Diagnosis of Familial Dysbetalipoproteinemia Based on the Lipid Abnormalities Driven by APOE2/E2 Genotype.

BACKGROUND: Familial dysbetalipoproteinemia (FDBL) is a monogenic disease due to variants in APOE with a highly variable phenotype. Current diagnostic lipid-based methods have important limitations. The objective is twofold: to define characteristics of dysbetalipoproteinemia (DBL) based on the analysis of APOE in patients from a lipid unit and in a sample from the general population, and to propose a screening algorithm for FDBL. METHODS: Lipids and APOE genotype from consecutive unrelated subjects from Miguel Servet University Hospital (MSUH) (n 3603), subjects from the general population participants of the Aragon Workers Health Study (AWHS) (n 4981), and selected subjects from external lipid units (Ext) (n 390) were used to define DBL criteria and to train and validate a screening tool. RESULTS: Thirty-five subjects from MSUH, 21 subjects from AWHS, and 31 subjects from Ext were APOE2/2 homozygous. The combination of non high-density lipoprotein cholesterol (non-HDLc)/apoB 1.7 plus triglycerides/apoB 1.35, in mg/dL (non-HDLc [mmol/L]/apolipoprotein B (apoB) [g/L] 4.4 and triglycerides [mmol/L]/apoB [g/L] 3.5), provided the best diagnostic performance for the identification of subjects with hyperlipidemia and APOE2/2 genotype (sensitivity 100 in the 3 cohorts, and specificity 92.8 [MSUH], 80.9 [AWHS], and 77.6 [Ext]). This improves the performance of previous algorithms. Similar sensitivity and specificity were observed in APOE2/2 subjects receiving lipid-lowering drugs. CONCLUSIONS: The combination of non-HDLc/apoB and triglycerides/apoB ratios is a valuable tool to diagnose DBL in patients with hyperlipidemia with or without lipid-lowering drugs. FDBL diagnosis requires DBL and the presence of a compatible APOE genotype. Most adult APOE2/2 subjects express DBL, making FDBL as common as familial hypercholesterolemia in the population.

Diagnosis of remnant hyperlipidaemia.

PURPOSE OF REVIEW: In recent years, there has been interest for the development of simplified diagnosis algorithms of dysbetalipoproteinemia (DBL) in order to avoid the complex testing associated with the Fredrickson criteria (reference method). The purpose of this review is to present recent advances in the field of DBL with a focus on screening and diagnosis. RECENT FINDINGS: Recently, two different multi-step algorithms for the diagnosis of DBL have been published and their performance has been compared to the Fredrickson criteria. Furthermore, a recent large study demonstrated that only a minority (38%) of DBL patients are carriers of the E2/E2 genotype and that these individuals presented a more severe phenotype. SUMMARY: The current literature supports the fact that the DBL phenotype is more heterogeneous and complex than previously thought. Indeed, DBL patients can present with either mild or more severe phenotypes that can be distinguished as multifactorial remnant cholesterol disease and genetic apolipoprotein B deficiency. Measurement of apolipoprotein B as well as APOE gene testing are both essential elements in the diagnosis of DBL.

Establishing the relationship between familial dysbetalipoproteinemia and genetic variants in the APOE gene.

Familial Dysbetalipoproteinemia (FD) is the second most common monogenic dyslipidemia and is associated with a very high cardiovascular risk due to cholesterol-enriched remnant lipoproteins. FD is usually caused by a recessively inherited variant in the APOE gene (ε2ε2), but variants with dominant inheritance have also been described. The typical dysbetalipoproteinemia phenotype has a delayed onset and requires a metabolic hit. Therefore, the diagnosis of FD should be made by demonstrating both the genotype and dysbetalipoproteinemia phenotype. Next Generation Sequencing is becoming more widely available and can reveal variants in the APOE gene for which the relation with FD is unknown or uncertain. In this article, two approaches are presented to ascertain the relationship of a new variant in the APOE gene with FD. The comprehensive approach consists of determining the pathogenicity of the variant and its causal relationship with FD by confirming a dysbetalipoproteinemia phenotype, and performing in vitro functional tests and, optionally, in vivo postprandial clearance studies. When this is not feasible, a second, pragmatic approach within reach of clinical practice can be followed for individual patients to make decisions on treatment, follow-up, and family counseling.

The clinical and laboratory investigation of dysbetalipoproteinemia.

Familial dysbetalipoproteinemia (type III hyperlipoproteinemia) is a potentially underdiagnosed inherited dyslipidemia associated with greatly increased risk of coronary and peripheral vascular disease. The mixed hyperlipidemia observed in this disorder usually responds well to appropriate medical therapy and lifestyle modification. Although there are characteristic clinical features such as palmar and tuberous xanthomata, associated with dysbetalipoproteinemia, they are not always present, and their absence cannot be used to exclude the disorder. The routine lipid profile cannot distinguish dysbetalipoproteinemia from other causes of mixed hyperlipidemia and so additional investigations are required for confident diagnosis or exclusion. A range of investigations that have been proposed as potential diagnostic tests are discussed in this review, but the definitive biochemical test for dysbetalipoproteinemia is widely considered to be beta quantification. Beta quantification can determine the presence of "ß-VLDL" in the supernatant following ultracentrifugation and whether the VLDL cholesterol to triglyceride ratio is elevated. Both features are considered hallmarks of the disease. However, beta quantification and other specialist tests are not widely available and are not high-throughput tests that can practically be applied to all patients with mixed hyperlipidemia. Using apolipoprotein B (as a ratio either to total or non-HDL cholesterol or as part of a multi-step algorithm) as an initial test to select patients for further investigation is a promising approach. Several studies have demonstrated a high degree of diagnostic sensitivity and specificity using these approaches and apolipoprotein B is a relatively low-cost test that is widely available on high-throughput platforms. Genetic testing is also important in the diagnosis, but it should be noted that most individuals with an E2/2 genotype do not suffer from remnant hyperlipidemia and around 10% of familial dysbetalipoproteinemia cases are caused by rarer, autosomal dominant mutations in APOE that will only be detected if the gene is fully sequenced. Wider implementation of diagnostic pathways utilizing apo B could lead to more rational use of specialist investigations and more consistent detection of patients with dysbetalipoproteinemia. Without the application of a consistent evidence-based approach to identifying dysbetalipoproteinemia, many cases are likely to remain undiagnosed.

Evaluation of the Non-HDL Cholesterol to Apolipoprotein B Ratio as a Screening Test for Dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia is associated with the accumulation of remnant lipoproteins and premature cardiovascular disease. Identification of dysbetalipoproteinemia is important because family members may be affected. Diagnostic testing involves demonstration of ß-lipoprotein in the VLDL fraction or characterization of apo E3. These investigations are complex and relatively expensive. The ratios of apo B to total cholesterol and triglycerides have been proposed as screening tests. However, the ratio of non-HDL cholesterol to apo B (NHDLC/apoB) could offer improved performance as the confounding effect of variations in HDL cholesterol is removed. METHODS: We evaluated NHDLC/apoB as a screening test for dysbetalipoproteinemia, using ß-quantification analysis as a reference standard. Data from 1637 patients referred over a 16-year period for ß quantification were reviewed retrospectively. In 63 patients, diagnostic criteria for dysbetalipoproteinemia (VLDL cholesterol/triglyceride ratio ≥0.69 and presence of ß-VLDL) were fulfilled, and 1574 patients had dysbetalipoproteinemia excluded. RESULTS: Mean NHDLC/apoB in patients with dysbetalipoproteinemia was 7.3 mmol/g (SD, 1.5 mmol/g) and with dysbetalipoproteinemia excluded was 4.0 mmol/g (SD, 0.5 mmol/g). The optimum cutoff of >4.91 mmol/g achieved a diagnostic sensitivity of 96.8% (95% CI, 89.0-99.6) and specificity of 95.0% (95% CI, 93.8-96.0). NHDLC/apoB offered improved performance compared to total cholesterol/apoB [diagnostic sensitivity 92.1% (95% CI, 82.4-97.4) and specificity 94.5% (95% CI, 93.2-95.6) with a cutoff of >6.55 mmol/g]. NHDL/apoB reference ranges were not sex-dependent, although there was a significant difference between men and women for total cholesterol/apoB. CONCLUSIONS: NHDLC/apoB offers a simple first-line test for dysbetalipoproteinemia in selecting patients with mixed hyperlipidemia for more complex investigations.

Hyperlipoproteinemia type 3: the forgotten phenotype.

Hyperlipoproteinemia type 3 (HLP3) is caused by impaired removal of triglyceride-rich lipoproteins (TGRL) leading to accumulation of TGRL remnants with abnormal composition. High levels of these remnants, called ß-VLDL, promote lipid deposition in tuberous xanthomas, atherosclerosis, premature coronary artery disease, and early myocardial infarction. Recent genetic and molecular studies suggest more genes than previously appreciated may contribute to the expression of HLP3, both through impaired hepatic TGRL processing or removal and increased TGRL production. HLP3 is often highly amenable to appropriate treatment. Nevertheless, most HLP3 probably goes undiagnosed, in part because of lack of awareness of the relatively high prevalence (about 0.2% in women and 0.4-0.5% in men older than 20 years) and largely because of infrequent use of definitive diagnostic methods.

[Familial type III hyperlipoproteinemia].

Familial type III hyperlipoproteinemia(HLP) is characterized by increased plasma triglyceride(TG) and plasma remnant lipoproteins(chyromicron remnants and VLDL remnants i.e. IDL). Remnants predispose affected subjects to premature or accelerated atherosclerosis. Clinical features of type III HLP with apo E2/2 genotype are examined in 26 Japanese patients. Mean levels of plasma TG, total cholesterol, LDL cholesterol and remnant cholesterol(RLP-C) were 374, 256, 74 and 49 mg/dL, respectively. High plasma RLP-C levels above 30 mg/dL and high plasma RLP-C/plasma TG ratio above 0.1 are very useful for diagnosis of type III HLP. Fifty-four point two percent of the patients had diabetes mellitus and 66.2 % of the patients had metabolic syndrome. Diabetes and obesity contribute to the occurrence of type III HLP with apo E2/2 genotype in Japan. Coronary heart disease(CHD) occurred in 41.7% of the patients. Type III HLP is strongly associated with atherosclerosis in Japan.

Dysbetalipoproteinemia: Differentiating Multifactorial Remnant Cholesterol Disease From Genetic ApoE Deficiency.

CONTEXT: Dysbetalipoproteinemia (DBL) is characterized by the accumulation of remnant lipoprotein particles and associated with an increased risk of cardiovascular and peripheral vascular disease (PVD). DBL is thought to be mainly caused by the presence of an E2/E2 genotype of the apolipoprotein E (APOE) gene, in addition to environmental factors. However, there exists considerable phenotypic variability among DBL patients. OBJECTIVE: The objectives were to verify the proportion of DBL subjects, diagnosed using the gold standard Fredrickson criteria, who did not carry E2/E2 and to compare the clinical characteristics of DBL patients with and without E2/E2. METHODS: A total of 12 432 patients with lipoprotein ultracentrifugation as well as APOE genotype or apoE phenotype data were included in this retrospective study. RESULTS: Among the 12 432 patients, 4% (n = 524) were positive for Fredrickson criteria (F+), and only 38% (n = 197) of the F+ individuals were E2/E2. The F+ E2/E2 group had significantly higher remnant cholesterol concentration (3.44 vs 1.89 mmol/L) and had higher frequency of DBL-related xanthomas (24% vs 2%) and floating beta (95% vs 11%) than the F+ non-E2/E2 group (P < 0.0001). The F+ E2/E2 group had an independent higher risk of PVD (OR 11.12 [95% CI 1.87-66.05]; P = 0.008) events compared with the F+ non-E2/E2 group. CONCLUSION: In the largest cohort of DBL worldwide, we demonstrated that the presence of E2/E2 was associated with a more severe DBL phenotype. We suggest that 2 DBL phenotypes should be distinguished: the multifactorial remnant cholesterol disease and the genetic apoE deficiency disease.

A simplified diagnosis algorithm for dysbetalipoproteinemia.

BACKGROUND: Dysbetalipoproteinemia (DBL) is a disease of remnant lipoprotein accumulation caused by a defective apolipoprotein (apo) E and is associated with a considerable atherogenic burden. However, there exists confusion concerning the diagnosis of this disorder, and as a consequence, misdiagnosis is frequent. OBJECTIVE: The objective of the present study is to propose an algorithm for the diagnosis of DBL using simple clinical variables. METHODS: In a large cohort of 12,434 dyslipidemic patients, 4891 patients presented with mixed dyslipidemia (total cholesterol ≥ 5.2 mmol/L [200 mg/dL] and triglycerides ≥ 2.0 mmol/L [175 mg/dL]), and 188 DBL patients were identified based on the presence of an elevated very-low-density lipoprotein cholesterol/triglyceride ratio and were carriers of apoE2/E2. The APOE genotype or phenotype as well as the lipoprotein ultracentrifugation results were available for all patients. RESULTS: Among the laboratory variables associated with the lipid profile, the non-high-density lipoprotein cholesterol (HDL-C)/apoB ratio was the best predictor of DBL diagnosis based on the C-statistic. Previous proposed criteria had either low sensitivity or low specificity for the diagnosis of DBL. Using a non-HDL-C/apoB cut point of 3.69 mmol/g (1.43 in conventional units) followed by the presence of apoE2/E2 resulted in a good sensitivity (94.8%), negative predictive value (99.8%), specificity (99.6%), positive predictive value (88.5%), accuracy (99.4%), and area under the curve (0.97 [0.95-0.99]) for the prediction of DBL. CONCLUSION: We therefore propose a 3-step algorithm for the diagnosis of DBL using total cholesterol and triglycerides as a first step, the non-HDL-C/apoB ratio as a second screening criterion and finally the APOE genotype, lipoprotein ultracentrifugation, or electrophoresis as a confirmatory test.

ApoB in clinical care: Pro and Con.

Whether apoB adds significantly to the assessment of the risk and therapy of the atherogenic dyslipoproteinemias has been vigorously contested over many years. That trapping of apoB lipoprotein particles within the arterial wall is fundamental to the initiation and maturation of atherosclerotic lesions within the arterial wall is now widely accepted. At the same time, the concept that primary prevention should be based on the risk of a cardiovascular event, a measure that integrates the effects of age, sex, blood pressure, lipids and other factors, has also become widely accepted. Within the risk framework, the issue becomes whether apoB adds significantly to the assessment of risk. On the other hand, it can be argued that the risk model undervalues how important a role that LDL and blood pressure play as causes of atherosclerosis and that when considered as causes, the importance of apoB emerges. These are the two sides of the debate that will be presented in the article that follows: one will highlight the pros of measuring apoB, the second the cons. The reader can make up his or her mind which side of the issue they favour.

Familial dysbetalipoproteinemia: a potentially fatal disorder.

Familial dysbetalipoproteinemia is an inherited disorder in which both cholesterol and triglycerides are elevated in the plasma of the blood, which pre-disposes people to coronary artery disease and peripheral vascular disease. We report two young boys with multiple cutaneous xanthomas and grossly abnormal serum cholesterol and triglycerides. Two of the family members had died of cardiovascular accidents in young age and rest of the family members had deranged lipid profile. Patients were managed with lipid lowering drugs and fat restriction diet. All family members were counseled and advised regular exercise and follow-up.

The spectrum of type III hyperlipoproteinemia.

BACKGROUND: Type III hyperlipoproteinemia is a highly atherogenic dyslipoproteinemia characterized by hypercholesterolemia and hypertriglyceridemia due to markedly increased numbers of cholesterol-enriched chylomicron and very-low-density lipoprotein (VLDL) remnant lipoprotein particles. Type III can be distinguished from mixed hyperlipidemia based on a simple diagnostic algorithm, which involves total cholesterol, triglycerides, and apolipoprotein B (apoB). However, apoB is not measured routinely. OBJECTIVE: The objective of the present study was to determine if patients with type III could be distinguished from mixed hyperlipidemia based on lipoprotein lipids. METHODS: Classification was based first on total cholesterol and triglyceride and then on the apoB diagnostic algorithm using apoB plus total cholesterol plus triglycerides, and validated by sequential ultracentrifugation. Four hundred and forty normals, 637 patients with hypertriglyceridemia, and 714 with hypertriglyceridemia and hypercholesterolemia were studied. Plasma lipoproteins were separated by sequential ultracentrifugation and heparin-manganese precipitation. Cholesterol, triglyceride, and apoB were measured in plasma and isolated lipoprotein fractions. RESULTS: Of the 1351 patients with hypertriglyceridemia, 49 had type III hyperlipoproteinemia, as diagnosed by the apoB algorithm and validated by ultracentrifugation. Plasma triglycerides were higher in the type III subjects: 4.16 mmol/L (3.35-6.08, 25th-75th percentile), but there was considerable overlap with the hypertriglyceridemic subjects 2.65 mmol/L (1.91-4.20, 25th-75th percentile) and the combined hyperlipidemic subjects 3.02 mmol/L (2.07-5.32, 25th-75th percentile). Similarly, total cholesterol was 4.79 mmol/L (4.31-5.58, 25th-75th percentile) for type III vs 5.5 mmol/L (4.64-5.78, 25th-75th percentile) and 7.02 mmol/L (6.39-7.96, 25th-75th percentile), respectively. By contrast, as identified by the apoB algorithm, the VLDL-C/TG, VLDL-C/VLDL-TG, VLDL-C/VLDL apoB, and VLDL apoB/LDL apoB ratios were all higher in type III than in the other hypertriglyceridemic dyslipoproteinemias with the exception of type V as diagnosed by the apoB algorithm. CONCLUSION: Cholesterol and triglycerides cannot reliably distinguish type III hyperlipoproteinemia from mixed hyperlipidemia. Adding apoB and applying the apoB algorithm makes reliable diagnosis possible and easy. However, unless apoB is introduced into routine clinical care, type III hyperlipoproteinemia will often not be recognized. Given the cardiovascular risk associated with type III and its responsiveness to treatment, this should not be acceptable.

Serum remnant lipoprotein cholesterol/triglyceride ratio as an index for screening familial type III hyperlipidaemia.

BACKGROUND: An elevated serum remnant lipoprotein cholesterol (RLP-C)/triglyceride (TG) ratio has not been evaluated as an index of familial type III hyperlipidaemia defined by the presence of beta-VLDL and apolipoprotein (Apo) E2/2 phenotype in the Japanese hyperlipidaemic population. METHODS: Serum lipids and lipoproteins from 514 individuals (200 men and 314 women, mean age 58 years) with total cholesterol >6.22 mmol/L and TG between 2.26 mmol/L and 9.04 mmol/L, selected from 25,080 subjects visiting the clinics for health checkup were analysed for a possible relationship with familial type III hyperlipoproteinaemia. RESULTS: Median RLP-C concentration and RLP-C/TG ratio were 0.30 and 0.11 mmol/L, respectively. When compared between subjects with (31 cases) and without (483 cases) a broad-beta band on electrophoresis, the RLP-C concentrations and RLP-C/TG ratio were 0.77 +/- 0.43 mmol/L versus 0.34 +/- 0.16 mmol/L (P<0.0001) and 0.15 +/- 0.023 versus 0.11 +/- 0.027 (P<0.0001), respectively. Three cases with broad-beta band positive (the presence of beta-VLDL) showed RLP-C/TG ratio greater than 0.23 and RLP-C greater than 0.78 mmol/L, suggestive of type III hyperlipoproteinaemia, despite a lack of characteristic Apo E2/2 homozygosity. Cases with Apo E/Apo CIII ratio greater than 1.0 were not detected in this study group. CONCLUSION: Serum RLP-C concentration and RLP-C/TG ratio, together with Apo E/Apo CIII ratio appear to be useful for screening familial type III hyperlipidaemia in the Japanese hyperlipidaemic population.

Comparison of Lipoprotein Electrophoresis and Apolipoprotein E Genotyping in Investigating Dysbetalipoproteinemia.

Dysbetalipoproteinemia is often associated with apolipoprotein E2E2 homozygosity; however, lipoprotein electrophoresis may also be used to assist in the diagnosis. The aim of this study was to compare apolipoprotein E (apo E) genotyping and lipoprotein electrophoresis in investigating dysbetalipoproteinemia. Data were collected over a three-year period from a lipid clinic in a tertiary referral centre and reviewed for apo E genotyping and lipoprotein electrophoresis. Sixty-two patients had both apo E genotyping and lipoprotein electrophoresis. Of these, 16 patients showed broad beta band on electrophoresis. However, only 3 of them had apo E2E2 homozygosity on genotyping. Lipoprotein electrophoresis and apo E genotyping results showed poor concordance. This was primarily due to visual interpretation error of lipoprotein electrophoresis which may over diagnose dysbetalipoproteinemia.

Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy.

Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E gene (APOE). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.

Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder.

PURPOSE OF REVIEW: To review pathophysiological, epidemiological and clinical aspects of familial dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. RECENT FINDINGS: Familial dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most familial dysbetalipoproteinemia patients are homozygous for apolipoprotein ε2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although familial dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an ε2ε2 genotype 15% develops familial dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of familial dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of familial dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in familial dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. SUMMARY: Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.

Tuberous xanthomas associated with olanzapine therapy and hypertriglyceridemia in the setting of a rare apolipoprotein E mutation.

OBJECTIVE: To describe a patient with tuberous xanthomas and high levels of cholesterol and triglycerides, who was found to have type III hyperlipoproteinemia (HLP) and a rare apolipoprotein E (apoE) mutation. METHODS: We present a case report with extensive clinical, laboratory, and genetic documentation. RESULTS: A 33-year-old African American man presented for evaluation of hypertriglyceridemia. His medical history was remarkable for schizophrenia necessitating ongoing olanzapine therapy for the past 6 years. A few months after olanzapine treatment was begun, he noted the development of nontender, firm, papular skin lesions on his elbows and knees. His family history was negative for lipid disorders or premature vascular disease. Physical examination revealed the presence of prominent tuberous xanthomas on both elbows and knees. Results of a lipid panel demonstrated a total cholesterol level of 374 mg/dL (9.7 mmol/L) and triglycerides of 828 mg/dL (9.3 mmol/L). A work-up for causes of secondary hyper-triglyceridemia was negative. Results of apoE genotyping by a commercial laboratory showed the E3/E3 genotype, based on gene sequencing at codons 112 and 158. Because the skin lesions were typical for type III HLP, his entire apoE gene was sequenced. This analysis revealed an apoE2/E2 (arginine 145 to cysteine) mutation, previously reported to be a rare cause of type III HLP in 5 patients of African descent. Triglyceride-lowering therapy with gem-fibrozil was initiated, in addition to lifestyle modification. At follow-up several months later, total cholesterol was 276 mg/dL (7.14 mmol/L) and triglycerides were 479 mg/dL (5.41 mmol/L). CONCLUSION: We speculate that olanzapine therapy, with its known metabolic side effects, exacerbated this patient's underlying lipoprotein metabolic abnormality. To our knowledge, this is the first report of an association between olanzapine therapy and tuberous xanthomas and the sixth report of this rare apoE2/E2 (arginine 145 to cysteine) mutation in the literature.