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Unusual presentation of cholesteryl ester storage disease (CESD): report on a new family
132
Tuesday 11 October 1994: Poster Abstracts Dyslipoproteinemias
Thus, in this kindred there is evidence of sex dimorphism in the expression of CAD in FH, based on the delayed expression of CAD and longer life expectancy in HMZ females than HMZ males, and the similar age at onset of symptomatic CAD in HMZ females and HTZ males. Unusual presentation of cholesteryl ester storage disease (CESD): renort on a new familv F6ger B, Shin- Y, S&l w, m, L&hleitner M, Hoppichler F, Ritsch A, Patsch JR, Dept. of Med., Univ. qf Innsbruck,
p/
Anichstrasse 35, A-6020 Innsbruck, Austria
The hallmarks of CESD are hepatomegaly and hyperlipoproteinemia. The clinical abnormalities in these patients are due to a complete deficiency of lysosomal acid lipase resulting in cholesteryl ester accumulation in various tissues. Mildly elevated transaminases (aspartate aminotransferase 21 units/l; alanine aminotransferase 23 units/l) and discrete hepatomegaly were noted in H.M., an apparently healthy female, in her thirties. A liver biopsy obtained at age 39 revealed lipid storage in hepatic parenchymal and Kupffer cells, compatible with the suspected lipid storage disease. Acid lipase activity determined in leucocytes averaged 0.2 pmol/min/mg protein (control range 1540 pmol/min/mg protein), i.e. about 1% of the lower limit of healthy controls. The presentation of H.M. is rather unusual in several respects: (i) at age 44, H.M. is one of the oldest patients with CESD reported and nevertheless is still completely asymptomatic. (ii) Ophthalmic fundoscopy revealed multiple bilateral white discolorations, probably representing local lipid storage. Lipid storage in the retina has been reported in Wolman’s disease, another manifestation of acid lipase deficiency, but not in CESD. (iii) The plasma lipoprotein abnormalities in CESD may include the HDL. A remarkable preponderance of HDLz has been reported in patient 23 (Schmitz et al The Metabolic Basis of Inherited Disease 1989; 1623-1644). This is at variance with our findings. In H.M. cholesterol, triglycerides, HDL2 cholesterol and HDb cholesterol averaged 246, 138, 5 and 30 mg/dl during treatment with cholestyramine (12 g/day) and pravastatin (40 mg/day). Therefore, even in advanced adulthood, CESD may remain completely asymptomatic and may be an underrated cause of secondary hyperlipoproteinemia and, consequently, atherosclerosis. Familial defective apu B-100 (FDB) in France: frequency and clinical presentation in families w, De Gennes JL, Dairou F, Lecerf JM, Gardette J, Bruckert E, Bernard C, Lagarde JP, Tmffert J, Hejblum G, Benlian P,
11561
H6pital Piti& 83 Boulevard de I’Hfipital, 75013 Paris, France
FDB is a monogenic disorder caused by a receptor bindingdefective mutation of apo B-100. The R3500E apo B mutation has been reported as a significant cause of hypercholesterolemia in Northern Europe. Conversely, FDB seems rare in Southern Europe. Although FDB manifests by a primary inherited hypercholesterolemia, its clinical presentation may vary from one population to another. Our aim was to estimate FDB frequency in France and to analyze associated clinical features in families. A primer-mismatch PCR-based method was used for mutation detection from dried blood spots. We screened 895 unrelated hyperlipidemic subjects, among whom 321 subjects had primary isolated hypercholesterolemia (TC > 300 mg/dl). 24 hypercholesterolemic subjects (7.5%) were heterozygous for FDB. We estimated FDB frequency at about l/700 in France. FDB families were studied: among 137 subjects, 65 were FDB heterozygotes. 30% of carriers had tendinous xanthomas after age 18, and 27% had coronary arterial disease after age 40. Plasma levels of TC (327 It 0.56 mg/dl), LDLCT (2.49 f 0.46 mg/dl) and apo B (1.69 5 0.32 mg/dl) were elevated and still varied with age
and sex. Triglyceride levels were higher (P < 0.001) and HDL-CT lower (P < 0.005) in carriers versus non carriers. Lp(a) levels were similar, most subjects were E3/3. In three large families (87 subjects), penetrance of hypercholesterolemia defined by elevated TC, LDL-CT and apo B levels was 97%. Therefore FDB is frequent in France and is associated with primary inherited hypercholesterolemia. Recurrent and novel LDL-receptor gene mutations causing heterozygote familial hypercholesterolemia in La Habana PerreiraE, FerreraR, Hermelin B, Bernard C, Bertrand V, & J&n& Bereziat G, Lab. de Biochimie, H6pital Saint Antoine, 184
11571
rue du Faubourg, St. Antoine, 75012 Paris, France
Familial hypercholesterolemia (FH) has been described in various populations. In most countries, heterogeneity of LDL receptor gene mutations underlie its pathogenesis and different mutations have been reported in Latin America. Two unrelated families of Spanish descent, originating from La Habana, exhibited a phenotype of heterozygous FH. This was assessed in probands by the presence of extravascular cholesterol deposits and premature coronary arterial disease and was confirmed by elevated plasma TC, LDL-C and apo B, up to twice the values observed in their unaffected relatives. The R35OOEapo B gene mutation was absent. Southern blotting using 6 different enzymes failed to detect any gross gene rearrangement on the LDL receptor gene. Segregation analysis of eight polymorphic markers analyzed by PCR indicated the LDL receptor gene as the predisposing locus in both families. PCR amplification of the 18 exons followed by automated sequencing of PCR products (Applied Biosystems) allowed identification of two heterozygote mutations. A G + A substitution in exon 9 creates a V408M mutation, which is observed in the Netherlands and is one of the Afrikaner founder mutations. However, the associated haplotype differs in this case from the previously reported. The second defect is a G --t A substitution in exon 6 creating a E256K mutation in the 7th highly conserved cystein-rich repeat of the binding domain. This novel mutation disrupts a Mnl I restriction site, segregates with one marker haplotype and hypercholesterolemia in the family. Both mutations involve CpG dimers, supporting mutagenic mechanisms at these sites, and molecular heterogeneity of LDL receptor gene mutations, causing FH. Beneficial effects of wax-matrix sustained-release niacin on lipid-transport system in patients tith hypercholesterolemia w, Perova NV, Kiseleva NG, Olferiev AM, Gorskova IN, Ozerova IN, Aronov DM, Akhmedzhanov NM, Propimy GA,
11581
National Res. Centre for Preventive Med., Lane, Moscow 101953 Russia
10, Petroverigsky
The objective of this study was to assess the efficacy of waxmatrix sustained-release niacin (‘Endur-acin’, Endurance Products Co, USA) on lipid-transport system in patients with hyperlipidemia. Patients aged 26-69 (n = 69) with total cholesterol (C) values 225-300 mg/dl after 2 months’ hypolipidemic diet were included in a blind, cross-over 6-month trial. They were randomized into two groups: Endur-acin 2 months, placebo 2 months, Endur-acin 2 months (EPE group, n = 39 patients) and placebo 2 months, Endur-acin 2 months, Endur-acin 2 months (PEE group, n = 30 patients). Drug dose was 1.5-2.0 g/d?y. Total C, triglycerides (Tg) and HDL-C levels were determined enzymatitally, apo A-I and apo B by ‘rocket’ electroimmunoassay. Plasma cholesteryl ester transfer protein (CETP) activity and plasma cholesterol esterifying capacity were assayed using radioisotopic methods.
Atherosclerosis X, Montreal, October 1994
Tuesday 11 October 1994: Poster Abstracts Dyslipoproteinemias
Thus, in this kindred there is evidence of sex dimorphism in the expression of CAD in FH, based on the delayed expression of CAD and longer life expectancy in HMZ females than HMZ males, and the similar age at onset of symptomatic CAD in HMZ females and HTZ males. Unusual presentation of cholesteryl ester storage disease (CESD): renort on a new familv F6ger B, Shin- Y, S&l w, m, L&hleitner M, Hoppichler F, Ritsch A, Patsch JR, Dept. of Med., Univ. qf Innsbruck,
p/
Anichstrasse 35, A-6020 Innsbruck, Austria
The hallmarks of CESD are hepatomegaly and hyperlipoproteinemia. The clinical abnormalities in these patients are due to a complete deficiency of lysosomal acid lipase resulting in cholesteryl ester accumulation in various tissues. Mildly elevated transaminases (aspartate aminotransferase 21 units/l; alanine aminotransferase 23 units/l) and discrete hepatomegaly were noted in H.M., an apparently healthy female, in her thirties. A liver biopsy obtained at age 39 revealed lipid storage in hepatic parenchymal and Kupffer cells, compatible with the suspected lipid storage disease. Acid lipase activity determined in leucocytes averaged 0.2 pmol/min/mg protein (control range 1540 pmol/min/mg protein), i.e. about 1% of the lower limit of healthy controls. The presentation of H.M. is rather unusual in several respects: (i) at age 44, H.M. is one of the oldest patients with CESD reported and nevertheless is still completely asymptomatic. (ii) Ophthalmic fundoscopy revealed multiple bilateral white discolorations, probably representing local lipid storage. Lipid storage in the retina has been reported in Wolman’s disease, another manifestation of acid lipase deficiency, but not in CESD. (iii) The plasma lipoprotein abnormalities in CESD may include the HDL. A remarkable preponderance of HDLz has been reported in patient 23 (Schmitz et al The Metabolic Basis of Inherited Disease 1989; 1623-1644). This is at variance with our findings. In H.M. cholesterol, triglycerides, HDL2 cholesterol and HDb cholesterol averaged 246, 138, 5 and 30 mg/dl during treatment with cholestyramine (12 g/day) and pravastatin (40 mg/day). Therefore, even in advanced adulthood, CESD may remain completely asymptomatic and may be an underrated cause of secondary hyperlipoproteinemia and, consequently, atherosclerosis. Familial defective apu B-100 (FDB) in France: frequency and clinical presentation in families w, De Gennes JL, Dairou F, Lecerf JM, Gardette J, Bruckert E, Bernard C, Lagarde JP, Tmffert J, Hejblum G, Benlian P,
11561
H6pital Piti& 83 Boulevard de I’Hfipital, 75013 Paris, France
FDB is a monogenic disorder caused by a receptor bindingdefective mutation of apo B-100. The R3500E apo B mutation has been reported as a significant cause of hypercholesterolemia in Northern Europe. Conversely, FDB seems rare in Southern Europe. Although FDB manifests by a primary inherited hypercholesterolemia, its clinical presentation may vary from one population to another. Our aim was to estimate FDB frequency in France and to analyze associated clinical features in families. A primer-mismatch PCR-based method was used for mutation detection from dried blood spots. We screened 895 unrelated hyperlipidemic subjects, among whom 321 subjects had primary isolated hypercholesterolemia (TC > 300 mg/dl). 24 hypercholesterolemic subjects (7.5%) were heterozygous for FDB. We estimated FDB frequency at about l/700 in France. FDB families were studied: among 137 subjects, 65 were FDB heterozygotes. 30% of carriers had tendinous xanthomas after age 18, and 27% had coronary arterial disease after age 40. Plasma levels of TC (327 It 0.56 mg/dl), LDLCT (2.49 f 0.46 mg/dl) and apo B (1.69 5 0.32 mg/dl) were elevated and still varied with age
and sex. Triglyceride levels were higher (P < 0.001) and HDL-CT lower (P < 0.005) in carriers versus non carriers. Lp(a) levels were similar, most subjects were E3/3. In three large families (87 subjects), penetrance of hypercholesterolemia defined by elevated TC, LDL-CT and apo B levels was 97%. Therefore FDB is frequent in France and is associated with primary inherited hypercholesterolemia. Recurrent and novel LDL-receptor gene mutations causing heterozygote familial hypercholesterolemia in La Habana PerreiraE, FerreraR, Hermelin B, Bernard C, Bertrand V, & J&n& Bereziat G, Lab. de Biochimie, H6pital Saint Antoine, 184
11571
rue du Faubourg, St. Antoine, 75012 Paris, France
Familial hypercholesterolemia (FH) has been described in various populations. In most countries, heterogeneity of LDL receptor gene mutations underlie its pathogenesis and different mutations have been reported in Latin America. Two unrelated families of Spanish descent, originating from La Habana, exhibited a phenotype of heterozygous FH. This was assessed in probands by the presence of extravascular cholesterol deposits and premature coronary arterial disease and was confirmed by elevated plasma TC, LDL-C and apo B, up to twice the values observed in their unaffected relatives. The R35OOEapo B gene mutation was absent. Southern blotting using 6 different enzymes failed to detect any gross gene rearrangement on the LDL receptor gene. Segregation analysis of eight polymorphic markers analyzed by PCR indicated the LDL receptor gene as the predisposing locus in both families. PCR amplification of the 18 exons followed by automated sequencing of PCR products (Applied Biosystems) allowed identification of two heterozygote mutations. A G + A substitution in exon 9 creates a V408M mutation, which is observed in the Netherlands and is one of the Afrikaner founder mutations. However, the associated haplotype differs in this case from the previously reported. The second defect is a G --t A substitution in exon 6 creating a E256K mutation in the 7th highly conserved cystein-rich repeat of the binding domain. This novel mutation disrupts a Mnl I restriction site, segregates with one marker haplotype and hypercholesterolemia in the family. Both mutations involve CpG dimers, supporting mutagenic mechanisms at these sites, and molecular heterogeneity of LDL receptor gene mutations, causing FH. Beneficial effects of wax-matrix sustained-release niacin on lipid-transport system in patients tith hypercholesterolemia w, Perova NV, Kiseleva NG, Olferiev AM, Gorskova IN, Ozerova IN, Aronov DM, Akhmedzhanov NM, Propimy GA,
11581
National Res. Centre for Preventive Med., Lane, Moscow 101953 Russia
10, Petroverigsky
The objective of this study was to assess the efficacy of waxmatrix sustained-release niacin (‘Endur-acin’, Endurance Products Co, USA) on lipid-transport system in patients with hyperlipidemia. Patients aged 26-69 (n = 69) with total cholesterol (C) values 225-300 mg/dl after 2 months’ hypolipidemic diet were included in a blind, cross-over 6-month trial. They were randomized into two groups: Endur-acin 2 months, placebo 2 months, Endur-acin 2 months (EPE group, n = 39 patients) and placebo 2 months, Endur-acin 2 months, Endur-acin 2 months (PEE group, n = 30 patients). Drug dose was 1.5-2.0 g/d?y. Total C, triglycerides (Tg) and HDL-C levels were determined enzymatitally, apo A-I and apo B by ‘rocket’ electroimmunoassay. Plasma cholesteryl ester transfer protein (CETP) activity and plasma cholesterol esterifying capacity were assayed using radioisotopic methods.
Atherosclerosis X, Montreal, October 1994