10-Year Comparative Follow-up of Familial versus Multifactorial Chylomicronemia Syndromes.

CONTEXT: The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown. OBJECTIVE: The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population. METHODS: Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up. RESULTS: Patients with FCS were younger than those with MCS (34.3 ±â€…13.6 vs 45.2 ±â€…12.6 years, P < 0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least 1 episode of acute hypertriglyceridemic pancreatitis (AHP) (hazard ratio [HR] = 3.6; P < 0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HR = 0.3; P = 0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (odds ratio [OR] = 22.8; P < 0.01 in FCS and OR = 30.3; P < 0.01 in MCS). CONCLUSION: The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.

Practical definitions of severe versus familial hypercholesterolaemia and hypertriglyceridaemia for adult clinical practice.

Diagnostic scoring systems for familial hypercholesterolaemia and familial chylomicronaemia syndrome often cannot differentiate between adults who have extreme dyslipidaemia based on a simple monogenic cause versus people with a more complex cause involving polygenic factors and an environmental component. This more complex group of patients carries a substantial risk of atherosclerotic cardiovascular disease in the case of marked hypercholesterolaemia and pancreatitis in the case of marked hypertriglyceridaemia. Complications are mainly a function of the degree of disturbance in lipid metabolism resulting in elevated lipid levels, so the added value of knowing the precise genetic cause in clinical decision making is unclear and does not lead to clinically meaningful benefit. We propose that for severe elevations of plasma low density lipoprotein cholesterol or triglyceride, the primary factor driving intervention should be the biochemical perturbation rather than the clinical risk score. This underscores the importance of expanding the definition of severe dyslipidaemias and to not rely solely on clinical scoring systems to identify individuals who would benefit from appropriate treatment approaches. We advocate for the use of simple, practical, clinical, and largely biochemically based definitions for severe hypercholesterolaemia (eg, LDL cholesterol >5 mmol/L) and severe hypertriglyceridaemia (triglyceride >10 mmol/L), which complement current definitions of familial hypercholesterolaemia and familial chylomicronaemia syndrome. Irrespective of the precise genetic cause, individuals diagnosed with severe hypercholesterolaemia and severe hypertriglyceridaemia require intensive therapy, including special consideration for new effective but more expensive therapies.

Apo C-II deficiency type Bari.

We formerly studied an Italian family with apo C-II deficiency. Two probands were homozygous for the defect (unmeasurable circulating apolipoprotein C-II and absence of C-II bands on immunoelectrophoresis). We documented the synthesis of the protein at the intestinal level in the probands with immunohistological techniques. With the purpose of investigating the molecular basis of the defect, Southern analysis, polymerase chain reaction (PCR) amplification and sequence analysis were carried out on one of the two cases. We identified a point mutation C to G transversion in the third exon of the gene causing a premature stop codon. Our hypothesis is that the truncated protein of 36 aa., instead of 79 aa., lacks its functional domain. This causes inefficiency in the activation of lipoprotein lipase (LPL) and the instability of the circulating molecule, which could have an higher catabolic rate compared to a normal protein. The faster disappearance from the circulating compartment make it unmeasurable. The mutation destroys a Rsa I site, present in the normal gene sequence. We suggest the use of this site for a rapid Restriction Fragment Length Polymorphism (RFLP) on PCR amplification products to screen this defect in the Italian population.

[Lipoprotein lipase deficiencies]. / Les déficits en lipoprotéine lipase.

Lipoprotein lipase (LPL) is an enzyme which plays a major role in the metabolism of circulating triglyceride-rich lipoproteins. It hydrolyzes chylomicron and VLDL triglycerides, thereby delivering fatty acids to tissues for storage or oxidation. In order to gain insight into the molecular basis of LPL deficiency, the structure of the LPL gene (ten exons and nine introns spanning about 30 kb) is first set out in relation to the different domains of the LPL protein. There is a high sequence homology between the aminoacids of LPL and of other lipases, such as hepatic triglyceride lipase (HL) and pancreatic lipase (PL). The PL catalytic triad Ser132, Asp156, His241 is also present in LPL. Absence of LPL activity can result from absence of LPL protein synthesis (Brunzell class I), or from the synthesis of an LPL protein devoid of enzymatic activity consequently to a mutation (class II). LPL can also be unable to bind to endothelial cells--a defect combined with deficient enzymatic activity--(class III). Among the known mutations of the LPL gene (such as nonsense, frameshift, abnormality in intron-exon junction, deletion, duplication) resulting in pathological cases, the most frequent are punctual mutations located mainly in exons 4, 5 and 6, leading to the substitution of an aminoacid for another in essential domains of LPL. The combined deficiency LPL + HL has also been described. The study of the abnormalities of the LPL gene, known only since the years 1990-1991, allows not only to better understand the pathology of LPL deficiencies, but also to point out which aminoacids play a major role in LPL activity.

Defective enzyme protein in lipoprotein lipase deficiency.

A monoclonal antibody to lipoprotein lipase (LPL) has been used in an enzyme-linked immunosorbent assay (ELISA) for LPL protein mass. Measurement of LPL immunoreactive mass in pre- and postheparin plasma distinguished three classes of abnormalities in patients with classical deficiency of lipoprotein lipase activity. The class I defect consisted of the absence of LPL immunoreactive homodimer in pre- and postheparin plasma compatible with a potential 'null allele'. Patients with a class II defect had almost no LPL immunoreactive mass in preheparin plasma but showed an increase in their LPL mass of 68 +/- 23 ng ml-1 (mean +/- SD) after heparin. Patients with the class III defect had considerable amounts of LPL immunoreactive material in preheparin plasma (159 +/- 190 ng ml-1). Heparin administration, however, caused very little additional release of LPL into the plasma (16 +/- 51 ng ml-1). Thus although both class II and class III patients had an LPL protein with abnormal catalytic activity, class III patients also appeared to have a defect in heparin binding of LPL. To test this hypothesis, postheparin plasma of classes II and III patients was analysed by heparin-Sepharose chromatography. In contrast to class II patients, the LPL immunoreactive mass of class III patients did not show affinity for the heparin and eluted in the column void volume, suggesting the class III defect is also associated with a defect in heparin binding.