Metabolism Clinical and Experimental VOL.
XXVI,
PRELIMINARY
C. J. Glueck, kindred
with
transmission proteinemia
of
density
Familial
Hyperalphalipoproteinemia
P. M. Gartside,
R. C.
four-generation familial
vertical
hyperalphalipo-
was ascertained
ment of elevated
1977
REPORT
Neonatal
A
MAY
NO. 5
by measure-
levels of cord blood
lipoprotein
cholesterol
high-
(C-HDL)
Tsang,
M. J. Mellies, and P. M. Steiner
in a neonatal cord
blood
propositus.
studies and longitudinal the diagnosis proteinemia
Quantitation
coupled
C-HDL
of
with
family
follow-up
allows
of familial
hyperalphalipo-
in infancy.
F
AMILIAL HYPERALPHALIPOPROTEINEMIA is characterized by distinctive elevations of high-density lipoprotein cholesterol (C-HDL), with normal levels of triglyceride, normal low-density lipoprotein cholesterol (C-LDL), and normal very-low-density lipoprotein cholesterol (C-VLDL).‘,’ Kindred members have prolonged life expectancy,‘,2 with reduced cardiac morby virtue of HDL-mediated mobilization of bidity or mortality,2,3 presumably cholesterol from the arterial wall.4,5 In 18 kindreds with familial hyperalphalipoproteinemia, segregation analysis suggested a major gene effect and autosomal dominant transmission, but C-HDL was not bimodally distributed.’ Hyperalphalipoproteinemia was fully penetrant in children at genetic risk,’ but no neonates were available for study in the original 18 kindreds.1,2 In the current report, a kindred with four-generation vertical transmission of familial hyperalphalipoproteinemia was ascertained by high cord blood C-HDL in a neonatal propositus.
From rhe Deparrmems Division of Pedialric Received/or
01 Pediatrics
Research,
and Medicine,
University of Cincinnati,
General
Clinical
Cincinnari.
Research
Cenrer.
and Fels
Ohio.
publicarion July 16. 1976.
Supported in part by General Clinical
Research Center Gram RR 00068-14.
was done during Dr. Gfueck’s fenure as an Established
Investigator
A porlion
of the American
ofrhis work
Heart
Associa-
tion. 1971~1976. Reprint requesrs should be addressed to Dr. General Clinical
Research
Unit.
University
C. J. Glueck.
ofCincinnati
Direcror,
Research
Lipid
Center,
Research
234 Goodman
Clinic
and
SI..
Cin-
cinnati. Ohio 45229. @ 1977 bv Grune & Stratton,
Inc.
Mefobolism, Vol. 26, No. 5 (May), 1977
469
470
GLUECK ET AL.
HVER-ALPHA oqe, cwse of death NOT SAMPLED
Fig. 1.
Neonate’s lineage.
MATERIALS Cord blood total cholesterol. the neonatal
propositus
C-HDL.
during
manganese VLDL
was 50 mg/dl,
the 95th
in all other kindred
Clinics Manual.’
position,
accurate
was made’ quantitation
after a 12-hr overnight
live births.’
percentile
57.9
mg/dl.
were done following
methods
mother
(IV-4,
Fig.
I),
additional
of C-HDL.
Blood
samples
fast, into tubes containing
point
(I
mg/ml).
Research
of the heparin-
precipitation drawn
ol
and lipoprotein
of the Lipid
were
EDTA
cutof
Lipid
assessment
to insure that there was complete
in the
in these 500 con-
An arbitrary
C-HDL
in
“Nor-
of C-HDL
for C-HDL
of elevated cord blood
members
In the neonate’s
precipitation
with
were quantiated”.’
unselected
studied.6 The 90th percenttle
was then used for identitication
quantitations
and triglyceride
lipids in 3000
were taken from analysis of the distribution
first 500 of 3000 neonates previously secutive live births
C-LDL,
a study of plasma
mal limits” for cord blood C-HDL
50 mg/dl
AND METHODS
C-VLDL,
of LDL
in the
and
recumbent
All subjects were
receiving their usual diets and had had no recent weight loss. Hyperalphalipoproteinemia an “upper teinemia
normal
limit”
in affected
in kindred for C-HDL
kindred
members
progestin oral contraceptives, carbon
pesticides.’
post partum), great-uncles
Lipids
and
I. Table
(other
lipoproteins
intake, were
great-grandparents,
than
the neonate)
as per previous
was not secondary
excessive ethanol
grandparents,
(Fig.
members
of 70 mg/dl
studies.’
to pregnancy,
or unusual exposure
quantitated aunts,
uncles,
in the
was identified
using
Hyperalphalipopro-
estrogens,
or estrogen-
to chlorinated
neonate’s
tirst cousins,
parents great-aunts.
hydro(4 mo and
I).
RESULTS
The neonate had normal cord blood total cholesterol and triglyceride. Her C-HDL of 52 was elevated [ >90th percentile for C-HDL (50 mg/dl) for the 500 neonates studied] (Fig. 1, Table 1). Her cord blood C-LDL of 9 mg/dl was below the 2.5th percentile for C-LDL (10 mg/dl) in normal neonates. No other kindred members had low levels of C-LDL. At follow-up at age 8; mo her C-HDL was distinctively elevated (101 mg/dl), but C-LDL and total plasma cholesterol were normal. The neonate’s mother, grandmother, great-aunt, and
HYPERALPHALIPOPROTEINEMIA
471
Table 1. Kindred Chart Chol*
C-HDL
C-LDl
(mg/dU
(mg/dQ
(mg/dU
Kindred Position
Sex
I1
M
37t
d. 37, tuberculosis
2
F
W
d. 98. carcinoma
II 1
F
2
F
3
M
Age (vr)
Comment
d. 2, diptheria
2t 2t
d. 2, diptherio
76
192
58
120
68
285
89
181
66
4
F
71
5
M
65t
d. 65. ?
6
M
62t
d. 62, tuberculosis
III 1
M
59
196
51
119
117
2
F
54
229
63
155
56
3
M
53
251
51
186
71
4
F
53
269
105
172
76
5
M
46
190
66
117
35
6
F
55
207
76
115
80
7
F
46
IV 1
F
22
205
68
128
2
F
15
178
62
108
36
3
M
25
238
44
174
88
237
110
113
68
HALP*
HALP HALP Not sampled
45
4
F
24
5
M
25
6
F
27
189
53
120
80
7
M
16
135
47
79
46
8
F
14
140
58
74
41
9
F
13
118
54
59
25
(V 11)
F
cord blood
65
52
9
19
Neonatal HALP
(‘1 2
F
8f mo
188
101
79
43
HALP at 8f mo
M
16mo
153
44
97
60
3
F
3
181
52
118
54
HALP Not sampled
*Chol, cholesterol; TG, triglycerides; HALP, hyperolphalipoproteinemia. tAge ot death. INeonate studied.
great-grandmother had hyperalphalipoproteinemia; all were in excellent health, took no medications, and had normal physical examinations (Fig. 1, Table 1). Four-generation vertical transmission of hyperalphalipoproteinemia was consistent with that of an autosomal dominant trait.’ The neonate’s great-greatgrandmother died of carcinoma at age 98, having had good health until late in her ninth decade. No adults in the kindred had known morbid or mortal ischemic heart disease. DISCUSSION
Quantitation of C-HDL in cord blood, coupled with extensive family sampling and longitudinal follow-up, may allow ascertainment in infancy of familial hyperalphalipoproteinemia. Even for restricted segments of the distribution (the upper 10th percentile), the predictability of cord blood C-HDL to C-HDL later in life has not been longitudinally assessed. The upper 10th percentile for increased cord blood C-HDL probably represents a heterogenous group, some
472
GLUECK ET At.
of whom
apparently
“polygenic,”
have
“monogenic”
and others (speculatively
hyperalphalipoproteinemia,
the majority)
centile for reasons which remain to be elucidated. neonatal and familial
hyperalphalipoproteinemia
of the neonates with elevated underway,
C-HDL
In diverse populations,
‘” I? including
and Greenland
lence of coronary
heart
pendent
and
of total
disease.
In
atherogenic
and
disease. This LDL
the total group of 3000)” is still
negative
correlation
In addition
morbidity
Ga.. Japanese
is probably
mortality
hyperalphalipoproteinemia
the
ratio, C-LDL/C-HDL,
’ have prolonged from
ischemic
atherogenic
to
of I.21 + 0.06 (mean population
The antiatherosclerotic
related to its putative
etfect of HDL
Neonatal portunity
diagnosis
of familial
for longitudinal
affected children
is probably
clearance of cholesterol
and allows
prospective
bers of the negative correlation
of C-HDL
during growth
anti-
group. p < 0.01.’
from the arterial
hyperalphalipoproteinemia
study of C-HDL
heart
=t SEM)
was half the ratio of 2.4 * 0.12 found in a control to bind lipids’” and to facilitate
inde-
to population-based
hyperalphalipoproteinemia’ and
lipoprotein
of
was inversely related to the preva-
cholesterol.“’
reduced
familial
incidence
since evaluation
blacks in Evans County,
Eskimos, C-HDL
studies,‘O ” kindreds with familial life expectancy
The projected is unknown,
others 10th per-
incidence would appear to be I /3000.
but a “minimum”
in Hawaii,
(from
lie in the upper
provides
ability w~II.~,’ an op-
and development
assessment in affected
kindred
in
mem-
with ischemic heart disease.
REFERENCES I. Glueck CJ, Fallat RW, Millet F. et al: Familial hyperalphalipoproteinemia: Studies in eighteen kindreds. Metabolism 24: 1243. 1975 2. Glueck CJ. Gartside P. Fallat RW. et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:94l-957. 1976 3. Glueck CJ. Fallat RW. Spadafora M. et al: Longevity syndromes. Circulation [Suppl] 2~72. 1975 4. Glueck CJ: Alpha-lipoprotein cholesterol. beta-lipoprotein cholesterol. and longevity. Artery 2:196 199, 1976 5. Miller GJ, Miller NE: Plasma high density lipoprotein concentration and development of ischemic heart disease. Lancet I:16 1975 6. Tsang RC. Glueck CJ, Fallat RW. et al: Neonatal familial hypercholesterolemia. Am J Dis Child 129:83. 1975 7. Tsang RC, Fallat RW, Glueck CJ: Cholesterol at birth and age I: Comparison of normal and hypercholesterolemic neonates. Pediatrics 53:458, 1974 8. Lipid Research Clinics Program. Manual of Laboratory Operations. vol I. Washington. D.C.. U.S. GPO. 1974
9. lshikawa TT. Brazter JB. Steiner PM. et al: A study of the heparin-manganese chloride method for determination of plasma alphalipoprotein cholesterol concentration. Lipids I I:628 633. 1976 IO. Castellt WP. Doyle JT. Gordon T. et al: HDL cholesterol levels (HDLC) in coronary heart disease (CHD): A cooperative lipoprotein phenotyping study. Ctrculation [Suppl] 2:51 52. 2196. 1975 I I. Tyroler HA. Hames CC. Krishan I. et al: Black-white differences in serum lipids and lipoproteins in Evans County. Prevent Med 4:541. 1975 12. Gulbrandsen CL. Rhoades GC. Kagan A: Cholesterol fractions and coronary heart disease in Hawaiian Japanese men. Circulation 50 (Suppl 31: 100. I974 13. Bang HW. Dyerberg J. Neilson A: Plasma lipid and lipoprotein patterns in Greenlandic West-Coast Eskimos. Lancet I: I 143. 1971 14. Tall AR, Small DM, Shipley GG, et al: Apoprotein stability and lipid-protein interactions in human plasma high-density lipoproteins. Proc Natl Acad Sci USA 72:4940. 1975
XXVI,
PRELIMINARY
C. J. Glueck, kindred
with
transmission proteinemia
of
density
Familial
Hyperalphalipoproteinemia
P. M. Gartside,
R. C.
four-generation familial
vertical
hyperalphalipo-
was ascertained
ment of elevated
1977
REPORT
Neonatal
A
MAY
NO. 5
by measure-
levels of cord blood
lipoprotein
cholesterol
high-
(C-HDL)
Tsang,
M. J. Mellies, and P. M. Steiner
in a neonatal cord
blood
propositus.
studies and longitudinal the diagnosis proteinemia
Quantitation
coupled
C-HDL
of
with
family
follow-up
allows
of familial
hyperalphalipo-
in infancy.
F
AMILIAL HYPERALPHALIPOPROTEINEMIA is characterized by distinctive elevations of high-density lipoprotein cholesterol (C-HDL), with normal levels of triglyceride, normal low-density lipoprotein cholesterol (C-LDL), and normal very-low-density lipoprotein cholesterol (C-VLDL).‘,’ Kindred members have prolonged life expectancy,‘,2 with reduced cardiac morby virtue of HDL-mediated mobilization of bidity or mortality,2,3 presumably cholesterol from the arterial wall.4,5 In 18 kindreds with familial hyperalphalipoproteinemia, segregation analysis suggested a major gene effect and autosomal dominant transmission, but C-HDL was not bimodally distributed.’ Hyperalphalipoproteinemia was fully penetrant in children at genetic risk,’ but no neonates were available for study in the original 18 kindreds.1,2 In the current report, a kindred with four-generation vertical transmission of familial hyperalphalipoproteinemia was ascertained by high cord blood C-HDL in a neonatal propositus.
From rhe Deparrmems Division of Pedialric Received/or
01 Pediatrics
Research,
and Medicine,
University of Cincinnati,
General
Clinical
Cincinnari.
Research
Cenrer.
and Fels
Ohio.
publicarion July 16. 1976.
Supported in part by General Clinical
Research Center Gram RR 00068-14.
was done during Dr. Gfueck’s fenure as an Established
Investigator
A porlion
of the American
ofrhis work
Heart
Associa-
tion. 1971~1976. Reprint requesrs should be addressed to Dr. General Clinical
Research
Unit.
University
C. J. Glueck.
ofCincinnati
Direcror,
Research
Lipid
Center,
Research
234 Goodman
Clinic
and
SI..
Cin-
cinnati. Ohio 45229. @ 1977 bv Grune & Stratton,
Inc.
Mefobolism, Vol. 26, No. 5 (May), 1977
469
470
GLUECK ET AL.
HVER-ALPHA oqe, cwse of death NOT SAMPLED
Fig. 1.
Neonate’s lineage.
MATERIALS Cord blood total cholesterol. the neonatal
propositus
C-HDL.
during
manganese VLDL
was 50 mg/dl,
the 95th
in all other kindred
Clinics Manual.’
position,
accurate
was made’ quantitation
after a 12-hr overnight
live births.’
percentile
57.9
mg/dl.
were done following
methods
mother
(IV-4,
Fig.
I),
additional
of C-HDL.
Blood
samples
fast, into tubes containing
point
(I
mg/ml).
Research
of the heparin-
precipitation drawn
ol
and lipoprotein
of the Lipid
were
EDTA
cutof
Lipid
assessment
to insure that there was complete
in the
in these 500 con-
An arbitrary
C-HDL
in
“Nor-
of C-HDL
for C-HDL
of elevated cord blood
members
In the neonate’s
precipitation
with
were quantiated”.’
unselected
studied.6 The 90th percenttle
was then used for identitication
quantitations
and triglyceride
lipids in 3000
were taken from analysis of the distribution
first 500 of 3000 neonates previously secutive live births
C-LDL,
a study of plasma
mal limits” for cord blood C-HDL
50 mg/dl
AND METHODS
C-VLDL,
of LDL
in the
and
recumbent
All subjects were
receiving their usual diets and had had no recent weight loss. Hyperalphalipoproteinemia an “upper teinemia
normal
limit”
in affected
in kindred for C-HDL
kindred
members
progestin oral contraceptives, carbon
pesticides.’
post partum), great-uncles
Lipids
and
I. Table
(other
lipoproteins
intake, were
great-grandparents,
than
the neonate)
as per previous
was not secondary
excessive ethanol
grandparents,
(Fig.
members
of 70 mg/dl
studies.’
to pregnancy,
or unusual exposure
quantitated aunts,
uncles,
in the
was identified
using
Hyperalphalipopro-
estrogens,
or estrogen-
to chlorinated
neonate’s
tirst cousins,
parents great-aunts.
hydro(4 mo and
I).
RESULTS
The neonate had normal cord blood total cholesterol and triglyceride. Her C-HDL of 52 was elevated [ >90th percentile for C-HDL (50 mg/dl) for the 500 neonates studied] (Fig. 1, Table 1). Her cord blood C-LDL of 9 mg/dl was below the 2.5th percentile for C-LDL (10 mg/dl) in normal neonates. No other kindred members had low levels of C-LDL. At follow-up at age 8; mo her C-HDL was distinctively elevated (101 mg/dl), but C-LDL and total plasma cholesterol were normal. The neonate’s mother, grandmother, great-aunt, and
HYPERALPHALIPOPROTEINEMIA
471
Table 1. Kindred Chart Chol*
C-HDL
C-LDl
(mg/dU
(mg/dQ
(mg/dU
Kindred Position
Sex
I1
M
37t
d. 37, tuberculosis
2
F
W
d. 98. carcinoma
II 1
F
2
F
3
M
Age (vr)
Comment
d. 2, diptheria
2t 2t
d. 2, diptherio
76
192
58
120
68
285
89
181
66
4
F
71
5
M
65t
d. 65. ?
6
M
62t
d. 62, tuberculosis
III 1
M
59
196
51
119
117
2
F
54
229
63
155
56
3
M
53
251
51
186
71
4
F
53
269
105
172
76
5
M
46
190
66
117
35
6
F
55
207
76
115
80
7
F
46
IV 1
F
22
205
68
128
2
F
15
178
62
108
36
3
M
25
238
44
174
88
237
110
113
68
HALP*
HALP HALP Not sampled
45
4
F
24
5
M
25
6
F
27
189
53
120
80
7
M
16
135
47
79
46
8
F
14
140
58
74
41
9
F
13
118
54
59
25
(V 11)
F
cord blood
65
52
9
19
Neonatal HALP
(‘1 2
F
8f mo
188
101
79
43
HALP at 8f mo
M
16mo
153
44
97
60
3
F
3
181
52
118
54
HALP Not sampled
*Chol, cholesterol; TG, triglycerides; HALP, hyperolphalipoproteinemia. tAge ot death. INeonate studied.
great-grandmother had hyperalphalipoproteinemia; all were in excellent health, took no medications, and had normal physical examinations (Fig. 1, Table 1). Four-generation vertical transmission of hyperalphalipoproteinemia was consistent with that of an autosomal dominant trait.’ The neonate’s great-greatgrandmother died of carcinoma at age 98, having had good health until late in her ninth decade. No adults in the kindred had known morbid or mortal ischemic heart disease. DISCUSSION
Quantitation of C-HDL in cord blood, coupled with extensive family sampling and longitudinal follow-up, may allow ascertainment in infancy of familial hyperalphalipoproteinemia. Even for restricted segments of the distribution (the upper 10th percentile), the predictability of cord blood C-HDL to C-HDL later in life has not been longitudinally assessed. The upper 10th percentile for increased cord blood C-HDL probably represents a heterogenous group, some
472
GLUECK ET At.
of whom
apparently
“polygenic,”
have
“monogenic”
and others (speculatively
hyperalphalipoproteinemia,
the majority)
centile for reasons which remain to be elucidated. neonatal and familial
hyperalphalipoproteinemia
of the neonates with elevated underway,
C-HDL
In diverse populations,
‘” I? including
and Greenland
lence of coronary
heart
pendent
and
of total
disease.
In
atherogenic
and
disease. This LDL
the total group of 3000)” is still
negative
correlation
In addition
morbidity
Ga.. Japanese
is probably
mortality
hyperalphalipoproteinemia
the
ratio, C-LDL/C-HDL,
’ have prolonged from
ischemic
atherogenic
to
of I.21 + 0.06 (mean population
The antiatherosclerotic
related to its putative
etfect of HDL
Neonatal portunity
diagnosis
of familial
for longitudinal
affected children
is probably
clearance of cholesterol
and allows
prospective
bers of the negative correlation
of C-HDL
during growth
anti-
group. p < 0.01.’
from the arterial
hyperalphalipoproteinemia
study of C-HDL
heart
=t SEM)
was half the ratio of 2.4 * 0.12 found in a control to bind lipids’” and to facilitate
inde-
to population-based
hyperalphalipoproteinemia’ and
lipoprotein
of
was inversely related to the preva-
cholesterol.“’
reduced
familial
incidence
since evaluation
blacks in Evans County,
Eskimos, C-HDL
studies,‘O ” kindreds with familial life expectancy
The projected is unknown,
others 10th per-
incidence would appear to be I /3000.
but a “minimum”
in Hawaii,
(from
lie in the upper
provides
ability w~II.~,’ an op-
and development
assessment in affected
kindred
in
mem-
with ischemic heart disease.
REFERENCES I. Glueck CJ, Fallat RW, Millet F. et al: Familial hyperalphalipoproteinemia: Studies in eighteen kindreds. Metabolism 24: 1243. 1975 2. Glueck CJ. Gartside P. Fallat RW. et al: Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med 88:94l-957. 1976 3. Glueck CJ. Fallat RW. Spadafora M. et al: Longevity syndromes. Circulation [Suppl] 2~72. 1975 4. Glueck CJ: Alpha-lipoprotein cholesterol. beta-lipoprotein cholesterol. and longevity. Artery 2:196 199, 1976 5. Miller GJ, Miller NE: Plasma high density lipoprotein concentration and development of ischemic heart disease. Lancet I:16 1975 6. Tsang RC. Glueck CJ, Fallat RW. et al: Neonatal familial hypercholesterolemia. Am J Dis Child 129:83. 1975 7. Tsang RC, Fallat RW, Glueck CJ: Cholesterol at birth and age I: Comparison of normal and hypercholesterolemic neonates. Pediatrics 53:458, 1974 8. Lipid Research Clinics Program. Manual of Laboratory Operations. vol I. Washington. D.C.. U.S. GPO. 1974
9. lshikawa TT. Brazter JB. Steiner PM. et al: A study of the heparin-manganese chloride method for determination of plasma alphalipoprotein cholesterol concentration. Lipids I I:628 633. 1976 IO. Castellt WP. Doyle JT. Gordon T. et al: HDL cholesterol levels (HDLC) in coronary heart disease (CHD): A cooperative lipoprotein phenotyping study. Ctrculation [Suppl] 2:51 52. 2196. 1975 I I. Tyroler HA. Hames CC. Krishan I. et al: Black-white differences in serum lipids and lipoproteins in Evans County. Prevent Med 4:541. 1975 12. Gulbrandsen CL. Rhoades GC. Kagan A: Cholesterol fractions and coronary heart disease in Hawaiian Japanese men. Circulation 50 (Suppl 31: 100. I974 13. Bang HW. Dyerberg J. Neilson A: Plasma lipid and lipoprotein patterns in Greenlandic West-Coast Eskimos. Lancet I: I 143. 1971 14. Tall AR, Small DM, Shipley GG, et al: Apoprotein stability and lipid-protein interactions in human plasma high-density lipoproteins. Proc Natl Acad Sci USA 72:4940. 1975
