Alternative titles; symbols
SNOMEDCT: 34349009; ORPHA: 530849; DO: 0111421, 1171;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q23.3 | Hyperchylomicronemia, late-onset | 144650 | Autosomal dominant | 3 | APOA5 | 606368 |
A number sign (#) is used with this entry because of evidence that type V hyperlipoproteinemia can be caused by mutations in the APOA5 gene (606368).
Type V of Fredrickson is characterized by increased amounts of chylomicrons and very low density lipoprotein (VLDL) and decreased LDL and high density lipoprotein (HDL) in the plasma after a fast. Numerous conditions cause this phenotype, including insulin-dependent diabetes mellitus, contraceptive steroids, alcohol abuse, and glycogen storage disease I (232200). Features include bouts of abdominal pain and eruptive xanthoma. Fredrickson and Lees (1966) observed parental consanguinity, suggesting recessive inheritance.
Nagasaka et al. (2003) described 2 unrelated premature females with transient type V hyperlipidemia and low lipoprotein lipase (LPL; 238600) activity at 1 to 2 months of age without deficiencies of LPL or apoCII (608083) proteins or detectable inhibitors and without mutations in the LPL or APOC2 genes. The authors postulated the presence of an unidentified LPL inhibitor, perhaps a maternal factor such as estrogen.
While genetic factors account for a large proportion of the rare type I hyperlipidemia (238600), the complex interaction between genetics and environment is only partly understood in the more common type V hyperlipidemia. Marcais et al. (2005) reported what they considered to be a new form of familial hyperchylomicronemia with vertical transmission, late onset, incomplete penetrance, and an unusual resistance to conventional treatment. They identified a Q139X truncating mutation in the APOA5 gene (606368.0001) as the determinant of this dyslipidemia based on the following: (a) observation in 2 pedigrees that hyperchylomicronemia occurred only in the Q139X carriers and cosegregated with the Q139X mutant allele in 1 pedigree; (b) presence in the carriers of the 15-kD peptide corresponding to the N-terminal end of APOA5, as expected for a truncation at residue 139; and (c) altered association of wildtype APOA5 to plasma lipoproteins in all of the carriers from both families. Additionally, they demonstrated that severe hypertriglyceridemia in Q139X mutation carriers resulted from an LPL defect leading to lipolysis impairment. In both of the families studied, the dyslipidemia occurred exclusively in the Q139X carriers, none of whom had an identifiable deleterious mutation in the second APOA5 allele. This initially suggested that Q139X causes a dominant hyperchylomicronemia. Subsequent study of the second family indicated that the Q139X heterozygous genotype was incompletely penetrant, with only 2 out of 6 carriers affected. The role for compound heterozygosity with either the S19W mutation of APOA5 (606368.0002) or the APOA5*2 haplotype was indicated by the complete association of hyperchylomicronemia with these compound heterozygote genotypes. Marcais et al. (2005) showed that severe hyperchylomicronemia in homozygote and heterozygote Q139X carriers was caused by profound LPL defect, and they provided what appeared to be the first clear evidence in humans of a functional interplay between APOA5 and LPL.
Gregg et al. (1983) suggested that apoE4 (see 107741) is associated with severe type V hyperlipoproteinemia in a manner comparable to the association of apoE2 with type III hyperlipoproteinemia (617347).
Fredrickson, D. S., Lees, R. S. Familial hyperlipoproteinemia.In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.) : The Metabolic Basis of Inherited Disease. (2nd ed.) New York: McGraw-Hill (pub.) 1966.
Gregg, R. E., Zech, L. A., Brewer, H. B., Jr. Apolipoprotein E alleles in severe hypertriglyceridaemia. (Letter) Lancet 321: 353 only, 1983. Note: Originally Volume I. [PubMed: 6130351] [Full Text: https://doi.org/10.1016/s0140-6736(83)91653-7]
Marcais, C., Verges, B., Charriere, S., Pruneta, V., Merlin, M., Billon, S., Perrot, L., Drai, J., Sassolas, A., Pennacchio, L. A., Fruchart-Najib, J., Fruchart, J.-C., Durlach, V., Moulin, P. Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J. Clin. Invest. 115: 2862-2869, 2005. [PubMed: 16200213] [Full Text: https://doi.org/10.1172/JCI24471]
Nagasaka, H., Kikuta, H., Chiba, H., Murano, T., Harashima, H., Ohtake, A., Senzaki, H., Sasaki, N., Inoue, I., Katayama, S., Shirai, K., Kobayashi, K. Two cases with transient lipoprotein lipase (LPL) activity impairment: evidence for the possible involvement of an LPL inhibitor. Europ. J. Pediat. 162: 132-138, 2003. [PubMed: 12655414] [Full Text: https://doi.org/10.1007/s00431-002-1133-3]
Nixon, J. C., Martin, W. G., Kalab, M., Monahan, G. J. Type V hyperlipoproteinemia: a study of a patient and family. Clin. Biochem. 2: 389-398, 1969.