dysregulation.

[20] Metabolomic Profiling for Identification of Novel Biomarkers and Mechanisms Related to Common Cardiovascular Diseases: Form and Function

Authors: Svati H. Shah, W. Kraus, C. Newgard
Year: 2012
Venue: Circulation
URL: https://www.semanticscholar.org/paper/54a51dd998a16a06162956d38c9a13501fadeeef
DOI: 10.1161/CIRCULATIONAHA.111.060368
PMID: 22927473
PMCID: 4374548
Citations: 358
Influential citations: 8
Summary: Comprehensive metabolic profiling, or “metabolomics” is increasingly being applied to CVD, leading to recent discoveries with both form and function implications, and recent progress in this rapidly expanding area is reviewed.
Evidence snippets:
Snippet 1 (score: 0.374) > The hierarchy of molecular control of biological systems passes from gene through gene modification (epigenetics) to gene expression (transcriptomics) to protein expression (proteomics) to metabolites/metabolic pathways (metabolomics) to clinical phenotype or outcome (Figure 3, top). In this scheme, metabolism sits closest in proximity to clinical phenotype and is therefore a strong candidate for identifying causative molecular mechanisms for disease. However, in identifying genes responsible for the metabolic intermediates that affect outcome, it is clear that the biological complexity of the system increases as one passes from gene to outcome, 17 thus making the task of identifying the specific pathways involved in genetic cause or mediation of disease quite daunting-conceptually, experimentally, and statistically. The experimental challenge is illustrated by the fact that the 9p21 genetic locus undoubtedly contains the strongest and most consistent genetic marker of CVD risk identified so far, 50 yet 5 years after its discovery, the biological mechanism or pathway by which this genetic variant mediates disease is still a mystery. > The statistical challenge is illustrated by our own recent work and similar studies being performed by others (Figure 3, bottom). In our CATHGEN cohort, we have genome-wide association study data containing 10 6 single-nucleotide polymorphisms on 3500 individuals, whole-genome transcript data with 2ϫ10 4 gene tags on 1500 of the same individuals, data for Ͼ70 metabolites on 3500 individuals, and at least 10 outcomes or phenotypes on close to 10 000 individuals. Our work to date reveals strong associations of specific genetic loci with the cluster of small-to medium-chain dicarboxylated acylcarnitines found in the same population to be prognostic for incident cardiovascular events. The potential functional relationships between these genetic loci and variation in the dicarboxylated acylcarnitines are currently being investigated. The statistical complexity and the risk for false discovery (the multiple-comparisons problem) are daunting, exceeding 10 13 comparisons in each individual in the study population. Thus, in moving forward, we propose to adopt both the classic and retrograde approaches summarized in Figure 3. In the classic genetic variant mapped to outcome approach, used in the majority of genome-wide association studies published to date, the risk is that although

Notes

This provider combines search_papers_by_relevance with snippet_search.
No synthesis or second-stage model call is performed.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	39
Resolved	39
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	39
On topic	17
Off topic	0

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Term Validation

No ontology term identifiers were found in this report.

Falcon ▸

Chylomicron Retention Disease: Disease-Characteristics Research Report

Edison Scientific Literature 39 citations 2026-09-05T18:07:16.471470

Chylomicron Retention Disease: Disease-Characteristics Research Report

Executive summary

Chylomicron retention disease (CRD), or Anderson disease, is an ultra-rare, usually infancy-onset Mendelian disorder in which biallelic pathogenic variants in SAR1B impair COPII-dependent export of pre-chylomicrons from the enterocyte endoplasmic reticulum (ER) to the Golgi. Dietary lipid consequently accumulates within enterocytes, postprandial chylomicrons and apolipoprotein B-48 are absent or markedly reduced, and patients develop fat malabsorption, diarrhea, steatorrhea, growth failure, hypocholesterolemia, and fat-soluble-vitamin deficiency. Lifelong dietary and vitamin treatment usually controls gastrointestinal disease and substantially reduces irreversible neurologic, retinal, skeletal, muscular, and cardiac complications, but it does not correct the underlying trafficking defect. Evidence remains dominated by case reports, small cohorts, cell systems, and engineered animals; there are no randomized therapeutic trials or validated survival estimates.

The following table summarizes the principal knowledge-base fields.

Domain	Key finding/statistic	Evidence type	Ontology suggestions
Identity/etiology	Chylomicron retention disease (CRD; Anderson disease) is an ultra-rare, autosomal-recessive intestinal lipid-malabsorption disorder caused principally by biallelic SAR1B loss-of-function variants; estimated prevalence is <1 per 1,000,000 (OpenTargets Search: chylomicron retention disease-SAR1B, peretti2018lessonsfromchylomicron pages 1-3)	Aggregated disease resource; human molecular evidence	MONDO:0009528; chylomicron retention disease; Anderson disease
Core phenotype frequencies	In a molecularly confirmed 16-patient cohort/literature synthesis: diarrhea 100%, steatorrhea 85%, failure to thrive 80%, abdominal distension 65%, vomiting 60%, elevated CK 60%, vitamin E deficiency 95%, vitamin A deficiency 70%, and vitamin D and K deficiencies 45% each (peretti2010guidelinesforthe pages 3-4)	Human clinical cohort and literature review	Chronic diarrhea; steatorrhea; failure to thrive; abdominal distension; vomiting; elevated serum creatine kinase; fat-soluble-vitamin deficiency
Lipid signature	Low total cholesterol, LDL-C, and HDL-C occurred in 100% of the summarized genotyped cases; triglycerides were normal in 90%, and the oral fat-load response was negative in 100% (peretti2010guidelinesforthe pages 3-4)	Human biochemical evidence	Hypocholesterolemia; decreased LDL cholesterol; decreased HDL cholesterol; normal circulating triglyceride concentration
Diagnostic signature	Typical combination: infancy-onset fat malabsorption, total/LDL cholesterol near 50% of normal, moderately low HDL, normal triglycerides, absent postprandial chylomicrons/apoB-48, white duodenal mucosa, and enterocytes distended by lipid droplets or membrane-bound chylomicron-like particles; confirm with biallelic SAR1B variants (georges2011molecularanalysisand pages 1-2, peretti2018lessonsfromchylomicron pages 1-3, ferreira2018chylomicronretentiondisease pages 6-7)	Human laboratory, endoscopic, histopathologic, and genetic evidence	Absent postprandial chylomicrons; lipid accumulation in enterocytes; white intestinal mucosa; small-intestinal biopsy
Mechanism	SEC12-mediated GDP–GTP exchange activates SAR1B at ER exit sites; SAR1B recruits SEC23–SEC24 and SEC13–SEC31 COPII coats. Pathogenic dysfunction blocks pre-chylomicron ER-to-Golgi trafficking and/or Golgi fusion, causing enterocyte lipid retention and reduced intestinal lipid export (tang2023cargoselectionin pages 2-3, levy2024unravelingchylomicronretention pages 7-9)	Human genetics plus biochemical and cell-biological evidence	GO:0006888 ER-to-Golgi vesicle-mediated transport; COPII-coated ER-to-Golgi transport vesicle; GTPase activity; protein transport
Secondary mechanisms	SAR1B-deficient Caco-2/15 cells have reduced chylomicron and HDL formation, impaired cholesterol efflux, and increased lipid peroxidation; oxidative stress, inflammation, and ER stress are plausible downstream contributors, but their clinical importance remains incompletely established (sane2017understandingchylomicronretention pages 9-10, levy2024unravelingchylomicronretention pages 10-12, levy2024unravelingchylomicronretention pages 1-2)	In-vitro evidence; review-level inference for human complications	Oxidative stress; endoplasmic-reticulum stress; inflammatory response; cholesterol efflux
Genetics/variants	SAR1B (formerly SARA2; chromosome 5q31.1) has eight exons. Representative disease variants include frameshift *p.Leu28Argfs7 and p.Asp48Thrfs17, nonsense p.Glu122, exon-2 deletion, and missense p.Asp137Asn, p.Ser179Arg, and p.Gly185Val** (charcosset2008andersonorchylomicron pages 1-2, georges2011molecularanalysisand pages 1-2, charcosset2008andersonorchylomicron pages 8-9)	Human germline molecular evidence and functional modeling	SAR1B; secretion-associated Ras-related GTPase 1B; germline pathogenic variant; loss of function
Modifiers/expressivity	Clinical severity varies even among variants predicted to abolish function. Increased intestinal SAR1A expression does not fully compensate; a co-occurring PCSK9 p.Leu21dup variant showed no clear additional effect. Proposed modifiers such as APOB, MTTP, and ABCG5/ABCG8 remain unproven (georges2011molecularanalysisand pages 8-11, georges2011molecularanalysisand pages 1-2, charcosset2008andersonorchylomicron pages 8-9)	Human expression data; candidate-modifier inference	Variable expressivity; SAR1A; PCSK9; APOB; MTTP; ABCG5; ABCG8
Treatment doses	Supportive therapy includes restriction of long-chain fat, adequate calories, optional medium-chain triglycerides, omega-6 at 3–5% of energy, omega-3 at 0.5–1%, vitamin E 50 IU/kg/day, vitamin A 15,000 IU/day, vitamin K 15 mg/week, and vitamin D 800–1,200 IU/day or age-adjusted intermittent dosing. Doses require biochemical and toxicity monitoring (peretti2010guidelinesforthe pages 10-11, peretti2010guidelinesforthe pages 9-10)	Expert guideline based on literature and two-center experience	Low-fat diet; medium-chain triglyceride supplementation; vitamin E supplementation; vitamin A supplementation; vitamin D supplementation; vitamin K supplementation; dietary counseling
Surveillance	Annual childhood assessment: growth, gastrointestinal and neurologic symptoms, diet, lipid profile, liver enzymes, fat-soluble vitamins, essential fatty acids, CBC, and CK. After age 10, liver ultrasound and neurologic, muscular, ophthalmologic, and bone assessment approximately every three years; adult echocardiography every three years was proposed (peretti2010guidelinesforthe pages 10-11, peretti2010guidelinesforthe pages 9-10)	Expert guideline/clinical practice recommendation	Growth monitoring; liver ultrasonography; ophthalmologic examination; neurologic examination; bone densitometry; echocardiography
Models/recent research	CRISPR Sar1b-mutant/deletion mice reproduce steatorrhea, malabsorption, failed chylomicron secretion, hypocholesterolemia, and hypoalphalipoproteinemia; homozygous states are usually embryonic/neonatal lethal. An 8-week, 60%-fat diet exposed genotype- and sex-dependent lipid, insulin, hepatic-steatosis, fatty-acid, and ER-stress effects; females were relatively protected (auclair2023highfatdietreveals pages 1-2, levy2024unravelingchylomicronretention pages 10-12, auclair2023highfatdietreveals pages 11-13, auclair2023highfatdietreveals pages 9-10)	Genetically engineered mouse models; 2023 experimental study	Mus musculus; high-fat diet; intestinal lipid accumulation; hepatic steatosis; insulin resistance; ER stress
Prognosis	Gastrointestinal symptoms often improve rapidly with fat restriction, but fat intolerance persists and steatorrhea did not adapt after about five years. Early treatment was associated with absence of clinical/electrophysiologic neuro-ophthalmologic complications in 12/16 patients; delayed diagnosis can lead to permanent growth, neurologic, retinal, muscular, cardiac, hepatic, or skeletal morbidity (peretti2018lessonsfromchylomicron pages 3-4, peretti2010guidelinesforthe pages 3-4, peretti2010guidelinesforthe pages 9-10)	Longitudinal human cohorts and expert synthesis	Growth delay; peripheral neuropathy; ataxia; retinopathy; myopathy; cardiomyopathy; hepatic steatosis; reduced bone mineralization

Table: Compact evidence table summarizing the identity, phenotype frequencies, diagnostic signature, molecular mechanism, genetics, management, models, and prognosis of chylomicron retention disease. Evidence types and suggested ontology concepts are included for knowledge-base annotation.

1. Disease information

Definition and identifiers

CRD is a hereditary disorder of intestinal chylomicron secretion and lipid absorption. Its characteristic biochemical combination is low total cholesterol, LDL cholesterol, and HDL cholesterol, generally normal fasting triglycerides, and absent postprandial chylomicrons/apoB-48. It is distinct from defects that prevent apoB-lipoprotein assembly altogether because circulating LDL and apoB-100 remain detectable, albeit reduced (georges2011molecularanalysisand pages 1-2, peretti2018lessonsfromchylomicron pages 1-3).

Key identifiers and terminology

MONDO: MONDO:0009528.
OMIM phenotype: commonly catalogued as chylomicron retention disease, MIM 246700. Some older literature used MIM 607689; this inconsistency reflects historical nomenclature and should be checked against the current OMIM release before database ingestion.
Causal gene: SAR1B, OMIM 607690; Ensembl ENSG00000152700; former symbol SARA2*; approved name “secretion associated Ras-related GTPase 1B” (OpenTargets Search: chylomicron retention disease-SAR1B, georges2011molecularanalysisand pages 1-2).
Synonyms: Anderson disease, Anderson’s disease, chylomicron retention disease, chylomicron-retention disease, intestinal hypobetalipoproteinemia, and historically “Anderson syndrome.”
Orphanet: the disease is represented in Orphanet, but an ORPHA number was not independently verified in the retrieved evidence.
ICD/MeSH: no CRD-specific ICD-10 or ICD-11 code was demonstrated in the retrieved literature. Coding generally falls under broader disorders of lipoprotein metabolism or intestinal malabsorption. A dedicated MeSH descriptor was likewise not established here; “Lipid Metabolism, Inborn Errors” and “Malabsorption Syndromes” are appropriate indexing concepts.

The evidence in this report is principally aggregated disease-level evidence from published cohorts, reviews, molecular studies, and disease databases. It is not an analysis of individual electronic health records.

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

The canonical cause is germline biallelic loss-of-function or function-disrupting variation in SAR1B, inherited autosomal recessively. Open Targets identifies SAR1B as the sole strongly supported target associated with MONDO:0009528 and links the association to human publications including PMID 12692552, 18786134, 19274794, and 21235735 (OpenTargets Search: chylomicron retention disease-SAR1B).

Rare phenocopies or unresolved cases exist. A Japanese patient with the clinical and histologic phenotype had maternal uniparental disomy of chromosome 7 and a normal SAR1B coding sequence, suggesting that regulatory defects or another lipid-export gene may occasionally produce a CRD-like phenotype. This does not overturn SAR1B as the established cause of typical CRD (georges2011molecularanalysisand pages 1-2).

Risk factors

Genetic: two pathogenic SAR1B alleles; parental consanguinity increases the probability of homozygosity. Family history may be absent because heterozygotes generally have normal lipid profiles.
Environmental/lifestyle: environmental exposure does not initiate the Mendelian disease. A high intake of long-chain triglycerides increases steatorrhea and enterocyte lipid loading; diarrhea commonly recurs when fat is reintroduced (peretti2018lessonsfromchylomicron pages 3-4, peretti2010guidelinesforthe pages 3-4).
Age and sex: onset is usually during the first six months. No convincing human sex bias is established.
Infectious/toxic/occupational factors: none established.

Protective factors

No protective SAR1B allele has been validated. Clinically protective measures are early recognition, restriction of long-chain dietary fat, adequate essential fatty acids and calories, and high-dose fat-soluble vitamins—particularly vitamin E. Early therapy was associated with absence of clinical or electrophysiologic neuro-ophthalmologic disease in 12 of 16 patients in the principal two-center experience (peretti2010guidelinesforthe pages 9-10).

Gene–environment interaction

Diet alters phenotype severity rather than disease occurrence. In Sar1b-mutant mice, an eight-week diet containing 60% fat exposed genotype- and sex-dependent changes in weight, adiposity, insulin resistance, hepatic steatosis, fatty-acid composition, cholesterol regulation, and intestinal ER stress. Female mice were relatively protected, but this sex effect remains a model-organism observation and should not be assumed in humans (levy2024unravelingchylomicronretention pages 10-12, auclair2023highfatdietreveals pages 11-13, auclair2023highfatdietreveals pages 9-10).

3. Phenotypes

The most useful frequency data derive from a literature synthesis and molecularly confirmed cohort of 16 patients, not a population registry. Therefore, estimates are susceptible to ascertainment and small-sample bias.

Phenotype	Type, onset/course, reported frequency	Suggested HPO annotation
Chronic diarrhea	Symptom; usually 1–6 months; improves rapidly with fat restriction but recurs with fat	Chronic diarrhea
Steatorrhea/fat malabsorption	Symptom/laboratory; chronic and diet-responsive; 85%	Steatorrhea; intestinal fat malabsorption
Failure to thrive/growth retardation	Clinical sign; infancy onset; 80%; reported growth deficit −1 to −4 SD	Failure to thrive; growth delay
Abdominal distension	Sign; early; 65%	Abdominal distention
Vomiting	Symptom; early and variable; 60%	Vomiting
Hypocholesterolemia	Laboratory; persistent; low total cholesterol and LDL in 100%	Hypocholesterolemia; decreased LDL cholesterol
Low HDL cholesterol	Laboratory; 100% in summarized genotyped cases	Decreased HDL cholesterol concentration
Normal fasting triglycerides	Laboratory discriminator; 90%	Normal circulating triglyceride concentration
Absent postprandial chylomicrons/apoB-48	Functional laboratory hallmark; negative oral fat load in 100%	Absent postprandial chylomicrons
Vitamin E deficiency	Laboratory; severe and persistent; 95%	Vitamin E deficiency
Vitamins A, D, K deficiency	Laboratory; 70%, 45%, and 45%, respectively	Vitamin A/D/K deficiency
Elevated creatine kinase	Laboratory/muscular sign; 60%, often 1.5–4× normal	Elevated serum creatine kinase
Hepatic steatosis/hepatomegaly	Sign/imaging; approximately 15–20% in reported series; usually mild	Hepatic steatosis; hepatomegaly
Neuropathy, areflexia, ataxia, myopathy	Later complications, particularly if untreated; variable and less severe than in abetalipoproteinemia	Peripheral neuropathy; areflexia; ataxia; myopathy
Retinopathy	Late, potentially permanent complication; uncommon at presentation	Pigmentary retinopathy/retinal degeneration
Reduced mineralization/delayed bone age	Chronic complication	Osteopenia; delayed skeletal maturation

These frequencies are supported by the 16-patient synthesis: diarrhea 100%, steatorrhea 85%, growth failure 80%, distension 65%, vomiting and high CK 60%, vitamin E deficiency 95%, and low LDL/HDL 100% (peretti2010guidelinesforthe pages 3-4). Quality-of-life instruments such as EQ-5D, SF-36, or PROMIS have not been validated in CRD. Likely burdens include dietary restriction, recurrent gastrointestinal symptoms, frequent biochemical surveillance, impaired childhood growth, and preventable neurologic disability.

4. Genetic and molecular information

Gene and protein

SAR1B lies at 5q31.1, contains eight exons, and has predicted alternative exon-2 splicing. It encodes a 198-amino-acid Ras/ARF-family small GTPase. Human SAR1A and SAR1B differ at only 20 residues, but SAR1B binds SEC23 more strongly, has distinct GTPase-exchange kinetics, and is particularly important for intestinal chylomicron export (georges2011molecularanalysisand pages 1-2, tang2023cargoselectionin pages 2-3).

Representative pathogenic variants

Reported disease alleles include:

Frameshift: p.Leu28Argfs*7, p.Asp48Thrfs*17, and c.83_84delTG (p.Leu28Argfs*7).
Nonsense: p.Glu122*.
Deletion: whole exon 2 deletion, functionally described as p.Met1_His43del.
Missense: p.Asp137Asn, p.Ser179Arg, and p.Gly185Val (charcosset2008andersonorchylomicron pages 1-2, georges2011molecularanalysisand pages 1-2, charcosset2008andersonorchylomicron pages 8-9).

Frameshift/nonsense/deletion alleles generally produce absent or severely truncated proteins and are mechanistically loss-of-function. Missense substitutions can disrupt GTP binding/hydrolysis, SEC12 activation, SEC23 interaction, membrane association, or coat dynamics. The variants are germline, not somatic. The retrieved literature did not provide current gnomAD frequencies or a complete ClinVar classification table; each variant should therefore be rechecked in current ClinVar/gnomAD before assigning an ACMG class.

Expressivity, modifiers, and other genomic mechanisms

Clinical severity varies even among families carrying variants predicted to cause severe dysfunction, so a simple genotype–phenotype correlation is not established. Intestinal SAR1A rises approximately 1.4–2.7-fold in affected biopsies but does not compensate for a roughly two-thirds reduction in SAR1B. A co-occurring PCSK9 p.Leu21dup allele had no demonstrable additional effect. APOB, MTTP, ABCG5/ABCG8, transcriptional regulators, and dietary exposure are candidate modifiers, but none is validated as a CRD modifier (georges2011molecularanalysisand pages 8-11, georges2011molecularanalysisand pages 1-2, charcosset2008andersonorchylomicron pages 8-9).

No reproducible disease-specific DNA methylation, histone, chromatin, repeat-expansion, mitochondrial-DNA, or large chromosomal-abnormality mechanism is established. The chromosome-7 uniparental-disomy case is exceptional rather than the canonical mechanism.

5. Environmental information

CRD is not caused by toxins, radiation, pollution, smoking, alcohol, occupation, or infection. Dietary long-chain triglyceride is the most important phenotype-modifying exposure. Medium-chain triglycerides bypass chylomicron packaging to a greater extent and can provide calories, although their routine amount must be individualized. Excessively strict fat avoidance can worsen essential-fatty-acid deficiency; treatment therefore balances symptom control against growth and omega-3/omega-6 requirements (peretti2010guidelinesforthe pages 10-11, peretti2010guidelinesforthe pages 1-3).

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic SAR1B pathogenic variants lead to reduced or dysfunctional SAR1B GTPase in absorptive small-intestinal enterocytes.
Defective SEC12-mediated nucleotide exchange or abnormal GTP hydrolysis/membrane interaction leads to impaired SAR1B cycling between GDP-bound inactive and GTP-bound active states.
Abnormal active SAR1B leads to defective recruitment or dynamics of the SEC23–SEC24 inner COPII coat and SEC13–SEC31 outer coat at ER exit sites.
Defective COPII assembly/scission and/or pre-chylomicron-vesicle fusion with Golgi leads to failed ER-to-Golgi export of unusually large apoB-48-containing pre-chylomicrons.
Failed export leads to intracellular retention of triglyceride-rich droplets and membrane-bound chylomicron-like particles in villus enterocytes.
Enterocyte retention leads to absent postprandial chylomicrons, reduced delivery of dietary triglyceride, cholesterol, essential fatty acids, and fat-soluble vitamins to blood and peripheral tissues.
Reduced lipid export leads to steatorrhea, chronic diarrhea, abdominal distension, hypocholesterolemia, low HDL, malnutrition, and growth failure.
Chronic vitamin E/essential-fatty-acid deficiency leads to neurologic, retinal, muscular, hematologic, and skeletal complications.
Branch—intracellular lipid accumulation probably leads to lipid peroxidation, ER stress, and inflammatory signaling; this branch is demonstrated in cell/animal models but remains incompletely validated as a driver of human complications.
Branch—SAR1B expression in liver and muscle may lead to hepatic, skeletal-muscle, and cardiac manifestations when function is severely impaired; extra-intestinal causality is supported but less firmly characterized than the enterocyte defect (levy2024unravelingchylomicronretention pages 10-12, georges2011molecularanalysisand pages 11-12, tang2023cargoselectionin pages 2-3, levy2024unravelingchylomicronretention pages 7-9).

Cellular and biochemical detail

SEC12 activates SAR1B at the ER membrane. SAR1B-GTP inserts an amphipathic helix, deforms the membrane, recruits SEC23/SEC24 and subsequently SEC13/SEC31, and helps generate and uncoat COPII carriers. SEC23/SEC31 stimulate GTP hydrolysis, allowing coat disassembly. Disruption at either nucleotide exchange or hydrolysis can therefore block secretion (georges2011molecularanalysisand pages 11-12, levy2024unravelingchylomicronretention pages 7-9).

In healthy duodenum, Sar1 protein is concentrated apically in enterocytes of the upper two-thirds of villi. CRD biopsies show reduced, heterogeneous Sar1 staining around large lipid droplets. SAR1B normally exceeds SAR1A expression approximately 2.5–3-fold in intestine (georges2011molecularanalysisand pages 8-11).

Suggested GO terms: ER-to-Golgi vesicle-mediated transport (GO:0006888); COPII-coated vesicle budding; GTPase activity; lipid transport; chylomicron assembly; cholesterol efflux; response to ER stress; response to oxidative stress. Suggested CL term: absorptive intestinal epithelial cell/enterocyte. Relevant pathways include Reactome COPII-mediated vesicle transport and intestinal lipoprotein assembly; canonical Wnt, MAPK, mTOR, and PI3K–AKT dysregulation are not established primary mechanisms.

Molecular profiling and advanced technologies

Patient-biopsy RT-qPCR demonstrated reduced SAR1B and compensatory but inadequate SAR1A expression. Caco-2/15 CRISPR disruption reduced chylomicron output and HDL biogenesis/cholesterol efflux; complete suppression of chylomicron secretion required combined SAR1A/SAR1B disruption, demonstrating paralog redundancy. Increased malondialdehyde supported lipid peroxidation (sane2017understandingchylomicronretention pages 9-10, levy2024unravelingchylomicronretention pages 10-12).

Recent work has integrated lipid profiles, fatty-acid composition, expression of PCSK9/LDLR, NPC1L1, SCARB1, ABCG8, MTTP, HMGCR, SREBP2, ABCA1, and LXRα, and ER-stress markers PERK, IRE1, GRP78, and ATF6 in engineered mice. No disease-specific human single-cell or spatial-transcriptomic atlas, validated proteomic signature, or clinical multi-omics classifier was identified (levy2024unravelingchylomicronretention pages 10-12, auclair2023highfatdietreveals pages 9-10).

7. Anatomical structures affected

Primary organ/system: proximal small intestine and digestive system.
Tissue/cell: villus epithelium, especially mature absorptive enterocytes. Suggested terms: UBERON “duodenum,” “jejunum,” “small intestine,” “intestinal villus”; CL “enterocyte.”
Subcellular sites: ER membrane/ER exit sites, COPII-coated transport carriers, pre-chylomicron transport vesicles, Golgi apparatus, and cytoplasmic lipid droplets. Suggested GO-CC terms: endoplasmic reticulum membrane, ER exit site, COPII-coated ER-to-Golgi transport vesicle, Golgi apparatus, lipid droplet.
Secondary organs: liver (steatosis/cytolysis), skeletal muscle (high CK/myopathy), peripheral nervous system, retina, skeleton, and occasionally heart.
Localization/lateralization: diffuse intestinal involvement; no meaningful unilateral or bilateral pattern (peretti2018lessonsfromchylomicron pages 1-3, georges2011molecularanalysisand pages 8-11).

8. Temporal development

Symptoms usually begin chronically or insidiously between one and six months, sometimes neonatally. Only about one-third of reported children in an older synthesis were diagnosed during the first year, illustrating diagnostic delay (peretti2010guidelinesforthe pages 3-4, peretti2018lessonsfromchylomicron pages 1-3).

Early disease consists of diarrhea, steatorrhea, vomiting/distension, and faltering growth. Intermediate disease includes persistent biochemical deficiencies, delayed growth or puberty, hepatic cytolysis/steatosis, and elevated CK. Advanced untreated disease may include neuropathy, areflexia, ataxia, myopathy, retinal disease, poor bone mineralization, and cardiomyopathy. CRD is lifelong: gastrointestinal symptoms improve within days or weeks of fat restriction, but there is no reliable remission or intestinal adaptation, and steatorrhea persisted after approximately five years of observation (peretti2018lessonsfromchylomicron pages 3-4, peretti2010guidelinesforthe pages 3-4, peretti2010guidelinesforthe pages 1-3).

Infancy and early childhood are critical intervention windows because malnutrition affects growth and prolonged vitamin E deficiency may cause irreversible neuro-retinal injury.

9. Inheritance and population

CRD is autosomal recessive. For two confirmed carrier parents, each pregnancy has the conventional 25% affected, 50% carrier, and 25% unaffected/non-carrier probabilities. Heterozygotes are generally clinically and biochemically normal. Penetrance of clearly pathogenic biallelic variants appears high, but formal age-dependent penetrance estimates do not exist; expressivity is variable (charcosset2008andersonorchylomicron pages 1-2, peretti2018lessonsfromchylomicron pages 1-3).

Estimated prevalence is <1 per 1,000,000. Approximately 60 patients, about 40 genotyped and carrying roughly 20 different mutations, had been reported by 2018; underdiagnosis is likely. Published families include French-Canadian, Turkish, Algerian, Portuguese, European, Japanese, and other ancestries. Founder effects have been suggested in clustered families but no global carrier frequency or robust incidence estimate is available. Both sexes are affected. Consanguinity is a recognized enrichment mechanism; anticipation and germline mosaicism are not characteristic (charcosset2008andersonorchylomicron pages 1-2, peretti2018lessonsfromchylomicron pages 1-3, georges2011molecularanalysisand pages 1-2).

10. Diagnostics

Practical diagnostic pathway

In an infant or child with chronic diarrhea, steatorrhea, or unexplained growth failure, measure fasting total cholesterol, LDL-C, HDL-C, triglycerides, apoB, vitamins A/D/E/K, INR, liver enzymes, CK, blood count, iron, and essential-fatty-acid profile.
Suspect CRD when total/LDL cholesterol is approximately 50% of normal, HDL is low, triglycerides remain normal, and vitamin E is markedly low.
Demonstrate absent or markedly reduced postprandial chylomicrons/apoB-48 after a supervised fat load where clinically safe. A negative fat load was reported in 100% of summarized genotyped cases.
Upper endoscopy after dietary fat exposure may show a white or stippled duodenal/jejunal mucosa.
Biopsy shows preserved villus architecture but lipid-distended enterocytes, large cytoplasmic droplets, and membrane-bound lipoprotein-sized particles.
Confirm with sequencing and deletion/duplication analysis of SAR1B; test parents for phase and enable cascade screening (georges2011molecularanalysisand pages 1-2, peretti2018lessonsfromchylomicron pages 1-3, ferreira2018chylomicronretentiondisease pages 6-7).

A representative abstract states: “The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile. Upper endoscopy and histology reveal fat-laden enterocytes whereas vitamin E deficiency is invariably present” (Peretti et al., published 22 September 2010; DOI 10.1186/1750-1172-5-24) (peretti2010guidelinesforthe pages 1-3).

Genetic-test selection

A hypocholesterolemia/fat-malabsorption panel should include at least SAR1B, MTTP, APOB, and often ANGPTL3, PCSK9, and other lipid genes. Single-gene SAR1B testing is efficient with a classic phenotype. WES/WGS is appropriate when panel testing is negative, the phenotype is syndromic, or regulatory/structural variation is suspected. Copy-number analysis is necessary because exon deletions occur. CMA, karyotyping, FISH, mitochondrial-DNA testing, and repeat-expansion assays are not first-line unless other clinical findings indicate them. RNA sequencing may clarify splice or regulatory variants but is not a routine validated diagnostic assay.

Differential diagnosis

Abetalipoproteinemia (MTTP): nearly absent apoB-containing lipoproteins, extremely low LDL and triglycerides, prominent acanthocytosis; CRD retains apoB-100/LDL and usually has normal triglycerides.
Biallelic APOB familial hypobetalipoproteinemia: severe apoB deficiency affecting intestinal and hepatic lipoproteins; genotype and lipid pattern distinguish it.
Heterozygous APOB/PCSK9 hypobetalipoproteinemia: usually little or no infantile malabsorption.
ANGPTL3 deficiency: combined hypolipidemia without characteristic fat-loaded enterocytes.
Celiac disease, cystic fibrosis/pancreatic insufficiency, congenital diarrheal disorders, cholestasis, food-protein disease: can cause malabsorption but not the characteristic normal-triglyceride hypocholesterolemia plus absent postprandial apoB-48.

Population newborn screening is not established. Targeted biochemical/genetic testing, sibling cascade testing, and parental carrier testing are appropriate (ferreira2018chylomicronretentiondisease pages 6-7, peretti2018lessonsfromchylomicron pages 1-3).

11. Outcome and prognosis

No reliable five- or ten-year survival, mortality rate, or life-expectancy estimate exists. Available evidence suggests that treated patients can reach adulthood and that morbidity, rather than early mortality, is the principal concern. Early therapy commonly resolves diarrhea and improves weight, while hypocholesterolemia and vitamin E deficiency may persist (peretti2010guidelinesforthe pages 9-10, ferreira2018chylomicronretentiondisease pages 5-6).

Delayed diagnosis can permanently compromise growth: seven patients in the major clinical experience failed to reach the 20th percentile of predicted growth potential. Potential complications include neuropathy, ataxia, myopathy, retinal degeneration, osteopenia, delayed puberty, coagulopathy, anemia, hepatic steatosis, and cardiomyopathy. Moderate macrovesicular steatosis is reported, but the guideline review found no established progression to steatohepatitis or cirrhosis. Prognostic factors are age at treatment, adequacy/adherence of vitamin E and caloric replacement, dietary control of malabsorption, and baseline neurologic or retinal injury (peretti2018lessonsfromchylomicron pages 3-4, peretti2010guidelinesforthe pages 3-4, peretti2010guidelinesforthe pages 9-10).

12. Treatment and current applications

Standard management

There is no approved disease-modifying drug, gene therapy, RNA therapy, cell therapy, or surgery. Treatment is lifelong nutritional therapy:

Restrict long-chain fat sufficiently to control diarrhea and steatorrhea without causing caloric deprivation.
Supply essential fatty acids: approximately 3–5% of energy as omega-6 and 0.5–1% as omega-3; soybean oil and fish were specifically suggested.
Consider medium-chain triglycerides as a chylomicron-independent energy source.
Vitamin E: approximately 50 IU/kg/day orally, adjusted to biochemical and safety monitoring.
Vitamin A: approximately 15,000 IU/day, adjusted to plasma level and toxicity risk.
Vitamin D: approximately 800–1,200 IU/day or age-adjusted intermittent regimens. Some reproduced guideline tables contain an apparent “IU/kg/day” transcription; the original regimen should be verified before prescribing.
Vitamin K: approximately 15 mg/week, adjusted to INR and vitamin status.
Correct iron, calcium, and other deficiencies as indicated (peretti2010guidelinesforthe pages 10-11, peretti2010guidelinesforthe pages 9-10).

These are historical expert-guideline doses, not substitutes for specialist prescribing. Hypervitaminosis A/D and vitamin E–related bleeding are relevant safety considerations. Suggested NCIT intervention concepts include dietary therapy, low-fat diet, nutritional supplementation, vitamin E, vitamin A, vitamin D, vitamin K, medium-chain triglyceride, and genetic counseling.

Monitoring

Annual childhood assessment should include height/weight, gastrointestinal and neurologic status, diet, lipid profile, liver enzymes, CK, blood count, fat-soluble vitamins, INR, and essential fatty acids. After age ten, liver ultrasound, neurologic/muscular and ophthalmologic examination, electrophysiology where indicated, and bone-density assessment approximately every three years were proposed. Adult echocardiography every three years was also suggested (peretti2010guidelinesforthe pages 10-11, peretti2010guidelinesforthe pages 9-10).

Experimental and translational applications

No CRD-specific interventional trial was identified. A ClinicalTrials.gov search returned an observational carotenoid study in hypocholesterolemia (NCT05208879, completed; n=10), but its direct CRD enrollment and disease-specific utility were not established. Other retrieved “Anderson” trials concerned Anderson–Fabry disease and were irrelevant.

SAR1B biology is being considered as a lipid-lowering target because reducing enterocyte lipoprotein export could lower circulating cholesterol. Experts caution that broad SAR1B inhibition could reproduce malabsorption, vitamin deficiency, liver or muscle effects, and secretory-pathway toxicity. Intestine-restricted, partial, or cargo-selective modulation would therefore be required (peretti2018lessonsfromchylomicron pages 3-4, tang2023cargoselectionin pages 2-3).

13. Prevention

Primary prevention through lifestyle or vaccination is not applicable to the occurrence of a recessive genetic disorder. Reproductive prevention options include carrier testing of relatives, genetic counseling, partner testing, prenatal diagnosis, and preimplantation genetic testing when familial variants are known. Secondary prevention consists of cascade testing and rapid evaluation of symptomatic siblings; universal newborn screening is not currently established. Tertiary prevention is central: early dietary treatment and vitamin replacement, growth monitoring, and surveillance of liver, nervous system, retina, muscle, heart, coagulation, and bone reduce complications. No infectious prophylaxis, immunization specific to CRD, or environmental public-health intervention is indicated.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart or zoonotic form was identified. SAR1B is evolutionarily conserved across vertebrates, and orthologs exist in mouse and zebrafish. CRD is neither infectious nor transmissible between species. Breed-specific disease and VBO annotations were not found. Comparative importance lies in conserved COPII trafficking rather than animal-health prevalence (charcosset2008andersonorchylomicron pages 1-2, auclair2023highfatdietreveals pages 1-2).

15. Model organisms and experimental systems

Cellular models

CRISPR-disrupted human Caco-2/15 intestinal cells show reduced chylomicron secretion, impaired HDL biogenesis and cholesterol efflux, and oxidative stress. Combined SAR1A/SAR1B loss causes a more complete secretory block than SAR1B loss alone, revealing redundancy. Limitations include transformed-cell metabolism, absence of systemic dietary physiology, and incomplete modeling of development (sane2017understandingchylomicronretention pages 9-10, tang2023cargoselectionin pages 2-3).

Zebrafish

Sar1b-deficient zebrafish reproduce intestinal lipid-absorption and trafficking defects and are useful for developmental imaging and mechanistic screening. Their lipoprotein physiology and early development differ from humans, limiting direct therapeutic extrapolation.

Mouse

CRISPR mice bearing a targeted deletion or a patient-analogous Sar1b mutation reproduce intestinal lipid accumulation, steatorrhea, malabsorption, failed chylomicron secretion, hypocholesterolemia, and low HDL. Homozygous deletion/mutation is usually embryonic or neonatal lethal, unlike most human patients, so heterozygous mice have been used for metabolic experiments even though human heterozygotes are generally asymptomatic. This genotype mismatch is an important limitation (auclair2023highfatdietreveals pages 1-2, auclair2023highfatdietreveals pages 11-13, lu2020consequencesofmutations pages 2-4).

The 2023 high-fat-diet study demonstrated that diet, sex, and allele type alter the model phenotype. It found changes in hepatic and intestinal steatosis, insulin sensitivity, saturated/polyunsaturated fatty-acid balance, omega-6/omega-3 ratio, and ER-stress responses. These data strengthen the concept that SAR1B regulates broader cholesterol and metabolic homeostasis, but small subgroup and histology sample sizes constrain inference (auclair2023highfatdietreveals pages 11-13, auclair2023highfatdietreveals pages 9-10, auclair2023highfatdietreveals pages 4-5).

Evidence hierarchy, recent developments, and limitations

The most authoritative clinical management evidence remains the 2010 two-center guideline because no newer controlled treatment study exists. Its abstract directly states that treatment includes “fat-soluble vitamin supplements and large amounts of vitamin E” and emphasizes maintaining both calories and essential fatty acids (published 22 September 2010; DOI 10.1186/1750-1172-5-24) (peretti2010guidelinesforthe pages 1-3).

The major recent synthesis is Levy et al., July 2024, Biomedicines 12:1548, DOI 10.3390/biomedicines12071548. Its abstract concludes that SAR1B loss-of-function not only predisposes to CRD but may “exacerbate oxidative stress, inflammation, and ER stress”; these secondary mechanisms are primarily based on cellular and animal evidence rather than prospective human data (levy2024unravelingchylomicronretention pages 1-2).

The principal recent primary mechanistic study is Auclair et al., September 2023, Journal of Lipid Research 64:100423, DOI 10.1016/j.jlr.2023.100423, which established diet-, sex-, and allele-dependent metabolic effects in engineered mice (auclair2023highfatdietreveals pages 1-2, auclair2023highfatdietreveals pages 9-10).

Overall certainty is high for autosomal-recessive SAR1B causation, impaired COPII-dependent pre-chylomicron trafficking, the biochemical/endoscopic signature, and benefit of early nutritional therapy. Certainty is moderate or low for exact prevalence, phenotype penetrance, genotype–phenotype correlation, human sex effects, secondary inflammatory/ER-stress mechanisms, long-term survival, optimal vitamin doses, and advanced therapeutics because CRD remains exceptionally rare and lacks registries or controlled trials.

References

(OpenTargets Search: chylomicron retention disease-SAR1B): Open Targets Query (chylomicron retention disease-SAR1B, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(peretti2018lessonsfromchylomicron pages 1-3): Noel Peretti. Lessons from chylomicron retention disease: a potential new approach for the treatment of hypercholesterolemia? Expert Opinion on Orphan Drugs, 6:163-165, Feb 2018. URL: https://doi.org/10.1080/21678707.2018.1438259, doi:10.1080/21678707.2018.1438259. This article has 4 citations.
(peretti2010guidelinesforthe pages 3-4): Noel Peretti, Agnès Sassolas, Claude C Roy, Colette Deslandres, Mathilde Charcosset, Justine Castagnetti, Laurence Pugnet-Chardon, Philippe Moulin, Sylvie Labarge, Lise Bouthillier, Alain Lachaux, and Emile Levy. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet Journal of Rare Diseases, 5:24-24, Sep 2010. URL: https://doi.org/10.1186/1750-1172-5-24, doi:10.1186/1750-1172-5-24. This article has 155 citations and is from a peer-reviewed journal.
(georges2011molecularanalysisand pages 1-2): Amandine Georges, Jessica Bonneau, Dominique Bonnefont-Rousselot, Jacqueline Champigneulle, Jean P Rabès, Marianne Abifadel, Thomas Aparicio, Jean C Guenedet, Eric Bruckert, Catherine Boileau, Alain Morali, Mathilde Varret, Lawrence P Aggerbeck, and Marie E Samson-Bouma. Molecular analysis and intestinal expression of sar1 genes and proteins in anderson's disease (chylomicron retention disease). Orphanet Journal of Rare Diseases, 6:1-1, Jan 2011. URL: https://doi.org/10.1186/1750-1172-6-1, doi:10.1186/1750-1172-6-1. This article has 89 citations and is from a peer-reviewed journal.
(ferreira2018chylomicronretentiondisease pages 6-7): Helena Ferreira, Raquel Nuñez Ramos, Cinthia Flores Quan, Susana Redecillas Ferreiro, Vanessa Cabello Ruiz, Javi Juampérez Goñi, Jesus Quintero Bernabeu, Oscar Segarra Cantón, and Marina Álvarez Beltran. Chylomicron retention disease: a description of a new mutation in a very rare disease. Pediatric Gastroenterology, Hepatology & Nutrition, 21:134-140, Apr 2018. URL: https://doi.org/10.5223/pghn.2018.21.2.134, doi:10.5223/pghn.2018.21.2.134. This article has 14 citations and is from a peer-reviewed journal.
(tang2023cargoselectionin pages 2-3): Vi T. Tang and David Ginsburg. Cargo selection in endoplasmic reticulum–to–golgi transport and relevant diseases. The Journal of Clinical Investigation, Jan 2023. URL: https://doi.org/10.1172/jci163838, doi:10.1172/jci163838. This article has 73 citations.
(levy2024unravelingchylomicronretention pages 7-9): Emile Levy, Catherine Fallet-Bianco, Nickolas Auclair, Natalie Patey, Valérie Marcil, Alain Théophile Sané, and Schohraya Spahis. Unraveling chylomicron retention disease enhances insight into sar1b gtpase functions and mechanisms of actions, while shedding light of intracellular chylomicron trafficking. Jul 2024. URL: https://doi.org/10.3390/biomedicines12071548, doi:10.3390/biomedicines12071548. This article has 1 citations.
(sane2017understandingchylomicronretention pages 9-10): Alain Théophile Sané, Ernest Seidman, Noel Peretti, Marie Laure Kleme, Edgard Delvin, Colette Deslandres, Carole Garofalo, Schohraya Spahis, and Emile Levy. Understanding chylomicron retention disease through sar1b gtpase gene disruption: insight from cell culture. Arteriosclerosis, Thrombosis, and Vascular Biology, 37:2243–2251, Dec 2017. URL: https://doi.org/10.1161/atvbaha.117.310121, doi:10.1161/atvbaha.117.310121. This article has 64 citations and is from a domain leading peer-reviewed journal.
(levy2024unravelingchylomicronretention pages 10-12): Emile Levy, Catherine Fallet-Bianco, Nickolas Auclair, Natalie Patey, Valérie Marcil, Alain Théophile Sané, and Schohraya Spahis. Unraveling chylomicron retention disease enhances insight into sar1b gtpase functions and mechanisms of actions, while shedding light of intracellular chylomicron trafficking. Jul 2024. URL: https://doi.org/10.3390/biomedicines12071548, doi:10.3390/biomedicines12071548. This article has 1 citations.
(levy2024unravelingchylomicronretention pages 1-2): Emile Levy, Catherine Fallet-Bianco, Nickolas Auclair, Natalie Patey, Valérie Marcil, Alain Théophile Sané, and Schohraya Spahis. Unraveling chylomicron retention disease enhances insight into sar1b gtpase functions and mechanisms of actions, while shedding light of intracellular chylomicron trafficking. Jul 2024. URL: https://doi.org/10.3390/biomedicines12071548, doi:10.3390/biomedicines12071548. This article has 1 citations.
(charcosset2008andersonorchylomicron pages 1-2): Mathilde Charcosset, Agnès Sassolas, Noël Peretti, Claude C. Roy, Colette Deslandres, Daniel Sinnett, Emile Levy, and Alain Lachaux. Anderson or chylomicron retention disease: molecular impact of five mutations in the sar1b gene on the structure and the functionality of sar1b protein. Molecular genetics and metabolism, 93 1:74-84, Jan 2008. URL: https://doi.org/10.1016/j.ymgme.2007.08.120, doi:10.1016/j.ymgme.2007.08.120. This article has 95 citations and is from a peer-reviewed journal.
(charcosset2008andersonorchylomicron pages 8-9): Mathilde Charcosset, Agnès Sassolas, Noël Peretti, Claude C. Roy, Colette Deslandres, Daniel Sinnett, Emile Levy, and Alain Lachaux. Anderson or chylomicron retention disease: molecular impact of five mutations in the sar1b gene on the structure and the functionality of sar1b protein. Molecular genetics and metabolism, 93 1:74-84, Jan 2008. URL: https://doi.org/10.1016/j.ymgme.2007.08.120, doi:10.1016/j.ymgme.2007.08.120. This article has 95 citations and is from a peer-reviewed journal.
(georges2011molecularanalysisand pages 8-11): Amandine Georges, Jessica Bonneau, Dominique Bonnefont-Rousselot, Jacqueline Champigneulle, Jean P Rabès, Marianne Abifadel, Thomas Aparicio, Jean C Guenedet, Eric Bruckert, Catherine Boileau, Alain Morali, Mathilde Varret, Lawrence P Aggerbeck, and Marie E Samson-Bouma. Molecular analysis and intestinal expression of sar1 genes and proteins in anderson's disease (chylomicron retention disease). Orphanet Journal of Rare Diseases, 6:1-1, Jan 2011. URL: https://doi.org/10.1186/1750-1172-6-1, doi:10.1186/1750-1172-6-1. This article has 89 citations and is from a peer-reviewed journal.
(peretti2010guidelinesforthe pages 10-11): Noel Peretti, Agnès Sassolas, Claude C Roy, Colette Deslandres, Mathilde Charcosset, Justine Castagnetti, Laurence Pugnet-Chardon, Philippe Moulin, Sylvie Labarge, Lise Bouthillier, Alain Lachaux, and Emile Levy. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet Journal of Rare Diseases, 5:24-24, Sep 2010. URL: https://doi.org/10.1186/1750-1172-5-24, doi:10.1186/1750-1172-5-24. This article has 155 citations and is from a peer-reviewed journal.
(peretti2010guidelinesforthe pages 9-10): Noel Peretti, Agnès Sassolas, Claude C Roy, Colette Deslandres, Mathilde Charcosset, Justine Castagnetti, Laurence Pugnet-Chardon, Philippe Moulin, Sylvie Labarge, Lise Bouthillier, Alain Lachaux, and Emile Levy. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet Journal of Rare Diseases, 5:24-24, Sep 2010. URL: https://doi.org/10.1186/1750-1172-5-24, doi:10.1186/1750-1172-5-24. This article has 155 citations and is from a peer-reviewed journal.
(auclair2023highfatdietreveals pages 1-2): Nickolas Auclair, Alain T. Sané, Léna Ahmarani, Nour-El-Houda Ould-Chikh, Nathalie Patey, Jean-François Beaulieu, Edgard Delvin, Schohraya Spahis, and Emile Levy. High-fat diet reveals the impact of sar1b defects on lipid and lipoprotein profile and cholesterol metabolism. Sep 2023. URL: https://doi.org/10.1016/j.jlr.2023.100423, doi:10.1016/j.jlr.2023.100423. This article has 10 citations and is from a peer-reviewed journal.
(auclair2023highfatdietreveals pages 11-13): Nickolas Auclair, Alain T. Sané, Léna Ahmarani, Nour-El-Houda Ould-Chikh, Nathalie Patey, Jean-François Beaulieu, Edgard Delvin, Schohraya Spahis, and Emile Levy. High-fat diet reveals the impact of sar1b defects on lipid and lipoprotein profile and cholesterol metabolism. Sep 2023. URL: https://doi.org/10.1016/j.jlr.2023.100423, doi:10.1016/j.jlr.2023.100423. This article has 10 citations and is from a peer-reviewed journal.
(auclair2023highfatdietreveals pages 9-10): Nickolas Auclair, Alain T. Sané, Léna Ahmarani, Nour-El-Houda Ould-Chikh, Nathalie Patey, Jean-François Beaulieu, Edgard Delvin, Schohraya Spahis, and Emile Levy. High-fat diet reveals the impact of sar1b defects on lipid and lipoprotein profile and cholesterol metabolism. Sep 2023. URL: https://doi.org/10.1016/j.jlr.2023.100423, doi:10.1016/j.jlr.2023.100423. This article has 10 citations and is from a peer-reviewed journal.
(peretti2018lessonsfromchylomicron pages 3-4): Noel Peretti. Lessons from chylomicron retention disease: a potential new approach for the treatment of hypercholesterolemia? Expert Opinion on Orphan Drugs, 6:163-165, Feb 2018. URL: https://doi.org/10.1080/21678707.2018.1438259, doi:10.1080/21678707.2018.1438259. This article has 4 citations.
(peretti2010guidelinesforthe pages 1-3): Noel Peretti, Agnès Sassolas, Claude C Roy, Colette Deslandres, Mathilde Charcosset, Justine Castagnetti, Laurence Pugnet-Chardon, Philippe Moulin, Sylvie Labarge, Lise Bouthillier, Alain Lachaux, and Emile Levy. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet Journal of Rare Diseases, 5:24-24, Sep 2010. URL: https://doi.org/10.1186/1750-1172-5-24, doi:10.1186/1750-1172-5-24. This article has 155 citations and is from a peer-reviewed journal.
(georges2011molecularanalysisand pages 11-12): Amandine Georges, Jessica Bonneau, Dominique Bonnefont-Rousselot, Jacqueline Champigneulle, Jean P Rabès, Marianne Abifadel, Thomas Aparicio, Jean C Guenedet, Eric Bruckert, Catherine Boileau, Alain Morali, Mathilde Varret, Lawrence P Aggerbeck, and Marie E Samson-Bouma. Molecular analysis and intestinal expression of sar1 genes and proteins in anderson's disease (chylomicron retention disease). Orphanet Journal of Rare Diseases, 6:1-1, Jan 2011. URL: https://doi.org/10.1186/1750-1172-6-1, doi:10.1186/1750-1172-6-1. This article has 89 citations and is from a peer-reviewed journal.
(ferreira2018chylomicronretentiondisease pages 5-6): Helena Ferreira, Raquel Nuñez Ramos, Cinthia Flores Quan, Susana Redecillas Ferreiro, Vanessa Cabello Ruiz, Javi Juampérez Goñi, Jesus Quintero Bernabeu, Oscar Segarra Cantón, and Marina Álvarez Beltran. Chylomicron retention disease: a description of a new mutation in a very rare disease. Pediatric Gastroenterology, Hepatology & Nutrition, 21:134-140, Apr 2018. URL: https://doi.org/10.5223/pghn.2018.21.2.134, doi:10.5223/pghn.2018.21.2.134. This article has 14 citations and is from a peer-reviewed journal.
(lu2020consequencesofmutations pages 2-4): Chung-Ling Lu and Jinoh Kim. Consequences of mutations in the genes of the er export machinery copii in vertebrates. Mar 2020. URL: https://doi.org/10.1007/s12192-019-01062-3, doi:10.1007/s12192-019-01062-3. This article has 25 citations and is from a peer-reviewed journal.
(auclair2023highfatdietreveals pages 4-5): Nickolas Auclair, Alain T. Sané, Léna Ahmarani, Nour-El-Houda Ould-Chikh, Nathalie Patey, Jean-François Beaulieu, Edgard Delvin, Schohraya Spahis, and Emile Levy. High-fat diet reveals the impact of sar1b defects on lipid and lipoprotein profile and cholesterol metabolism. Sep 2023. URL: https://doi.org/10.1016/j.jlr.2023.100423, doi:10.1016/j.jlr.2023.100423. This article has 10 citations and is from a peer-reviewed journal.

Artifacts

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Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	11
On topic	5
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	2
Resolved	2
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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MONDO:0009528 (4 mentions) - the report calls it "if available"; MONDO calls it chylomicron retention disease

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Inheritance

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

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References & Deep Research

References

Deep Research

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Chylomicron Retention Disease. Core disease mechanisms, molecular and cell...

Relevant Papers

[1] Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

[3] From Congenital Disorders of Fat Malabsorption to Understanding Intra-Enterocyte Mechanisms Behind Chylomicron Assembly and Secretion

[4] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

[5] Apolipoprotein B48 Knockout Ameliorates High-Fat-Diet-Induced Metabolic Impairment in Mice

[6] Differentially expressed serum proteins from obese Wistar rats as a risk factor for obesity-induced diseases

[7] Frontiers in metabolic physiology grand challenges

[8] Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

[9] Gut Microbiota as a Systemic Regulator: Immunological and Neurological Implications Beyond Digestive Disease

[10] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

[11] Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

[12] Induction of Body Weight Loss through RNAi-Knockdown of APOBEC1 Gene Expression in Transgenic Rabbits

[13] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

[14] Altered vitamin E status in Niemann-Pick type C disease

[15] 3-Hydroxystearic acid promotes cholesterol efflux and attenuates atherosclerosis via the ALKBH5/PAX-8/ABCA1 pathway

[16] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

[17] Toxicity and mechanistic analysis of di(2-ethylhexyl)phthalate in renal cell carcinoma progression: a systematic study with network toxicology and molecular docking strategies

[18] Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions

[19] Hypoxia-associated genes and metabolic abnormalities in peripheral blood mononuclear cells of type 1 diabetes mellitus patients

[20] Metabolomic Profiling for Identification of Novel Biomarkers and Mechanisms Related to Common Cardiovascular Diseases: Form and Function

Notes

Reference Validation

Term Validation

Chylomicron Retention Disease: Disease-Characteristics Research Report

Executive summary

1. Disease information

Definition and identifiers

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

Risk factors

Protective factors

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Gene and protein

Representative pathogenic variants

Expressivity, modifiers, and other genomic mechanisms

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Cellular and biochemical detail

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Practical diagnostic pathway

Genetic-test selection

Differential diagnosis

11. Outcome and prognosis

12. Treatment and current applications

Standard management

Monitoring

Experimental and translational applications

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems