Severe xanthomatosis associated with familial apolipoprotein E deficiency.
Open accessAbstract
AIM: To present the clinical, dermatological, and histological features of a patient with generalised xanthomatosis, familial apolipoprotein (apo) E deficiency, and unusual type III hyperlipoproteinaemia (HLP). METHODS: The underlying molecular defect was disclosed using molecular biological techniques. The unusual xanthomas were histologically analysed and the morphology of the abnormal lipoprotein particles examined using electron microscopy. RESULTS: A 10 base pair deletion in exon 4 of the proband's apo epsilon gene (base pairs 4037-4046 coding for amino acids 209-212 of the mature protein) was identified. This is predictive for a reading frameshift encoding a premature stop (TGA) in codon 229. The mutation is responsible for delayed catabolism of atherogenic lipoprotein remnants, lipid storage in monocyte/macrophages, and phenotypic expression of xanthomatosis early in life. CONCLUSIONS: Familial apo E deficiency is a rare genetic disease which offers the unique opportunity to study the impact of apo E on lipoprotein metabolism and development of atherosclerosis in humans.
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Written from the paper’s full text.
TL;DR
This case report describes a 30-year-old man with familial apolipoprotein E deficiency caused by a 10 base pair deletion in exon 4 of the apo E gene, presenting with severe generalised xanthomatosis and an unusual type III hyperlipoproteinaemia. The authors argue apo E deficiency is a rare human model for studying apo E's role in remnant catabolism and early atherosclerosis.
Key findings
- A 10 base pair deletion in exon 4 of the proband's apo E gene (base pairs 4037–4046, coding for amino acids 209–212 of the mature protein) was identified, predicted to cause a reading frameshift and a premature stop (TGA) in codon 229.
- The proband had xanthomas and hyperlipidaemia since about five years of age, with ear xanthomas, tubero-eruptive xanthomas on knees and elbows, and orange-yellowish palmar creases, soles, armpits, and hand joints; histology showed numerous benign histiocytic lipid-laden foam cells.
- Initial lipid values at age 30: total cholesterol 11.4 mmol/l, triglycerides 3.7 mmol/l, VLDL cholesterol 7.2, LDL cholesterol 3.2, and HDL cholesterol 1.1 mmol/l. After a low fat, low cholesterol diet plus micronised fenofibrate (200 mg/day), values at 12 months were cholesterol 6.5 and triglycerides 1.2 mmol/l, with VLDL cholesterol 2.1, LDL cholesterol 3.1, and HDL cholesterol 1.4 mmol/l.
- Electron microscopy showed heterogeneous VLDL, IDL, and LDL particles and smaller HDL particles in the proband than in controls; β-VLDL was also observed (not shown).
Methods
- Single case report: the proband (BG) was a slightly obese (78 kg, 171 cm, BMI 26.3 kg/m²) 30-year-old German man of Hungarian ancestry, identified while screening hyperlipidaemic subjects for apo E phenotypes.
- Fasting venous blood was analysed for total cholesterol, triglycerides, and HDL cholesterol using enzymatic kits; apo E phenotypes were determined by one dimensional isoelectric focusing; lipoproteins were separated by sequential ultracentrifugation into VLDL, IDL, LDL, and HDL.
- Genomic DNA from nucleated blood cells was analysed by PCR of the 3' part of exon 4, agarose gel sizing, TA cloning into pCR II-vector, and DNA sequencing with T7 DNA polymerase; lipoprotein particle morphology was examined by negative staining electron microscopy.
Limitations
- The paper states no formal limitations section. Evident from the text: this is a single case (n = 1), and the authors note that only two of the previously analysed familial apo E deficiency patients had their underlying molecular defects disclosed, so the molecular basis of the condition remains characterised in very few individuals.
- The authors note that the presence of a truncated apo E fragment with reduced lipoprotein affinity "does not preclude the proband's truncated apo E peptide preserving some of its physiological functions," leaving residual function unresolved.
- The report is descriptive; no functional receptor-binding or turnover assays are presented, and the atherosclerosis inference rests on foam cell histology and analogy to apo E deficient mice rather than direct clinical cardiovascular endpoints.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
1 of 12 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The most common underlying genetic defect for the lipoprotein abnormalities in type III HLP is the synthesis of an abnormal isoform of apo E, apo E2, which does not bind normally to lipoprotein receptors.
“The most common underlying genetic defect for the lipoprotein abnormalities in type III HLP is the synthesis of an abnormal isoform of apolipoprotein (apo) E, apo E2, which does not bind normally to lipoprotein receptors.6”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, Weber W, et al. Familial dysbetalipoproteinemia: abnormal binding of mutant apolipoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenals of rats, rabbits and cows.3JClin Invest 1981;68:1075-85. source
The Results identify apo E-D as the predominant isoform in all nine patients studied, and the paper equates E-D with E-2. The Discussion reports markedly defective receptor binding in six of the nine, but near-normal binding in the other three. This supports a common defect in this sample, not an unqualified claim that apo E2 binds abnormally or that it is the most common underlying genetic defect across type III HLP. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
The proband did not show any clinical and laboratory evidence of cardiovascular, renal, hepatic or endocrine disorders, except hyperlipidaemia.
“The proband did not show any clinical and laboratory evidence of cardiovascular, renal, hepatic or endocrine disorders, except hyperlipidaemia.”
Quote in the paperNot a substantial claim - Findingreasoning
The 10 base pair deletion is predictive for a reading frameshift encoding a premature stop (TGA) in codon 229.
“This is predictive for a reading frameshift encoding a premature stop (TGA) in codon 229.”
Quote in the paperSubstantial claim - Findingown data
Histological examination of the surgically removed ear xanthomas revealed numerous benign, histiocytic, lipid laden foam cells.
“Histo- logical examination revealed numerous benign, histiocytic, lipid laden foam cells (fig 5).”
- Also stated in: § Discussion · plain
“Histological examin- ation of the ear xanthomas in the proband also showed massive foam cell accumulation (fig 5).”
Quote in the paperNot a substantial claim - Also stated in: § Discussion · plain
- Findingown data
The proband had a history of xanthomas and hyperlipidaemia since about five years of age.
“He had had a history of xanthomas and hyperlipidaemia since about five years of age.”
Quote in the paperNot a substantial claim
- Findingnone given
Our patient expressed a severe clinical phenotype of the disease.
“Our patient, however, expressed a severe clinical phenotype of the disease.”
Quote in the paperSubstantial claim - Findingcitation
We identified a further subject with familial apo E deficiency and xanthomatosis.
“Recently, we identified a further subject with familial apo E deficiency and xanthomatosis.'4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Feussner G, Dobmeyer J, Grone H-J, Lohmer S, Wohlfeil S. A 10-bp deletion in the apolipoprotein E gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet 1996;58:281-91. source
- Findingown data
A 10 base pair deletion in exon 4 of the proband's apo E gene (base pairs 4037-4046 coding for amino acids 209-212 of the mature protein) was identified.
“A 10 base pair deletion in exon 4 of the proband's apo £ gene (base pairs 4037-4046 coding for amino acids 209-212 ofthe mature protein) was identified.”
- Also stated in: § Abstract · plain
“The molecular defect was a 10 base pair deletion in exon 4 of the proband's apo £ gene.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationreasoning
The mutation is responsible for lipid storage in monocyte/macrophages.
“The mutation is responsible for delayed catabolism of atherogenic lipoprotein remnants, lipid storage in monocyte/macrophages, and phenotypic expression of xanthomatosis early in life.”
Quote in the paperSubstantial claim - Premisecitation
Affected subjects with type III HLP develop accelerated atherosclerosis involving both coronary and peripheral arteries.
“Affected sub- jects develop accelerated atherosclerosis in- volving both coronary and peripheral arteries.'”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Mahley RW, Rall SC Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th Edn. New York: McGraw-Hill Book Co., 1995:1953-80.
Not checked in the free run.
- Interpretationreasoning
This molecular defect leads to severe generalised atypical xanthomatosis.
“This molecular defect leads to severe general- ised atypical xanthomatosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
The mutation is responsible for delayed catabolism of atherogenic lipoprotein remnants.
“The mutation is responsible for delayed catabolism of atherogenic lipoprotein remnants, lipid storage in monocyte/macrophages, and phenotypic expression of xanthomatosis early in life.”
Quote in the paperSubstantial claim - Premisereasoning
Type III HLP is a multifactorial disease; additional genetic or environmental factors are required for its phenotypic expression.
“This suggests that type III HLP is a multifactorial disease-that is, additional factors, either genetic or environmental, are required for its phenotypic expression.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Utermann G. Apolipoprotein E polymorphism in health and disease. Am HeartJ 1987;113:433-40. source
- Premisecitation
In only two of the analysed patients with familial apo E deficiency have the underlying molecular defects been disclosed.
“In only two of the analysed patients have the underlying molecular defects been dis- closed.'213”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites '213
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
A severe form of type III HLP is caused by complete or relative lack of functionally active apo E (familial apo E deficiency).
“A severe form of type III HLP is caused by com- plete or relative lack of functionally active apo E (familial apo E deficiency).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 8'-2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Xanthomatosis in children or adolescents is rather rare in classic type III HLP, where xanthomas do not usually develop before the fourth or fifth decade of life.
“Xanthomatosis in chil- dren or adolescents is rather rare in”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Mahley RW, Rall SC Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th Edn. New York: McGraw-Hill Book Co., 1995:1953-80.
Not checked in the free run.
- Premisecitation
In the other patient with familial apo E deficiency, a single nucleotide substitution of A for G converted amino acid 210 of the mature protein, tryptophan (TGG), to a premature chain termination codon (TAG), leading to synthesis of a truncated apo E peptide of 209 instead of the normal 299 amino acids.
“In the other case a single nucleotide substitution of an A for a G was identified, which converted amino acid 210 of the mature protein, tryptophan (TGG), to a premature chain termination codon (TAG), thus leading to the synthesis of a truncated apo E peptide of 209 instead of the normal 299 amino acids.'2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Lohse P, Brewer III HB, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB Jr. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J7 Lipid Res 1992;33:1583-90. source
- Interpretationreasoning
The mutation is responsible for phenotypic expression of xanthomatosis early in life.
“The mutation is responsible for delayed catabolism of atherogenic lipoprotein remnants, lipid storage in monocyte/macrophages, and phenotypic expression of xanthomatosis early in life.”
Quote in the paperSubstantial claim
- May combine two claims. 9
- Classified as probably not a substantial claim. 2
May combine two claims.
Findingown dataElectron microscopy of the proband's fasting plasma lipoproteins showed VLDL, IDL, and LDL particles that were heterogeneous in size, and smaller HDL particles than those seen in controls.
“In the proband electron microscopy showed VLDL, IDL, and LDL particles all of which were heterogeneous in size, and smaller HDL particles than those seen in the controls.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAt initial examination at age 30, the proband's total cholesterol was 11.4 mmol/l; triglycerides 3.7 mmol/l; VLDL cholesterol 7.2, LDL cholesterol 3.2, and HDL cholesterol 1.1 mmol/l.
“Lipid values at the time of the initial examination (at age 30) were total cholesterol 11.4 mmol/l; triglycerides 3.7 mmol/l; VLDL cholesterol 7.2, LDL cholesterol 3.2, and HDL cholesterol 1.1 mmol/l, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter 12 months of treatment with a low fat, low cholesterol diet and micronised fenofibrate (200 mg/day), the proband's serum cholesterol and triglyceride values were 6.5 and 1.2 mmol/l, respectively; VLDL cholesterol 2.1, LDL cholesterol 3.1, and HDL cholesterol 1.4 mmol/l.
“Recent serum cholesterol and triglyceride values were 6.5 and 1.2 mmol/l (12 months after start of 10 0 E 6_ E 4. o 5 10 15 Monfts Diet] Diet and micronised fenofibrate (200 mg/day) Figure 4 Time course of serum lipids (cholesterol and triglycerides) during lipid lowering treatment in the patient with apo E deficiency.treatment) (fig 4).”
- Also stated in: § Methods · plain
“VLDL cholesterol was 2.1, LDL cholesterol 3.1, and HDL cholesterol 1.4 mmol/l, respectively.”
Quote in the paperNot a substantial claim- Also stated in: § Methods · plain
May combine two claims.
Findingown dataPhysical examination at age 30 revealed unusual xanthomas on the ears, numerous tubero-eruptive xanthomas on the knees and elbows, and orange-yellowish discolourations in the creases of the palms (palmar xanthomas), soles, armpits, and joints of the hands.
“Physical examination (at age 30) revealed unusual xan- thomas on the ears (fig 1), numerous tubero- eruptive xanthomas on his knees and elbows (fig 2), and orange-yellowish discolourations in the creases of the palms (palmar xanthomas) (fig 3), soles, armpits, and in the joints of the hands.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe skin changes regressed slightly with treatment but are still distinctly prevalent.
“The skin changes re- gressed slightly with treatment but are still dis- tinctly prevalent.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPalmar xanthomas occur in type III HLP patients at a rate of 39%.
“Typical (and nearly pathognomonic) findings are palmar xanthomas (orangeyellowish discolourations of the palmar creases) which have been reported to occur in these patients at a rate of 39%.3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Feussner G, Wagner A, Kohl B, Ziegler R. Clinical features of type III hyperlipoproteinemia: analysis of 64 patients. Clin Invest 1994;71:362-6. source
Classified as probably not a substantial claim.
Interpretationnone givenFamilial apo E deficiency offers the unique opportunity to study the impact of apo E on lipoprotein metabolism and development of atherosclerosis in humans.
“Familial apo E deficiency is a rare genetic disease which offers the unique opportunity to study the impact of apo E on lipoprotein metabolism and development of atherosclerosis in hu- mans.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe proband in that other case was homozygous for this mutation, leading to a moderate form of type III HLP.
“The proband was homozygous for this mutation, leading to a moderate form of type III HLP.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Lohse P, Brewer III HB, Meng MS, Skarlatos SI, LaRosa JC, Brewer HB Jr. Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J7 Lipid Res 1992;33:1583-90. source
May combine two claims.
PremisecitationFamilial apo E deficiency is a rare genetic condition; only four independent cases have been reported.
“Familial apo E deficiency is a rare genetic disease which offers the unique opportunity to study the impact of apo E on lipoprotein metabolism and development of atherosclerosis in hu- mans.”
- Also stated in: § Abstract · plain
“This, however, is a rare genetic condition, and so far only four independent cases have been reported.8'-2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites 8'-2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Also stated in: § Abstract · plain
May combine two claims.
PremisereasoningApo E2 homozygosity is a necessary but not sufficient condition for the development of type III HLP.
“Therefore, apo E2 homozygosity is a necessary but not sufficient condition for the development of the disorder.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn one other patient with familial apo E deficiency, a point mutation in the 3' splice junction of the third intron of the apo E gene was found; as a consequence, apo E mRNA species contained chain termination codons within the intronic sequence coding for short apo E peptides that were not detectable by gel electrophoretic techniques.
“In one case a point mutation in the 3' splice junction of the third intron of the apo £ gene was found.13As a consequence, apo E mRNA species of this subject contained chain termination codons within the intronic sequence coding for short apo E peptides that were not detectable by gel electrophoretic techniques.'3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Cladaras C, Hadzopoulo-Cladaras M, Felber BK, Pavlakis G, Zannis VI. The molecular basis of a familial apo E deficiency. An acceptor splice site mutation in the third intron of the deficient apo E gene. J Biol Chem 1987;262:231015. source
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- Authors
- Feussner, G.
- Affiliations
- Heidelberg University (DE)
- Corresponding author
- Feussner, G
- Venue
- Journal of Clinical Pathology
- Publisher
- BMJ
- Published
- 1996-12
- Volume
- 49
- Issue
- 12
- Pages
- 985-989
- ISSN
- 0021-9746 (ISSN-L)
- 1472-4146
- PMC
- PMC499646
- OpenAlex
- W2157680049
- Semantic Scholar
- 1bc5e3220f50413ad5699d61da197c7df9ec4a28
- Cited by
- 10
- References
- 29
- Citations by year
- 2026: 1 · 2016: 1 · 2015: 2
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- xanthomatosis, exon 4 deletion, premature stop codon, remnant lipoproteins, atherogenic lipoproteins, atherosclerosis, lipoprotein metabolism
- MeSH terms
- Adult, Apolipoproteins E, Humans, Hyperlipoproteinemia Type III, Lipoproteins, Male, Microscopy, Electron, Xanthomatosis, Sequence Deletion
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-01.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-01.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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