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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3332-3337.)
© 1997 American Heart Association, Inc.

Articles

Neonatal Diagnosis of Familial Hypercholesterolemia in Newborns Born to a Parent With a Molecularly Defined Heterozygous Familial Hypercholesterolemia

Alpo F. Vuorio; Hannu Turtola; ; Kimmo Kontula

From Department of Medicine (A.F.V, K.K.), University of Helsinki, FIN-00290 Helsinki, Finland and Central Hospital of North Karelia (H.T.), FIN-80210 Joensuu, Finland.

Correspondence to Professor Kimmo Kontula, MD, Department of Medicine, University of Helsinki, FIN-00290 Helsinki, Finland.

	Abstract

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Abstract This study was designed to compare blood lipid levels in newborn individuals with molecularly defined heterozygous familial hypercholesterolemia [FH] to those in nonaffected babies and to clarify the value of lipid determinations in assessment of diagnosis of FH at birth and 1 year of age. Twenty-five babies were born to 21 parents with DNA-documented heterozygous FH. Analysis of their cord blood samples revealed 11 newborns with the FH-North Karelia [FH-NK] mutation, 3 newborns with the FH-Helsinki [FH-HKI] mutation, and 11 nonaffected newborns. Cord serum total [TC] and LDL cholesterol [LDL-C] levels (mean±SD) in affected newborns (2.60±0.70 and 1.77±0.56, respectively) were significantly (P<.001) higher than those in nonaffected ones (1.54±0.23 and 0.78±0.15, respectively) and another cohort of 30 randomly selected control samples from apparently healthy newborns (1.84±0.46 and 1.03±0.30, respectively). However, there was overlapping of individual lipid levels in these three groups precluding the use of TC or LDL-C determinations in neonatal diagnosis of FH. In contrast, 1 year follow-up samples from 10 affected and 7 nonaffected individuals, as well as additional samples collected from another group of 8 affected and 9 nonaffected individuals, indicated that serum cholesterol levels showed much greater increment in children with FH. Thus, at the age of 1 year the mean serum TC and LDL-C levels in the affected infants (8.38±1.18 and 7.02±1.07, respectively) were much higher (P<.001) than the corresponding levels (4.40±0.66 and 2.89±0.68, respectively) in the nonaffected infants, and the individual ranges of TC and LDL-C levels were nonoverlapping in these two groups. Serum HDL cholesterol [HDL-C] levels in 1-year-old children with FH (0.95±0.14) were approximately 20% lower than those of their nonaffected counterparts (1.16±0.15, P<.001), after being similar at birth. In conclusion, phenotypic expression of heterozygous FH, as defined by molecular analysis of genomic DNA, is evident in serum LDL-C (but not HDL-C) levels already at birth, but for diagnostic purposes blood lipid determinations carried out at the age of 1 year are highly superior to those performed at birth.

Key Words: receptors, low-density lipoprotein • mutation • polymerase chain reaction • cord blood • North Karelia

	Introduction

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FH is among the most common single-gene diseases, with an average worldwide prevalence of heterozygous subjects of approximately 1 in 500.¹ FH is due to mutations of the low-density lipoprotein [LDL] receptor gene, and a vast number of different DNA changes underlying FH have been characterized in detail.^1,2 If untreated, FH is associated with a significantly accelerated rate of atherosclerotic changes in major arteries underscoring the importance of its early detection and aggressive treatment by novel inhibitors of cholesterol biosynthesis. The very rare cases with the homozygous form of FH should not pose any diagnostic difficulties, but problems may arise with heterozygous patients in their adolescent years.³

In principle, the molecular nature of the underlying defect in FH varies from family to family, but in specific populations, including the French Canadians, South African Afrikaners, Christian Lebanese, Ashkenazi Jews as well as Finns, one to four founder mutations seem to account for the majority of mutant LDL receptor genes,¹ rendering population-genetic studies feasible. Either of the two deletions of the LDL receptor gene, FH-Helsinki [FH-HKI] or FH-North Karelia [FH-NK], is present in two-thirds of Finnish patients with heterozygous FH, and the FH-NK mutation, deleting seven nucleotides from exon 6 and representing a class 1 (null allele) phenotype of FH, accounts for 90% of FH cases in the Finnish North Karelia.⁴ This constellation provides extraordinary possibilities for population genetic studies on FH in the province of North Karelia, which has a population base of 180 000 inhabitants and a higher than average prevalence of coronary artery disease in Finland.

The atherosclerotic process appears to seed its origins already in childhood.⁵ A number of studies have indicated that preventive measures started at a young age may modify risk factors of atherosclerosis in a favorable way. In children with FH, lowering of atherogenic lipoprotein components can be achieved by dietary measures,^6,7 supplementation of diet with plant sterols⁸ or by use of cholesterol-lowering medication.⁷ Collectively, all these data underscore the importance of an early unequivocal diagnosis in the pediatric management of FH. A number of studies carried out in 1970s and 1980s suggest that FH screening based on lipid measurements in umbilical cord samples is well suited for studies in affected families but may be unreliable for FH screening in general population. The interpretation of these data are, however, hampered by the fact that classification into FH and non-FH categories was based solely on lipid measurements and pedigree information, rendering both wrong negative and wrong positive diagnoses possible. In order to provide insight into the discriminative power of serum lipid levels in early diagnosis of FH and to obtain information on changes of serum lipid levels in molecularly defined FH during the first year of life, we conducted the present prospective study in offspring of documented carriers of a mutant LDL receptor gene.

	Materials and Methods

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Patients and Controls
Cord blood samples were collected from 25 newborn babies whose mother or father had heterozygous familial hypercholesterolemia, documented by analysis of genomic DNA.¹⁰ Of the 21 affected parents, 18 (15 mothers, 3 fathers) were carriers of the FH-NK gene and 3 (all being mothers) carriers of the FH-HKI gene. Except for 1 non-FH infant who was delivered at pregnancy week 34 because of maternal preeclampsia, all the newborns were full term. In addition, 30 randomly collected cord blood samples of full term newborns delivered in the same hospital served as controls; only serum lipid levels were analyzed in these samples. Follow-up blood samples became available from 17 of the 25 newborns at approximately 1 year of age. In addition, during our survey of some 400 heterozygous FH patients in the Finnish North Karelia (Vuorio et al, unpublished data), we collected blood samples from another cohort of 17 children aged 1.0 to 2.0 years, consisting of 8 DNA-documented carriers of the FH-NK gene (age 1.5±0.2 y) and 9 DNA-verified non-FH siblings (age 1.6±0.1 year). Their lipid levels were also measured during the present study.

This study was carried out at the North Karelia Central Hospital, Joensuu, Finland, from January 1992 to August 1996. All the parents gave their informed consent to the present study.

Laboratory Methods
DNA was prepared from frozen EDTA-anticoagulated cord or venous blood samples. DNA analysis was carried out using the duplex PCR-test described previously, with minor modifications.¹⁰ In short, 5 oligonucleotide primers (P1-P5) were used in a PCR amplification reaction containing 150 ng of template DNA and the various ingredients listed in the original paper.¹⁰ After 30 PCR cycles for 1 minute at 95°C, 1 minute at 55°C and 1 minute at 72°C, the amplified DNA fragments were analyzed by electrophoresis (at 250 V for 5 hours) on nondenaturating 12% polyacrylamide gels using a buffer containing 0.09 mol/L boric acid, 0.002 mol/L EDTA, pH 7.5. After electrophoresis, the DNA fragments were visualized by ethidium bromide staining. Under these conditions, the primer pair P1-P2 results in the formation of a specific 93-bp band, whenever the FH-NK mutation is present in the sample, and the primer pair P3-P5 generates an amplified fragment of 159-bp in size, whenever the FH-HKI gene is present.¹⁰

Cord blood was collected in plain and EDTA-anticoagulated test tubes from the placental end of the cord. Because prolonged clamping of the cord is known to increase the possibility of maternal contribution to the cord blood,¹¹ great care was followed to take the samples immediately after cord clamping. Venous blood samples at the age of about 1 year were collected after a 12-hour fast. Serum was separated by low-speed centrifugation of blood. All serum and EDTA-anticoagulated whole-blood samples were stored at -20°C until analysis.

Serum total cholesterol [TC] and triglyceride [TG] concentrations were determined by enzymatic methods using commercial kits obtained from Boehringer-Mannheim. The concentration of serum HDL cholesterol [HDL-C] was measured enzymatically after precipitation of LDL and VLDL fractions with dextran sulfate and MgCl₂, and serum LDL cholesterol [LDL-C] level was calculated using the formula of Friedewald et al.¹²

Statistical Analysis
Data are presented mean±SE. The mean serum lipid levels in different groups of children were compared using the Mann-Whitney's nonparametric test. For comparison of intra-individual lipid values at birth and one year of age, Wilcoxon matched-pairs signed rank test was used. Before statistical comparison, serum TG levels were transformed logarithmically.

	Results

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Twenty-five babies were born to 21 couples in which either the male (n=3) or female (n=18) was a DNA-verified heterozygote for FH. Of these 25 newborns, 11 proved to be carriers of the FH-NK mutation, 3 had the FH-HKI mutation and 11 were nonaffected according to the duplex PCR assay for the 2 Finnish-type LDL receptor gene mutations (Table 1). In 17 cases, DNA samples from the same individual were available both at birth and the age of 1 year, and the result of genotyping was always the same.

View this table: [in this window] [in a new window]   Table 1. Serum Total Cholesterol (TC) and LDL Cholesterol (LDL-C) Levels in Cord Blood and in Follow-up Sample

TC and LDL cholesterol levels in cord serum from newborns (n=11) with the FH-NK mutation (2.62±0.73 and 1.78±0.57 mmol/L, respectively) and those (n=3) with the FH-HKI mutation (2.53±0.74 and 1.75±0.64 mmol/L, respectively) were not significantly different from each other. This data, as well as our earlier experience showing virtually identical serum TC and LDL-C levels in adult heterozygous FH-NK and FH-HKI patients,¹³ permitted us to pool lipid data in these two mutation categories (see below). Serum TC, LDL-C, HDL-C, or TG levels were not significantly different in cord sera of affected boys and girls (data not shown). Moreover, cord lipid levels in the affected newborns were independent on whether it was the father or the mother who was carrier of the mutant gene; for example, the LDL-C concentrations in cord serum in the former (n=3) and latter (n=11) group were 1.74±0.68 and 1.78±0.56 mmol/L, respectively (P=.64). Serum TC and LDL-C levels were distinctly high in 1 nonaffected newborn from a family with FH (Fig 1). The pregnancy in this case was complicated by preeclampsia and delivery was induced at the week 34 of pregnancy; therefore, this case was excluded from analysis of lipid data at birth but not from comparison of lipid levels at the age of 1 year. All the other pregnancies ended with a full term delivery.

View larger version (26K): [in this window] [in a new window]   Figure 1. Individual cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels in cord serum of randomly collected control newborns (n=30), as well as nonaffected (n=11) or affected (n=14) newborns born to a parent with a molecularly defined FH. , nonaffected children; , pregnancy complicated by preeclampsia; , FH-NK allele present; , FH-HKI allele present.

Mean TC and LDL-C levels in cord serum were significantly elevated in the affected newborns compared to those of nonaffected offspring of heterozygous FH subjects or those of 30 randomly collected control pregnancies (Fig 1, Table 2). There was, however, a considerable overlap between the ranges of individual lipid levels in these three groups. Cholesterol levels tended to be slightly higher in cord samples from randomly collected controls than those derived from pregnancies with a nonaffected child to a parent with heterozygous FH (Fig 1, Table 2). The concentrations of HDL-C and TG in cord serum were not significantly different in affected and nonaffected newborns of couples with one affected parent (Fig 1, Table 2).

View this table: [in this window] [in a new window]   Table 2. Serum Lipid Levels (mean±SD) at Birth and at 1 Year of Age in Different Groups of Children Studied

The mean (±SD) serum TC and LDL-C concentrations in the combined two groups of nonaffected newborns shown in Fig 1 were 1.77±0.43 and 0.97±0.29 mmol/L, respectively, yielding the 95th percentile values of 2.60 and 1.44 mmol/L, respectively, for these two variables. If these levels were used as diagnostic criteria as the upper normal limits, then 6 or 5, respectively, out of the 14 molecularly defined newborn FH subjects would have been diagnosed as non-FH babies.

Follow-up serum samples for lipid assays became available from 7 nonaffected and 9 nonaffected children at the age of 1 year. There was a steep, 3- to 4-fold increase of serum total and LDL cholesterol levels in both groups resulting in two totally nonoverlapping distributions at 1 year of age (Fig 2). Both serum HDL-C and TG concentrations increased significantly (P<.01) from birth to the age of 1 in both nonaffected and affected infants, but in absolute terms these increases were less substantial than that seen in LDL-C levels (Fig 2). Our previous survey on 400 heterozygous FH patients in North Karelia (Vuorio et al, unpublished data) had identified 17 children born to families with FH who were in the same age class (age between 1 to 2 years). Inspection of their individual TC and LDL-C levels showed that these concentrations similarly distinguished gene carriers and noncarriers (Fig 2). At the age of 1 to 2 years, the mean serum HDL-C concentration of the FH children (n=18) was significantly lower than that of the non-FH children (n=16) at this age (Table 2).

View larger version (21K): [in this window] [in a new window]   Figure 2. Serum cholesterol and LDL cholesterol levels in cord blood and at the age of 1 year in newborn children with or without a mutant LDL receptor gene. All newborns shown in this figure were born to families with one of the parents carrying a mutant LDL receptor gene. , nonaffected children at birth and at the age of 1 year; , pregnancy complicated by preeclampsia; (group N), nonaffected children aged 1 to 2 years identified during a previous survey; , children with the FH-NK allele at birth and at the age of 1 year; , child with the FH-HKI allele at birth and at the age of 1 year; and (group F), affected children aged 1 to 2 years identified as carriers of the FH-NK allele during a previous survey.

There was one affected pair of twins carrying the FH-NK deletion in the study cohort. In these girls serum and LDL-C levels were strikingly similar, both at birth and the age of 1 year.

	Discussion

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A wide consensus maintains that FH is phenotypically expressed from birth throughout the remaining life, whether present in its homozygous or heterozygous forms.^1,6 Exceptions to this rule may include specific DNA mutations with low phenotypic expression^14–17 and co-occurrence of a putative cholesterol-lowering gene in an affected family.¹⁸ Diagnostic attempts based on clinical characteristics and lipid determinations only may, however, result in equivocal information even within affected families,³ and a molecular analysis appears to be particularly useful in pediatric practice.¹⁹

While some earlier studies indicated cord blood cholesterol determinations to show promise in early screening for inherited hypercholesterolemia,^20,21 other studies have questioned this, with the possible exception of their use in newborn children of affected parents.^22–24 Some alternative approaches, instead of assaying cholesterol levels only, have been suggested to be useful, such as measurement of LDL-C,²⁵ LDL+VLDL cholesterol,^26,27 ß-lipoprotein,²⁸ apolipoprotein B,^29–31 or apolipoprotein A-I to B ratio³² in cord serum. In none of these earlier studies has FH been diagnosed by molecular genetic techniques.

We took advantage of the special circumstances in the Finnish North Karelia permitting analysis of cosegregation of hypercholesterolemia with a defective gene in affected families using a prospective design. Our data show that while mean serum TC and LDL-C levels in molecularly defined affected and nonaffected infants differ significantly from each other both at birth and age of 1 year, TC and LDL-C levels in individual subjects of the two groups are markedly overlapping in cord serum but nonoverlapping at the later date (Fig 1, 2). Thus, use of arbitrary cut-off values of 6 mmol/L and 5 mmol/L for serum total and LDL-C concentrations, respectively, would have differentiated our molecularly defined FH heterozygotes (n=18) and nonaffected children (n=16) from each other at the age of 1 year in this relatively small group of infants (Fig 2). It should be emphasized that our data were obtained in a study population that obeyed strict measures to control dietary fat, and the difference in serum cholesterol levels between 1-year-old affected and nonaffected subjects in a random population with no previously established diagnosis of parental FH may therefore not be equally striking.

Use of LDL-C measurements in cord serum, as suggested by Kwiterowich et al,²⁵ appeared to perform somewhat better in comparison to total cholesterol measurements to discriminate FH and non-FH newborns from each other, yet providing unsatisfactory diagnostic accuracy (Fig 1). Earlier studies have indicated that estimation of LDL-C levels in human cord serum derived by calculation from TC, HDL-C, and TG values using the Friedewald formula¹² correspond well to those obtained by ultracentrifugation.³³

Previous studies have indicated that a number of maternofetal factors such as gestational age, prematurity, respiratory distress, maternal diabetes, and preeclampsia may affect serum lipid levels at birth.^24,34,35 Our material included only one complicated pregnancy, and lipid data of the respective newborn were excluded from our data set. We did not see any correlation between gestational age and cord serum LDL-C levels in our study group, and lipid levels in cord sera after vaginal deliveries and cesarean sections were similar. None of the mothers used any type of lipid-lowering drugs during pregnancy. All mothers of the FH families had received a similar-type of dietary advisement, regardless of whether it was the mother or father who was affected and whether the newborn proved subsequently to have FH or not. This may be the reason why serum total and LDL-C levels in cord blood samples from pregnancies with either of the parents affected with FH tended to lower slightly in comparison to those in cord samples derived from a randomly selected population material (Fig 1).

Studies on longitudinal changes in serum lipid levels after birth have shown a rapid increase of serum cholesterol and apolipoprotein B levels during the first week of life, a less pronounced increment during the ensuing month, and relatively stable levels from the age of 6 months to 2 years.^36–39 Nutritional factors such as fatty acid composition of the diet may modify serum lipid levels or lipoprotein composition during the early weeks of human life^37,39 and during later phases of the first year of life.⁴⁰ We are not aware of similar week-to-week follow-up studies in newborn children with heterozygous FH, but reports on a few individual cases suggest that this increment of serum cholesterol takes place as quickly as in non-FH subjects.^22,24

The finding that serum HDL-C levels in affected children at the age of 1 year were 18% lower than those in nonaffected ones (Table 2) is in accordance with previous studies in children of age classes from 1 to 19 years.^6,19,41 It was of interest, however, that in our study this phenotypic difference was not yet manifest at birth (Fig 1, Table 2). Our data suggest that the difference in serum HDL-C levels in affected and nonaffected children is a secondary phenomenon, and appear when the human fetus switches from making use of carbohydrates as its principal caloric source⁴² to utilize fats as an important energy source after birth.

In conclusion, our study relying on the use of molecular methods to distinguish between carriers and noncarriers of a mutant LDL receptor gene indicate that, although serum LDL-C levels in affected children are significantly elevated from birth on, assessment of diagnosis of heterozygous FH using lipid determinations in cord blood is unreliable; a better discrimination is obtained when lipid determinations are carried out at the age of 1 year. In addition, our data suggest that children with FH are born with serum HDL-C levels similar to those in other newborns and that the subsequent rise in HDL-C levels during the first year of life is slightly less pronounced in children with FH than in children without it.

	Acknowledgments

 
The expert technical assistance of Ms Kaija Kettunen and Ms Susanna Tverin is gratefully acknowledged. We also thank Ms Eija Eklund-Mähönen and Dr Eeva Koistinen for their help in collection of the cord samples. This work was supported by grants from the Finnish Academy of Sciences, the Sigrid Juselius Foundation, the University of Helsinki, the Paulo Foundation, the Finnish Heart Foundation, the Orion Corporation Research Foundation, Finnish Cultural Foundation, and the Finnish Medical Society Duodecim.

Received February 11, 1997; accepted April 10, 1997.

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