Reduced psychological distress in familial chylomicronemia syndrome after patient support group intervention

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder that is associated with severe hypertriglyceridemia and complications that often include recurrent pancreatitis beginning in childhood. Patients with FCS frequently struggle to maintain normality in their lives as a consequence of the necessity to severely restrict their intake of dietary fat coupled with the constant threat of recurrent pancreatitis. Patients typically face a high level of psychological stress and anxiety in association with reduced measures of quality of life. Routine medical care for affected patients usually does not adequately address the day-to-day struggles that accompany a diagnosis of FCS, resulting in ongoing suffering for many patients. We describe herein the highly beneficial effects of a support group interaction for a patient with FCS.     

A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome

Familial chylomicronemia syndrome is characterized by severe elevation in serum triglycerides and an increased risk of acute pancreatitis. Although familial chylomicronemia syndrome is mainly caused by mutations in the lipoprotein lipase (LPL) gene, few causal mutations in other genes (ie, APOC2, APOA5, LMF1, and GPIHBP1) have also been reported. In this case report, we present the discovery of a novel mutation in the glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) gene and discuss its pathogenicity through a familial segregation study.     

Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management

Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Université de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana.     

Involvement of a homozygous exon 6 deletion of LMF1 gene in intermittent severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG), characterized by triglycerides (TG) permanently over 10 mmol/L, may correspond to familial chylomicronemia syndrome (FCS), a rare disorder. However, hypertriglyceridemic patients more often present multifactorial chylomicronemia syndrome (MCS), characterized by highly variable TG. A few nonsense variants of LMF1 gene were reported in literature in FCS patients. In this study, we described a woman with an intermittent severe HTG. NGS analysis and the sequencing of a long range PCR product revealed a homozygous deletion of 6507 base pairs in LMF1 gene, c.730-1528_898-3417del, removing exon 6, predicted to create an in-frame deletion of 56 amino acids, p.(Thr244_Gln299del). Despite an exon 6 homozygous deletion of LMF1, the patient’s highly variable lipid phenotype was suggestive of MCS diagnosis.     

家族性脂蛋白脂酶缺乏症的基因分析

目的分析中国家族性脂蛋白脂酶（ｌｉｐｏｐｒｏｔｅｉｎｌｉｐａｓｅ,ＬＰＬ）缺乏症的基因突变。方法以基因组ＤＮＡ为模板,借助聚合酶链反应扩增产物,用双脱氧末端终止法,对患者ＬＰＬ的ＤＮＡ序列进行检测。结果对ＬＰＬ基因的９个外显子测序,发现在第６外显子中一碱基发生错义突变,即６Ｇ９７９→Ａ（Ｇｌｕ２４２→Ｌｙｓ）,这是一杂合子的等位基因突变。结论ＬＰＬ基因在该位置的突变可能是导致患者ＬＰＬ活性显著降低和血清甘油三酯增高的原因。该位点的基因突变系首次报道。同时也为研究动脉粥样硬化和高脂血症等多种代谢疾病的发病机理提供了重要证据。     

Treatment of patients with familial defective apolipoprotein B-100 with pravastatin and gemfibrozil: a two-period cross-over study

Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period (8 weeks each) cross-over study with pravastatin and gemfibrozil. Cholesterol, LDL cholesterol, and apo B were reduced by 20–25% (P < 10^–4) by pravastatin and by 4–6% by gemfibrozil (pravastatin vs. gemfibrozil:P < 10^–4). Response to pravastatin was variable and not correlated to gender, age, or apo E genotype. Gemfibrozil lowered triglycerides by 25% (P < 10^–4) and raised HDL cholesterol by 11%. The effects of pravastatin on these two interrelated variables were significantly smaller. Both drugs increased Lp(a) significantly by about 10%. The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia.Abbreviations FDB familial defective apolipoprotein B-100 - LDL low density lipoprotein - VLDL very low density lipoprotein - HDL high density lipoprotein - LDL-R low density lipoprotein receptor - HMG CoA -hydroxy--methyl-glutaryl coenzyme A - FH familial hypercholesterolemia - TG triglycerides - apo B apolipoprotein B-100 - apo Al apolipoprotein Al - apo E apolipoprotein E - Lp(a) lipoprotein(a) - PCR polymerase chain reaction Correspondence to: P.S. Hansen     

Molecular analysis of familial androgen insensitivity syndrome due to replacement of glutamic acid 802 by lysine

We studied a Japanese family presenting at least two cases of complete androgen insensitivity syndrome (CAIS) and negative androgen receptor binding. The index subject showed a 46, XY karyotype and a complete female phenotype. For the purpose of further diagnosis and genetic counseling, molecular analysis of the androgen receptor (AR) gene was performed. Direct sequencing of the AR gene identified a mutation at nucleotide 2935 (A → G). This replacement was a novel missense mutation, resulting in the substitution of glutamic acid 802 by lysine which deleted a recognition site for EcoRI in exon 6 of the AR gene. We identified another affected individual, using chromosome and molecular analysis of the AR gene at exon 6. Furthermore, although heterozygote carriers could not be identified on clinical grounds, molecular identification of healthy individuals and heterozygote carriers in the family members provided definitive information for genetic counseling. We believe that the molecular analysis of familial CAIS is very informative for both the affected individuals and other family members. Received: July 31, 2000 / Accepted: August 31, 2000     

The mechanism of hyperlipidaemia in the nephrotic syndrome

The mechanism of hyperlipidaemia in the nephrotic syndrome has not been fully established. We propose that it results from hypoalbuminaemia due to inhibition of the reaction catalysed by lecithin cholesterol acyltransferase converting cholesterol of high density lipoproteins to cholesterol esters and to an inhibition of high density lipoprotein particle formation from very low density lipoproteins due to reduced activity of lipoprotein lipase.     

Closing the gap: Identification and management of familial hypercholesterolemia in an integrated healthcare delivery system

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that causes markedly elevated risk for early onset coronary artery disease. Despite availability of effective therapy, only 5–10% of affected individuals worldwide are diagnosed.ObjectiveTo develop and evaluate a novel approach for identifying and managing patients with FH in a large integrated health system with a diverse patient population, using inexpensive methods.MethodsUsing Make Early Diagnosis/Prevent Early Death (MEDPED) criteria, we created a method for identifying patients at high risk for FH within the Kaiser Permanente Northern California electronic medical record. This led to a pragmatic workflow for contacting patients, establishing a diagnosis in a dedicated FH clinic, and initiating management. We prospectively collected data on the first 100 patients to assess implementation effectiveness.ResultsNinety-three (93.0%, 95%CI: 86.1%–97.1%) of the first 100 evaluated patients were diagnosed with FH (median age = 38 years) of whom only 5% were previously recognized; 48% were taking no lipid-lowering therapy, and 7% had acute coronary symptoms. 82 underwent successful genetic testing of whom 55 (67.1%; 95%CI: 55.8%–77.1%) had a pathogenic mutation. Following clinic evaluation, 83 of 85 (97.6%) medication-eligible patients were prescribed combination lipid-lowering therapy. 20 family members in the healthcare system were diagnosed with FH through cascade testing.ConclusionsThis novel approach was effective for identifying and managing patients with undiagnosed FH. Care gaps in providing appropriate lipid-lowering therapy were successfully addressed. Further development and dissemination of integrated approaches to FH care are warranted.