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Differences in the phenotype between children with familial defective apolipoprotein B-100 and familial
S N Pimstone1, J C Defesche, S M Clee
1Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Insights
Familial defective apolipoprotein B-100 (FDB) in children shows milder cholesterol levels than familial hypercholesterolemia (FH). This genetic disorder
Area of Science:
- Genetics
- Biochemistry
- Pediatrics
Background:
- Familial defective apolipoprotein B-100 (FDB) is a genetic disorder causing high cholesterol.
- Phenotypes of FDB and familial hypercholesterolemia (FH) in children are not well-compared.
- Apolipoprotein B gene mutations are linked to elevated cholesterol.
Purpose of the Study:
- To compare the biochemical and clinical phenotypes of FDB and FH in children.
- To characterize the phenotype of FDB in a pediatric cohort.
- To investigate early-life penetrance of FDB mutations.
Main Methods:
- Studied 38 Dutch children (<20 years) with FDB from 21 families.
- Compared lipid/lipoprotein levels and clinical phenotype with 97 age-matched FH heterozygotes.
- Utilized molecular analysis for FH diagnosis and age/sex-matched controls.
Main Results:
- Female and male FDB carriers had significantly lower total cholesterol, LDL cholesterol, and apoB than FH heterozygotes.
- FDB carriers showed higher LDL and total cholesterol than age/sex-matched controls, even under 10 years.
- Female FDB heterozygotes had higher LDL cholesterol than males within the FDB group.
Conclusions:
- Children with FDB exhibit a milder biochemical phenotype compared to children with FH.
- The FDB phenotype is intermediate between control subjects and FH heterozygotes.
- Milder cholesterol elevation in FDB may contribute to a lower incidence of atherosclerosis in adults.
Abstract:
Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited genetic disorder resulting from a point mutation in the apolipoprotein (apo) B gene and is associated with significantly elevated plasma total and LDL cholesterol levels. Despite numerous descriptions outlining the phenotype of children with familial hypercholesterolemia (FH), no study has described the biochemical and clinical phenotype in a cohort of children with FDB. The phenotypes of FH and FDB, therefore, have not been compared in children. We have studied a cohort of 38 Dutch children (all <20 years old) with FDB from 21 different families. Lipid and lipoprotein levels and the clinical phenotype were compared with 97 age-matched FH heterozygotes, as defined by molecular analysis, and with age-matched non-FDB, non-FH control subjects. Female FDB carriers (n=23) had significantly lower total cholesterol (P<.001), LDL cholesterol (P=.001), total cholesterol:HDL ratio (P<.001), and apoB levels (P=.001) than age-matched female FH heterozygotes (n=50). Similar results were noted in male FDB carriers (n=15) compared with male FH heterozygotes (n=47; P=.005, P=.007, P=.014, and P=.074, respectively). Within the FDB group, female FDB heterozygotes had higher LDL cholesterol (P=.038) and a trend to higher total cholesterol levels (P=.165) than age-matched males. Both male and female FDB carriers had significantly higher total cholesterol, LDL cholesterol, and total cholesterol:HDL ratio than age- and sex-matched control subjects, which was evident even in children <10 years of age, providing additional evidence that this mutation is penetrant in early life. These results provide evidence for a milder biochemical phenotype in children with FDB than in children with FH. The phenotype observed is intermediate between that of control subjects and FH heterozygotes matched for age and sex. As the incidence of coronary artery disease is related to both the extent and duration of cholesterol elevation, our findings might explain in part the lower incidence of clinical atherosclerosis seen in adults with this condition than in adults with FH.