RESUMEN
OBJECTIVE: To ascertain whether the molecular characterization of a defect in the low-density lipoprotein (LDL) receptor gene (LDLR) in children with heterozygous familial hypercholesterolemia (heFH) identifies subjects at greater risk of developing premature coronary artery disease (pCAD) later in life. STUDY DESIGN: We investigated 264 children with heFH from 201 families, along with 148 affected parents and 100 unaffected siblings. The lipid profile was assessed before any treatment was provided, and genotype analysis was performed to characterize LDLR defects. In a subgroup of children with heFH and controls, we measured aorta and carotid intima-media thickness (aIMT and cIMT). The prevalence of pCAD in parents and/or grandparents with heFH was recorded. RESULTS: The children with heFH with a family history of pCAD had higher LDL cholesterol and apolipoprotein B levels and greater aIMT and cIMT than those with negative family history. Compared with carriers of LDLR-defective mutations, carriers of LDLR-negative mutations had a more severe phenotype, in terms of plasma lipid levels and IMT, and a higher prevalence of pCAD in first-degree relatives (36% vs 6.7%; P < .001). CONCLUSIONS: The study of heFH in children, in which other risk factors for CAD play a minor role, allows early identification of those at increased risk for developing pCAD, who merit more stringent clinical control and early pharmacologic treatment.
Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Hiperlipoproteinemia Tipo II/genética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Mutación , Adolescente , Adulto , Aorta/patología , Apolipoproteínas B/sangre , Arterias Carótidas/patología , Estudios de Casos y Controles , Niño , Preescolar , Colesterol/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Riesgo , Túnica Íntima/patología , Túnica Media/patología , Adulto JovenRESUMEN
Cholesteryl Ester Storage Disease (CESD) is a rare recessive disorder due to mutations in LIPA gene encoding the lysosomal acidic lipase (LAL). CESD patients have liver disease associated with mixed hyperlipidemia and low plasma levels of high-density lipoproteins (HDL). The aim of this study was the molecular characterization of three patients with CESD. LAL activity was measured in blood leukocytes. In two patients (twin sisters) the clinical diagnosis of CESD was made at 9 years of age, following the fortuitous discovery of elevated serum liver enzymes in apparently healthy children. They had mixed hyperlipidemia, hepatosplenomegaly, reduced LAL activity (approximately 5% of control) and heteroalleic mutations in LIPA gene coding sequence: (i) the common c.894 G>A mutation and (ii) a novel nonsense mutation c.652 C>T (p.R218X). The other patient was an 80 year-old female who for several years had been treated with simvastatin because of severe hyperlipidemia associated with low plasma HDL. In this patient the sequence of major candidate genes for monogenic hypercholesterolemia and hypoalphalipoproteinemia was negative. She was found to be a compound heterozygote for two LIPA gene mutations resulting in 5% LAL activity: (i) c.894 G>A and (ii) a novel complex insertion/deletion leading to a premature termination codon at position 82. These findings suggest that, in view of the variable severity of its phenotypic expression, CESD may sometimes be difficult to diagnose, but it should be considered in patients with severe type IIb hyperlipidemia associated with low HDL, mildly elevated serum liver enzymes and hepatomegaly.
Asunto(s)
Enfermedad de Acumulación de Colesterol Éster/genética , Enfermedad de Acumulación de Colesterol Éster/metabolismo , Esterol Esterasa/genética , Adolescente , Anciano de 80 o más Años , Enfermedad de Acumulación de Colesterol Éster/patología , Femenino , Pruebas Genéticas , Humanos , Lípidos/sangre , Hígado/metabolismo , Hígado/patología , Mutación , LinajeRESUMEN
A variety of rearrangements in the low-density lipoprotein receptor (LDLR) gene cause severe forms of familial hypercholesterolemia (FH). However, current methods for searching these abnormalities in FH samples, e.g., Southern and Northern Blot, are labor-intensive and not routinely used by diagnostic laboratories. We developed a simpler approach based on the quantitative polymerase chain reaction (PCR) amplification of part or all gene's coding sequences by a series of multiplex amplifications comprising three nonadjacent gene sections plus a fourth section used as an internal reference. Thereafter, the analysis of these PCR products by microchip electrophoresis revealed either deletions or duplications in the investigated gene sections through the simple comparison of electropherograms obtained from mutant and control samples. This required primers leading to well-resolved peaks with minimal size differences among coamplified products and PCR conditions allowing a linear quantitative response to template amount variations as those caused by duplication or deletion of specific gene sections. Also, the inclusion of exon 17 amplification product as an internal reference in each multiplex PCR allowed the normalization of quantitative results by dividing the area of each amplified section by the area of exon 17. The comparison of these ratios calculated from 10 carriers of 6 LDLR known rearrangements with those obtained from 14 control samples showed that gross deletions roughly halved and duplications doubled the ratio values of exons involved in the mutation. This allowed to distinguish gross mutations from sample-to-sample differences that reached at maximum 8% variation over mean values.