Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia.

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions.

Biochemical, Clinical, and Genetic Characteristics of Mexican Patients with Primary Hypertriglyceridemia, Including the First Case of Hyperchylomicronemia Syndrome Due to GPIHBP1 Deficiency.

Primary hypertriglyceridemia (PHTG) is characterized by a high concentration of triglycerides (TG); it is divided between familial hyperchylomicronemia syndrome and multifactorial chylomicronemia syndrome. In Mexico, hypertriglyceridemia constitutes a health problem in which the genetic bases have been scarcely explored; therefore, our objective was to describe biochemical-clinical characteristics and variants in the APOA5, GPIHBP1, LMF1, and LPL genes in patients with primary hypertriglyceridemia. Thirty DNA fragments were analyzed using PCR and Sanger sequencing in 58 unrelated patients. The patients' main clinical-biochemical features were hypoalphalipoproteinemia (77.6%), pancreatitis (18.1%), and a TG median value of 773.9 mg/dL. A total of 74 variants were found (10 in APOA5, 16 in GPIHBP1, 34 in LMF1, and 14 in LPL), of which 15 could be involved in the development of PHTG: 3 common variants with significative odds and 12 heterozygous rare pathogenic variants distributed in 12 patients. We report on the first Mexican patient with hyperchylomicronemia syndrome due to GPIHBP1 deficiency caused by three variants: p.R145*, p.A154_G155insK, and p.A154Rfs*152. Moreover, eleven patients were heterozygous for the rare variants described as causing PHTG and also presented common variants of risk, which could partially explain their phenotype. In terms of findings, two novel genetic variants, c.-40_-22del LMF1 and p.G242Dfs*10 LPL, were identified.

Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

Características fundoscópicas en tres casos de hiperquilomicronemia familiar / Fundoscopic characteristics in three cases of familial hyperchylomicronaemia

CASO CLÍNICO: Presentamos tres casos de pacientes con hiperquilomicronemia familiar y lipemia retinalis, y analizamos de forma comparada las características fundoscópicas de cada uno de ellos. DISCUSIÓN: El aspecto característico del fondo retiniano en color salmón-pálido corresponde con grados severos de lipemia retinalis. Los hallazgos relativos a la tonalidad del árbol vascular en segmentos distales constituyen probablemente el dato exploratorio que mejor orienta el diagnóstico oftalmológico en niveles inferiores de hipertrigliceridemia

CASES REPORT: Three cases are presented of patients with familial hyperchylomicronaemia and lipaemia retinalis, in whom an analysis is made of the fundoscopic characteristics of each of them. DISCUSSION: The typical appearance of the retinal fundus is pale salmon coloured and corresponds to levels of severe lipaemia retinalis. As regards the findings, the vascular tree tonality is probably the best exploratory evidence to help in the ophthalmological diagnosis

Genetics of Hypertriglyceridemia.

Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ~1 in 600 and is at least 50-100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or gene-environment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.

The burden of familial chylomicronemia syndrome in Canadian patients.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. OBJECTIVE: To understand the burden of illness of FCS on Canadian patients' lives. METHODS: IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. RESULTS: A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12 months, 46% of patients had an FCS-related hospitalization, averaging 3 nights' stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (> 75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%). CONCLUSIONS: This study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.

A lipoprotein lipase-GPI-anchored high-density lipoprotein-binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome.

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL-GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL-GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL-GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS.

Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo.

OBJECTIVE: Fatty acid uptake and oxidation characterize the metabolism of alternatively activated macrophage polarization in vitro, but the in vivo biology is less clear. We assessed the roles of LpL (lipoprotein lipase)-mediated lipid uptake in macrophage polarization in vitro and in several important tissues in vivo. Approach and Results: We created mice with both global and myeloid-cell specific LpL deficiency. LpL deficiency in the presence of VLDL (very low-density lipoproteins) altered gene expression of bone marrow-derived macrophages and led to reduced lipid uptake but an increase in some anti- and some proinflammatory markers. However, LpL deficiency did not alter lipid accumulation or gene expression in circulating monocytes nor did it change the ratio of Ly6Chigh/Ly6Clow. In adipose tissue, less macrophage lipid accumulation was found with global but not myeloid-specific LpL deficiency. Neither deletion affected the expression of inflammatory genes. Global LpL deficiency also reduced the numbers of elicited peritoneal macrophages. Finally, we assessed gene expression in macrophages from atherosclerotic lesions during regression; LpL deficiency did not affect the polarity of plaque macrophages. CONCLUSIONS: The phenotypic changes observed in macrophages upon deletion of Lpl in vitro is not mimicked in tissue macrophages.

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase.

The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant (kon) for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

Clinical and biochemical features of different molecular etiologies of familial chylomicronemia.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins. OBJECTIVES: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). METHODS: Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. RESULTS: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparin LPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels. CONCLUSION: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients.

Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder with loss of function mutations of lipoprotein lipase resulting in hypertriglyceridemia and accumulation of chylomicrons in plasma, often leading to acute pancreatitis. The mainstay of treatment is a specialized very-low-fat diet. Even adhering to the diet, some patients may experience high triglycerides and pancreatitis. There currently are no comprehensive dietary guidelines. OBJECTIVE: To report best practices and develop comprehensive dietary guidelines for nutrition therapy in patients with FCS. METHODS: Registered dietitian nutritionists (RDNs) convened to develop this report based on experience treating patients with FCS and a review of current literature on the topic. One author provided a patient perspective of living with FCS. RESULTS: This report provides guidelines and rationales for nutrition therapy associated with FCS across the life span. The top global guidelines are to (1) limit fat to <15 to 20 g per day (<10%-15% of total daily energy intake); (2) meet recommendations for essential fatty acids: α-linolenic acid and linoleic acid; (3) choose complex carbohydrate foods while limiting simple and refined carbohydrate foods; (4) supplement with fat-soluble vitamins, minerals, and medium-chain triglyceride oil, as needed; (5) adjust calories for weight management. Recommended foods include vegetables, whole grains, legumes, lean protein foods, fruits in limited amounts, and fat-free milk products without added sugars. Foods to avoid include alcohol and products high in sugar. CONCLUSIONS: These patient-centered nutrition guidelines provide guidance to help patients adhere to the recommended diet and optimize nutritional needs.

The burden of familial chylomicronemia syndrome: Results from the global IN-FOCUS study.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by a deficiency of lipoprotein lipase leading to extreme hypertriglyceridemia. Patients' burden of illness and quality of life have been poorly addressed in the literature. OBJECTIVE: To understand the ways in which FCS impacts patients' lives. METHODS: Investigation of Findings and Observations Captured in Burden of Illness Survey (IN-FOCUS) was a global web-based survey open to patients with FCS. Survey questions captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. RESULTS: Of 166 patients in 10 countries, 62% were from the United States and 70% were male. Median age at the time of the survey was 33 years, and median age at diagnosis was 9 years. Patients saw a mean of 5 physicians from different specialties before their FCS diagnosis and experienced multiple physical, emotional, and cognitive symptoms on a daily to monthly basis; 40% were admitted to the hospital in the past year. A lifetime mean of 13 episodes occurred in the 40% of patients with FCS-related acute pancreatitis. Most patients (>90%) found managing fat intake to be difficult, and 53% experienced symptoms despite adherence to their diets. FCS impacted employment status (94%), emotional/mental well-being (58%-66%), and social relationships (68%-82%). CONCLUSIONS: Patients with FCS experience significant clinical and psychosocial burdens that reduce their quality of life and limit employment and social interactions. Increased awareness among healthcare professionals of the multifaceted nature of the FCS disease burden may help expedite diagnosis and timely institution of treatment and broaden management considerations.

Lipoprotein Lipase Deficiency Impairs Bone Marrow Myelopoiesis and Reduces Circulating Monocyte Levels.

OBJECTIVE: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery. APPROACH AND RESULTS: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/Ghi). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density. CONCLUSIONS: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation.

Cell therapy could be a potential way to improve lipoprotein lipase deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is an autosomal recessive genetic disorder characterized by extreme hypertriglyceridemia, with no cure presently available. The purpose of this study was to test the possibility of using cell therapy to alleviate LPL deficiency. METHODS: The LPL coding sequence was cloned into the MSCV retrovirus vector, after which MSCV-hLPL and MSCV (empty construct without LPL coding sequence) virion suspensions were made using the calcium chloride method. A muscle cell line (C2C12), kidney cell line (HEK293T) and pre-adipocyte cell line (3 T3-L1) were transfected with the virus in order to express recombinant LPL in vitro. Finally, each transfected cell line was injected subcutaneously into nude mice to identify the cell type which could secret recombinant LPL in vivo. Control cells were transfected with the MSCV empty vector. LPL activity was analyzed using a radioimmunoassay. RESULTS: After virus infection, the LPL activity at the cell surface of each cell type was significantly higher than in the control cells, which indicates that all three cell types can be used to generate functional LPL. The transfected cells were injected subcutaneously into nude mice, and the LPL activity of the nearby muscle tissue at the injection site in mice injected with 3 T3-L1 cells was more than 5 times higher at the injection sites than at non-injected control sites. The other two types of cells did not show this trend. CONCLUSION: The subcutaneous injection of adipocytes overexpressing LPL can improve the LPL activity of the adjacent tissue of nude mice. This is a ground-breaking preliminary study for the treatment of LPL deficiency, and lays a good foundation for using cell therapy to correct LPL deficiency.

Incidental finding of severe hypertriglyceridemia in children. Role of multiple rare variants in genes affecting plasma triglyceride.

BACKGROUND: The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL). OBJECTIVE: Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. METHODS: We performed the parallel sequencing of 20 plasma TG-related genes. RESULTS: Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant. CONCLUSIONS: Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG.

The impact of lipoprotein lipase deficiency on health-related quality of life: a detailed, structured, qualitative study.

BACKGROUND: Lipoprotein lipase deficiency (LPLD) is an autosomal recessive inherited disorder caused by loss-of-function mutations in genes involved in the lipoprotein lipase pathway. It is characterised by chylomicronaemia, severe hypertriglyceridaemia and an increased risk of recurrent pancreatitis that often requires hospitalisation. This research aimed to improve our understanding of the debilitating impact that LPLD has on the daily lives of patients and their families. METHODS: The research comprised a 2-h interview with the patient and, where possible, a 1-h interview with a family member; a 1-week pre- and post-interview task (written and/or video diary); and a 30-45-min follow-up telephone interview. Feelings and thoughts at each stage of the disease journey were captured on a 0-10 rating scale, while the impact of disease on overall health status was measured via the EuroQoL 5 domains, 3 levels (EQ-5D-3L) questionnaire (descriptive and visual analogue scale). RESULTS: Of four patients identified, three (two female, one male) were recruited to participate in the study; the male patient did not complete the pre-interview task or consent to a family member interview. Demographics and medical history differed among patients in terms of age at symptom onset, their journey to LPLD diagnosis, treatments, the number of attacks of pancreatitis and lengths of hospitalisations. Health-related quality of life, assessed by the EQ-5D-3L, was poor during acute attacks of pancreatitis but was minimally impacted by their condition at interview. Patients described feeling apprehensive, frightened, anxious, depressed or frustrated during and after hospitalisations; spouses of the two female patients also reported being worried or afraid. LPLD affected many aspects of daily living, including diet; socialising and building relationships; state of mind (fear of another attack of pancreatitis or lack of disease control); college and working life (through absenteeism and consequent financial implications); and being reliant on family and friends for support. CONCLUSIONS: The interviews of the three patients with LPLD highlighted several concerns and emphasised the need for improved education, support, dietary advice and appropriate disease management. Additional support services would ease the fear and uncertainty surrounding attacks of pancreatitis, and would allow for improved treatment during hospitalisations.

Lipoprotein lipase deficiency leads to α-synuclein aggregation and ubiquitin C-terminal hydrolase L1 reduction.

We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.

Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain.

GPIHBP1, a glycosylphosphatidylinositol-anchored glycoprotein of microvascular endothelial cells, binds lipoprotein lipase (LPL) within the interstitial spaces and transports it across endothelial cells to the capillary lumen. The ability of GPIHBP1 to bind LPL depends on the Ly6 domain, a three-fingered structure containing 10 cysteines and a conserved pattern of disulfide bond formation. Here, we report a patient with severe hypertriglyceridemia who was homozygous for a GPIHBP1 point mutation that converted a serine in the GPIHBP1 Ly6 domain (Ser-107) to a cysteine. Two hypertriglyceridemic siblings were homozygous for the same mutation. All three homozygotes had very low levels of LPL in the preheparin plasma. We suspected that the extra cysteine in GPIHBP1-S107C might prevent the trafficking of the protein to the cell surface, but this was not the case. However, nearly all of the GPIHBP1-S107C on the cell surface was in the form of disulfide-linked dimers and multimers, whereas wild-type GPIHBP1 was predominantly monomeric. An insect cell GPIHBP1 expression system confirmed the propensity of GPIHBP1-S107C to form disulfide-linked dimers and to form multimers. Functional studies showed that only GPIHBP1 monomers bind LPL. In keeping with that finding, there was no binding of LPL to GPIHBP1-S107C in either cell-based or cell-free binding assays. We conclude that an extra cysteine in the GPIHBP1 Ly6 motif results in multimerization of GPIHBP1, defective LPL binding, and severe hypertriglyceridemia.

Hyperlipidemia resulting in abnormal density and signal intensity of blood in a neonate with lipoprotein lipase deficiency.

We present the imaging findings in an 8-week-old infant with LPL deficiency. Due to markedly increased lipoproteins in the serum, abnormal hypodensity and abnormal T1-weighted hyperintensity were identified in the dural venous sinuses and medullary veins.