SERUM LIPID AND APOLIPOPROTEIN A AND B LEVELS IN FAMILIAL HYPERCHOLESTEROLEMIA

Serum lipid and apolipoprotein A (apo A) and B (apo B) levels were studied in a family with familial hypercholesterolemia (FH), which comprised two heterozygous parents, five heterozygous children, one homozygote and one normal child. Lipid levels were compared with those of age- and sex-matched normal controls. All subjects with FH had total serum cholesterol and low density lipoprotein-cholesterol (LDL-C) levels greater than the 90th percentile value for the reference range. High density lipoprotein-cholesterol (HDL-C) levels were less than the corresponding 13th percentile in heterozygous subjects. The homozygous child had grossly elevated levels of LDL-C and apo B, and very low levels of HDL-C and apo A. The most powerful discriminating variable between normal, heterozygous and homozygous family members was the LDL-C/HDL-C ratio.     

Molecular screening of the glucokinase gene in familial Type 2 (non-insulin-dependent) diabetes mellitus

Summary The glucokinase locus has been implicated by linkage studies in several Caucasian pedigrees with early onset, autosomal dominant diabetes, and mutations have been identified in a large number of these pedigrees. Although mutations have been reported in some pedigrees with late onset Type 2 (non-insulin-dependent) diabetes mellitus, linkage studies of typical familial Type 2 diabetes did not suggest a major role for this locus. Nonetheless, linkage studies were consistent with the hypothesis that mutations of the glucokinase gene were responsible for the pathogenesis of Type 2 diabetes in a minority of pedigrees or one gene in a polygenic disorder. To systematically address this hypothesis, we examined 60 diabetic members of 18 pedigrees ascertained for two or more Type 2 diabetic siblings and eight unrelated diabetic spouses. Initially, the coding regions from each of the 11 glucokinase exons were examined by the sensitive technique of single strand conformation polymorphism analysis to screen for single nucleotide substitutions. Subsequently, we also sequenced each exon from an affected member of the single pedigree in which a glucokinase allele was most likely to segregate with diabetes. Single strand conformation polymorphism analysis detected only three variants, none of which altered the amino acid sequence. No coding or splice site mutations were detected. Likewise, no additional mutations were detected upon direct sequence analysis. However, additional screening of promoter and 3′ untranslated regions detected a variant pattern in the untranslated region of exon 10 which appeared to segregate with diabetes and impaired glucose tolerance in one pedigree. Sequence analysis demonstrated the deletion of a cytosine in exon 10 at position 906, but this deletion was not associated with Type 2 diabetes among unrelated spouses, was not linked to diabetes, and was not associated with significant elevations of fasting glucose or insulin among non-diabetic pedigree members. Similarly, two common variants in the islet promoter did not segregate with diabetes. We conclude that among typical familial Type 2 diabetes in a population representative of Northern European Caucasians, glucokinase mutations are an unlikely cause of diabetes. [Diabetologia (1994) 37: 182–187] Received: 10 June 1993 and in revised form: 20 August 1993     

Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical,genetic and atherosclerotic burden profile

Background and aims

Familial hypercholesterolemia (FH) is underdiagnosed and public cholesterol screening may be useful to find new subjects. In this study, we aim to investigate the prevalence of FH patients in a hospital screening program and evaluate their atherosclerotic burden using intima-media thickness (IMT).

Long-term follow-up and successful treatment of pulmonary alveolar proteinosis without hypercholesterolemia with statin therapy: a case report

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy is a novel treatment for PAP with hypercholesterolemia. However, this treatment has never been described in a patient without hypercholesterolemia. Here, we present a case of successful treatment with atorvastatin for a patient with possibly unclassified PAP without hypercholesterolemia who responded poorly to whole lung lavage therapy and inhaled granulocyte-macrophage colony-stimulating factor. After 18 months of atorvastatin treatment, the patient experienced improvements in dyspnea, radiographic abnormalities and pulmonary function. The present case study supports the feasibility of statin therapy for PAP regardless of the level of cholesterol.     

Apolipoprotein E and familial longevity

Exceptional longevity is associated with substantial heritability. The ?4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ?2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ?4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE ?2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ?4 allele and increase in the frequency of the ?2 allele contribute to longevity.     

Phenotypic characterization and predictive analysis of p.Asp47Asn LDL receptor mutation associated with Familial Hypercholesterolemia in a Chilean population

BackgroundFamilial hypercholesterolemia (FH) is an inherited disorder mainly caused by mutations in the LDL receptor (LDL-R) and characterized by elevation of low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease.ObjectiveIn this study, we evaluated the clinical phenotype of the p.Asp47Asn, described as an uncertain pathogenic variant, and its effect on the structure of LDL-R and ligand interactions with apolipoproteins.Methods27 children and adolescents with suspected FH diagnosis were recruited from a pediatric endocrinology outpatient clinic. Blood samples were collected after 12 h fasting for lipid profile analysis. DNA sequencing was performed for six FH-related genes by Ion Torrent PGM platform and copy number variation by MLPA. For index cases, a familial cascade screening was done restricted to the same mutation found in the index case. In silico analysis were developed to evaluate the binding capacity of LDL-R to apolipoproteins B100 and E.ResultsLipid profile in children and adolescents demonstrated higher LDL-C levels in p.Asp47Asn carriers compared to the wild type genotype. In silico analysis predicted a reduction in the binding capacity of the ligand-binding modules LA1-2 of p.Asp47Asn LDL-R for ApoB100 and ApoE, which was not produced by local structural changes or folding defects but as a consequence of a decreased apparent affinity for both apolipoproteins.ConclusionThe clinical phenotype and the structural effects of p.Asp47Asn LDL-R mutation suggest that this variant associates to FH.     

Prognostic impact of cascade screening for familial hypercholesterolemia on cardiovascular events

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein (LDL) receptor or associated genes, resulting in elevated serum cholesterol levels and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD).ObjectiveWe aimed to evaluate the prognostic impact of cascade screening for FH.MethodsWe retrospectively investigated the health records of 1050 patients with clinically diagnosed FH, including probands and their relatives who were cascade-screened, who were referred to our institute. We used Cox models that were adjusted for established ASCVD risk factors to assess the association between cascade screening and major adverse cardiac events (MACE). The median period of follow-up evaluating MACE was 12.3 years (interquartile ranges [IQR] = 9.1–17.5 years), and MACE included death associated with ASCVD, or acute coronary syndrome.ResultsDuring the observation period, 113 participants experienced MACE. The mean age of patients identified through cascade screening was 18-years younger than that of the probands (38.7 yr vs. 57.0 yr, P < 0.0001), with a lower proportion of ASCVD risk factors. Interestingly, patients identified through cascade screening under milder lipid-lowering therapies were at reduced risk for MACE (hazard ratio [HR] = 0.67; 95%CI = 0.44 to 0.90; P = 0.0044) when compared with the probands, even after adjusting for those known risk factors, including age, and prior ASCVD.ConclusionsThe identification of patients with FH via cascade screening appeared to result in better prognosis.     

A single pulmonary rheumatoid nodule masquerading as malignancy

We present a 54-year-old man, a heavy smoker, with clinical and laboratory evidence of familial hypercholesterolemia and an asymptomatic solitary pulmonary nodule (SPN) increasing in size on follow-up chest X–ray. Laboratory work-up revealed high titers of rheumatoid factor and the presence of acute phase reactants. Because of the patients age and history of smoking, open lung biopsy was performed to rule out malignancy. The biopsy showed histological features compatible with a rheumatoid nodule. Identical features were noted in the histological examination of the subcutaneous nodule. Usually, rheumatoid nodules occur in patients with active, long-standing rheumatoid arthritis (RA) with other extra-articular manifestations. The presence of a single pulmonary rheumatoid nodule as the first manifestation of RA is extremely rare. Histologic proof is often required since pulmonary carcinoma can present an identical clinical and radiological pattern. The diagnostic work-up and the differential diagnosis of an SPN, particularly in a heavy smoker, is a common clinical request and remains a diagnostic challenge.     

Reflex sympathetic dystrophy arising in a patient with familial Mediterranean fever

A 14-year-old girl with familial Mediterranean fever (FMF) had had acute attacks of fever, abdominal pain, and arthritis for 4 years. Her last arthritis attack was protracted, leading to reflex sympathetic dystrophy (RSD) in her right lower extremity. Physical therapy along with sympathetic ganglion block and corticosteroid therapy was used for the treatment. To our knowledge, this is the first reported case of RSD arising in a patient with FMF. Early recognition of RSD in FMF patients is important, and physical therapy should be applied along with medical treatment. Received: 26 March 1999 / Accepted: 20 July 1999