Background: Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for predicting of the prognosis and selecting appropriate therapy.
Materials and Methods: Genetic analysis was performed in two patients with primary hypocholesterolemia born from consanguineous parents. The oral fat tolerance test (OFTT) was performed in one patient with FHBL (apoB-87.77) and one with ABL as well as in four normal control subjects. After overnight fasting, blood samples were drawn. Serum lipoprotein and remnant-like particle (RLP) fractions were determined by HPLC analysis.
Results: Both patients with homozygous FHBL were asymptomatic probably because of preserved levels of fat-soluble vitamins, especially vitamin E. The patients with FHBL were homozygous because of novel apoB-83.52 and apoB-87.77 mutations, and although one of them (apoB-87.77) had fatty liver disease, microscopic findings suggesting nonalcoholic steatohepatitis were absent. Fasting apoB-48 and RLP-triglyceride levels in the patient with homozygous FHBL, which were similar to those in normal control subjects, increased after OFTT both in normal control subjects and the patient with FHBL but not in the patient with ABL, suggesting that the fat load administered was absorbed only in the patient with FHBL.
Conclusion: Although lipid levels in the patients with homozygous FHBL and ABL were comparable, fasting, postoral fat loading of apoB-48, as well as RLP-triglyceride levels, may help in the differential diagnosis of FHBL and ABL and provide a prompt diagnosis using genetic analysis in the future.
Abetalipoproteinemia Familial hypobetalipoproteinemia Oral fat tolerance test
Averna M, Seip RL, Mankowitz K, Schonfeld G (1993) Postprandial lipemia in subjects with hypobetalipoproteinemia and a single intestinal allele for apoB-48. J Lipid Res 34:1957–1967PubMedGoogle Scholar
Burnett JR, Bell DA, Hooper AJ, Hegele RA (2014a) Clinical utility gene card for: abetalipoproteinaemia - Update 2014. Eur J Hum Genet. doi:10.1038/ejhg.2014.224Google Scholar
Burnett JR, Bell DA, Hooper AJ, Hegele RA (2014b) Clinical utility gene card for: familial hypobetalipoproteinaemia (APOB) - Update 2014. Eur J Hum Genet. doi:10.1038/ejhg.2014.225Google Scholar
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37:161–165PubMedCrossRefGoogle Scholar
Groenewegen WA, Averna MR, Pulai J, Krul ES, Schonfeld G (1994) Apolipoprotein B-38.9 does not associate with apo[a] and forms two distinct HDL density particle populations that are larger than HDL. J Lipid Res 35:1012–1025PubMedGoogle Scholar
Hooper AJ, Robertson K, Barrett PH, Parhofer KG, van Bockxmeer FM, Burnett JR (2007) Postprandial lipoprotein metabolism in familial hypobetalipoproteinemia. J Clin Endocrinol Metab 92:1474–1478PubMedCrossRefGoogle Scholar
Inazu A, Nakajima K, Nakano T et al (2008) Decreased post-prandial triglyceride response and diminished remnant lipoprotein formation in cholesteryl ester transfer protein (CETP) deficiency. Atherosclerosis 196:953–957PubMedCrossRefGoogle Scholar
Katsuda S, Kawashiri MA, Inazu A et al (2009) Apolipoprotein B gene mutations and fatty liver in Japanese hypobetalipoproteinemia. Clin Chim Acta 399:64–68PubMedCrossRefGoogle Scholar
Kinoshita M, Kojima M, Matsushima T, Teramoto T (2005) Determination of apolipoprotein B-48 in serum by a sandwich ELISA. Clin Chim Acta 351:115–120PubMedCrossRefGoogle Scholar
Lee J, Hegele RA (2014) Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis 37:333–339PubMedCrossRefGoogle Scholar
Nakajima K, Saito T, Tamura A et al (1993) Cholesterol in remnant-like lipoproteins in human serum using monoclonal anti apo B-100 and anti apo A-I immunoaffinity mixed gels. Clin Chim Acta 223:53–71PubMedCrossRefGoogle Scholar
Ohashi K, Ishibashi S, Yamamoto M, Osuga J, Yazaki Y, Yukawa S, Yamada N (1998) A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus. Arterioscler Thromb Vasc Biol 18:1330–1334PubMedCrossRefGoogle Scholar
Parhofer KG, Barrett PH (2006) Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies. J Lipid Res 47:1620–1630PubMedCrossRefGoogle Scholar
Parhofer KG, Barrett PH, Aguilar-Salinas CA, Schonfeld G (1996) Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in human apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes. J Lipid Res 37:844–852PubMedGoogle Scholar
Pulai JI, Latour MA, Kwok PY, Schonfeld G (1998) Diabetes mellitus in a new kindred with familial hypobetalipoproteinemia and an apolipoprotein B truncation (apoB-55). Atherosclerosis 136:289–295PubMedCrossRefGoogle Scholar
Tada H, Kawashiri MA, Tanaka A et al (2012) Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia. Eur J Clin Invest 42:1094–1099PubMedCrossRefGoogle Scholar
Tarugi P, Averna M, Di Leo E et al (2007) Molecular diagnosis of hypobetalipoproteinemia: an ENID review. Atherosclerosis 195:e19–e27PubMedCrossRefGoogle Scholar
Turk U, Basol G, Barutcuoglu B, Sahin F, Habif S, Tarugi P, Bayindir O (2012) A 54-year-old diabetic man with low serum cholesterol. Clin Chem 58:826–829PubMedCrossRefGoogle Scholar
Usui S, Hara Y, Hosaki S, Okazaki M (2002) A new on-line dual enzymatic method for simultaneous quantification of cholesterol and triglycerides in lipoproteins by HPLC. J Lipid Res 43:805–814PubMedGoogle Scholar
Wetterau JR, Aggerbeck LP, Bouma ME et al (1992) Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258:999–1001PubMedCrossRefGoogle Scholar
Yang XP, Inazu A, Yagi K, Kajinami K, Koizumi J, Mabuchi H (1999) Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene. Arteioscler Thromb Vasc Biol 19:1950–1955CrossRefGoogle Scholar