Ctinical Genetics 1976: 9: 149-155
Further observations on familial hypobetaIiproteinaemia I. TAMIR, 0. LEVTOW, D. LOTAN,C. LEGUM,D. HELDENBERG, AND B. WERBIN Paediatric Metabolic Unit, Paediatric Department “B” and the Clinical Genetic Unit, Municipal-Governmental Health Centre, Sackler School of Medicine, Tel-Aviv, Israel A family with hypobetalipoproteinaemia with 10 affected members is described. In six patients low density lipoprotein cholesterol (LDL-c) concentrations were about 10 % of normal. In four LDL-c was reduced to about 50 % of normal; these four patients probably represent the “intermediate” form of hypobetalipoproteinaemia. This variation in total cholesterol concentration and LDL-c among the affected individuals of the same family could reflect differences of expression in a single aberrant gene or additive expression of a gene at a second locus. Received 5 March, revised 23 May, accepted for publication I August I975
Familial low density lipoprotein (LDL) deficiency (familial hypobetalipoproteinaemia) was first proposed by Fredrickson & Levy (1972) as a separate entity of dyslipoproteinaemia, based on the findings in four families previously reported in the literature (Van Buchem et al. 1966, Mars et al. 1969, Richet et al. 1969, Levy et al. 1970). Since then, two additional families have been described (Fosbrooke et al. 1973, Rerabek & Eliash 1973). All the subjects studied were characterized by markedly reduced concentrations of serum LDL. There were no clinical abnormalities, except in one woman aged 37 who had a neurological disorder (Mars et al. 1969). It was concluded (Levy et al. 1970, Mars et al. 1969) that the mode of transmission of this inherited disorder is probably autosomal dominant, although the possibility of polygenic determination of this trait was raised by Rerabek & Eliash (1973). We report a family with 10 affected
members in which additional information concerning this seemingly rare disorder was obtained. Patients
The propositus, 1112 in Fig. 1, was the outcome of an uneventful second pregnancy. His birth weight was 2,600 g. At 4 months he was hospitalized for investigation of microcephaly. His weight was then 5,100 g and his head circumference 35.5 cm. No other abnormalities were found on physical examination. During hospitalization infantile spasms were observed and the electroencephalographic recording confirmed the diagnosis. Biochemical screening of serum and urine, including amino acid analysis, revealed no abnormality except in lipids and lipoproteins. T h e karyotype was normal. A fat balance test (72 h collection on an intake of more than 30 g of fatl24 h) was normal (fecal fat 6.8 g/72 h). No acantho-
1 so
TAMIR ET AL
cytes were seen on repeated examination of wet blood smears. Air contrast studies were refused. A diagnosis of primary microcephaly was accepted as most likely. The incidental finding of a serum total (TC) Of 95 - lo5 mg”OO and the absence of a beta lipoprotein band on paper electrophoresis led us to investigate the child and his family for a lipoprotein disorder.
I
n
Flg. 1. Pedigree of family with hypobetalipoproteinaemia, 0 Normal
fl,o~o~~~liinrotein “Intermediate” hypobetalipoproteinaemia
Methods
All lipid and lipoprotein analyses were made after a fast of no less than 12 h. The presence of LDL was determined by immunoelectrophoresis (Rabinovitz & Schen 1965) and paper electrophoresis (Salt et al. 1960). The following serum lipids were measured: total cholesterol (Rappaport & Eichhorn 1960), triglyceride (TG) (Shafrir & Khassis 1969) and phospholipids (PL) (Bartlett
1959). The major phospholipid fractions were estimated following separation on thinlayer chromatography (solvent system- chloEstimaroform:methanol: water-80: 35: 5). tion of phosphorous in each fraction was done by the method of Bartlett (1959). Concentrations of cholesterol in the various lipoprotein classes were measured according to Friedewald et al. (1972). In four
Table 1
Clinical details, serum vitamin A. (i.u./lOO ml) and serum carotene (;)/lo0 ml) in a family with hypobetalipoproteinaemia
I
II
111
Age (Y)
Sex
1 2
56 50
M F
Died of “alcoholic cirrhosis” Healthy
1 2
25 27
F M
3 4
25 18
F F
Healthy Lental opacities Alternating strabismus Healthy Lental opacities Alternating strabismus
1 2
3 4 5 6 7
1‘I2 0.5 6‘12 3 4 6’11
M M F F F M
9
M
Clinical findings
Healthy Microcephaly, infantile spasms Myopia Healthy Healthy Myopia Myopia
1 Normal values for vitamin A > 100 i.u.1100 ml 2. Normal values for carotene > 120 yI100 ml - Not examined.
Vit.A’
Carotene2
-
-
105
152
130 55
140 32
60
28
65
-
65 45 65 54
34 26 34 57
42 75
-
39 112
-
158 168 105 150
2 3
4 5 6 7
919
13.36
98 5 3.37 187 f 8.49
63 C 4.94 66 +. 5.78 75 2 4.91
28 2.99 104 & 4.9 129 +. 11.43
*
9 58
79
86
62
98
-
55
-
80
44 8
98 10 18 14
77 105 102 122
74 89
100
-
LDL(c)
97
HDL(c)
-
*
7 0.71 18 1.49 15 5 2.23
*
17 6
8
23
9 8
15 10 15 7
10
-
VLDL(c)
0.487 C 0.085 1.644 2 0.146 1.791 5 0.203
0.688 0.633 0.114 0.674
0.090
0.595
1.273 0.095 0.176 0.114
1.030
-
'H"d-:,",'{ -
PL
+.
+.
* 5.16 10.64 8.96
103 196 123 190
155 118 192
244 124 173 178
191
96.9 181.9 219.7
1. Died in 1969. Results given are from medical charts 4 years prior to his death. 2. Repeat analysis with double amount of serum showed presence of beta lipoproteins. HDL(c) - High density lipoprotein-cholesterol LDL(c) - Low density lipoprotein-cholesterol VLDL(c) - Very low density lipoprotein-cholesterol N.C.a - 10 cord bloods (mean +. S.E.) N.C.b - 10 healthy children aged 1-12 years N.C.c - 10 healthy adults aged 1 8 6 7 years.
N.C-a N.Cb N.C-c
127 105
1
Ill
190 125 135 143
1 2 3 4
II
95-105('1 207
1 2
TC
I
No.
*
36 5 3.53 88 7.6 78 2 11.1
29
86
40
114
47 40 59
77 49 74 35
115
TG
normal normal no beta[*' normal
normal no beta(zJ no beta
normal no betacz) no betacz) no beta
normal
I
PaDer electrophoresis
no beta normal
-
normal
no beta no beta
-
normal no beta no beta no beta
normal
-
Immunoelectrophoresis
Electrophoresis of Iipoproteins
Serum lipids (rngA00 ml) and lipoproteins in family with hypobetalipoproteinaemia
Table 2
D
I -
rn
D
z
-rn
-I
0
I]
-0
0
D
I-
D
-I
m rn
0
D
.