Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment.

While type 1 hyperlipidemia is associated with lipoprotein lipase or apoCII deficiencies, the etiology of type 5 hyperlipidemia remains largely unknown. We explored a new candidate gene, APOA5, for possible causative mutations in a pedigree of late-onset, vertically transmitted hyperchylomicronemia. A heterozygous Q139X mutation in APOA5 was present in both the proband and his affected son but was absent in 200 controls. It was subsequently found in 2 of 140 cases of hyperchylomicronemia. Haplotype analysis suggested the new Q139X as a founder mutation. Family studies showed that 5 of 9 total Q139X carriers had hyperchylomicronemia, 1 patient being homozygote. Severe hypertriglyceridemia in 8 heterozygotes was strictly associated with the presence on the second allele of 1 of 2 previously described triglyceride-raising minor APOA5 haplotypes. Furthermore, ultracentrifugation fraction analysis indicated in carriers an altered association of Apoa5 truncated and WT proteins to lipoproteins, whereas in normal plasma, Apoa5 associated with VLDL and HDL/LDL fractions. APOB100 kinetic studies in 3 severely dyslipidemic patients with Q139X revealed a major impairment of VLDL catabolism. Lipoprotein lipase activity and mass were dramatically reduced in dyslipidemic carriers, leading to severe lipolysis defect. Our observations strongly support in humans a role for APOA5 in lipolysis regulation and in familial hyperchylomicronemia.

Association of APOA5 -1131T>C and S19W gene polymorphisms with both mild hypertriglyceridemia and hyperchylomicronemia in type 2 diabetic patients.

BACKGROUND: Two minor apolipoprotein A5 (APOA5) gene haplotypes, represented by -1131T>C and S19W polymorphisms, are strong determinants of plasma triglyceride (TG) concentration variability across human populations. Hypertriglyceridemia is frequent in type 2 diabetes (T2D) and hyperchylomicronemia is not uncommon. METHODS: We investigated the association of -1131T>C and S19W polymorphisms with diabetic dyslipidemia in 400 Caucasian T2D patients divided in 2 groups: group N with 130 normotriglyceridemics (TG<90th percentile) and group M with 270 moderately hypertriglyceridemics. A third group of 51 diabetic patients (group H) with history of hyperchylomicronemia (TG>15 mM) was also studied. RESULTS: The -1131C allele was more frequent in both mild and severe hypertriglyceridemia (20.6% vs 9.8% vs 5.0%, group H vs M vs N, p<0.001). The 19W allele was more frequent only in patients with hyperchylomicronemia (14.0% vs 6.5% vs 6.1%, group H vs M vs N, p=0.001). In group N+M, the -1131C allele was associated with higher TG (+13%, p=0.034) and lower HDLc (-10%, p=0.004). The 19W allele was only associated with lower HDLc (-9%, p=0.022). CONCLUSION: These results suggest that in T2D APOA5 polymorphisms contribute to modulate dyslipidemia. Both -1131T>C and S19W polymorphisms are associated with hyperchylomicronemia and only -1131T>C polymorphism with mild hypertriglyceridemia.

Combination of circulating antilipoprotein lipase (Anti-LPL) antibody and heterozygous S172 fsX179 mutation of LPL gene leading to chronic hyperchylomicronemia.

CONTEXT: Sporadic hyperchylomicronemia (type V hyperlipoproteinemia) results from complex interactions between genetic and environmental factors that often remain unknown. DESIGN: Upon investigation of a patient suffering from recurrent hypertriglyceridemic pancreatitis without family history or conventional secondary cause of dyslipidemia, we identified a previously unreported nonsense heterozygous lipoprotein lipase (LPL) gene mutation S172fsX179 associated with an antihuman LPL IgG. RESULTS: This autoantibody partially inhibited wild-type LPL activity in vitro. Furthermore, the patient's plasma triglyceride concentrations were efficiently decreased under immunosuppressive treatment, and this was confirmed by sequential withdrawal/reintroduction tests. CONCLUSIONS: We consider that this unique combination of a genetic defect and an autoimmune disease results in chronic major hypertriglyceridemia. Because immunosuppressive treatment can improve this dyslipidemia, assessment of anti-LPL autoantibody is worthwhile in unmanageable chronic major hypertriglyceridemia, even in the presence of a heterozygous LPL deficiency.

Clinical presentation of severe viral encephalitis with known causative agents in children: a retrospective study on 16 patients hospitalized in a pediatric intensive care unit (2008-2011).

A retrospective analysis was conducted in a French pediatric hospital in Lyon. Subjects were 16 patients diagnosed with acute viral encephalitis with identified causative agents who were admitted to the pediatric intensive care unit from 2008 to 2011. The median length of stay was 6 days. The outcome was favorable for 77% of the patients. Analysis of biological and clinical findings based on causative agents did not reveal clinical patterns or neurological findings specific to the causal viruses. Nevertheless, uncommon clinical pictures and severe neurological complications were highlighted, in particular for children with influenza-related encephalitis and herpes simplex encephalitis. This case series exemplifies the difficulties, even pitfalls, in establishing a diagnosis of encephalitis, especially in neonates. It points out significant differences in the clinical presentation of encephalitis in children compared with clinical pictures described in previously published large-scale studies on encephalitis mainly conducted in adults.