Share This Article:

Familial Hypercholesterolemia in an Azorean Family: A Novel Mutation in the Low-Density Lipoprotein Receptor Gene

Abstract Full-Text HTML XML Download Download as PDF (Size:1956KB) PP. 685-691
DOI: 10.4236/abb.2014.58081    2,905 Downloads   3,935 Views  

ABSTRACT

Familial hypercholesterolemia (FH) is one of the most prevalent autosomal dominant inherited disorders. Mutations have been found in at least 3 genes: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). We report on an Azorean family with FH due to a novel mutation in the LDLR gene across three generations. The index-case was first seen at our endocrinology consultation at 12 years old, because of delayed growth and development. Laboratorial investigations revealed a complete failure of the anterior hypophysis due to a congenital malformation of the sella turcica. A total cholesterol of 313 mg/dL (90 - 190 mg/dL) and low-density lipoprotein cholesterol (LDL-C) of 262 mg/dL (<115 mg/dL) was found in routine blood tests. There was a paternal history of hypercholesterolemia, corneal arcus and myocardial infarction at an early age. Screening for mutations in LDLR gene was carried out. In the affected cases, an intronic heterozygous point mutation (c.818-3C > G) causing a premature termination of transcription (stop codon) was identified.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Lourenço, R. , Martins, L. , Anselmo, J. , Soares, M. , Medeiros, A. , Bourbon, M. , César, R. and Gomes, F. (2014) Familial Hypercholesterolemia in an Azorean Family: A Novel Mutation in the Low-Density Lipoprotein Receptor Gene. Advances in Bioscience and Biotechnology, 5, 685-691. doi: 10.4236/abb.2014.58081.

References

[1] Goldstein, J.L., Hobbs, H. and Brown, M.S. (1995) Familial Hypercholesterolemia. In: Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D., Eds., The Metabolic and Molecular Bases of Inherited Disease, 7th Edition, McGraw-Hill, New York, 1981-2030.
[2] Bourbon, M., Rato, Q. and Investigators of the Portuguese FH Study (2006) Portuguese Familial Hypercholesterolemia Study: Presentation of the Study and Preliminary Results. Revista Portuguesa de Cardiologia, 25, 999-1013.
[3] Kwiterovich, P.O. (2008) Clinical and Laboratory Assessment of Cardiovascular Risk in Children: Guidelines for Screening, Evaluation and Treatment. Journal of Clinical Lipidology, 2, 248-266.
http://dx.doi.org/10.1016/j.jacl.2008.06.003
[4] Rader, D.J., Cohen, J. and Hobbs, H.H. (2003) Monogenetic Hypercholesterolemia: New Insights in Pathogenesis and Treatment. Journal of Clinical Investigation, 111, 1795-1803.
http://dx.doi.org/10.1172/JCI200318925
[5] Guardamagna, O., Restagno, G., Rolfo, E., Pederiva, C., Martini, S., Abello, F., Baracco, V., Pisciotta, L., Pino, E., Calandra, S. and Bertolini, S. (2009) The Type of LDLR Gene Mutation Predicts Cardiovascular Risk in Children with Familial Hypercholesterolaemia. Journal of Pediatrics, 155, 199-204.
http://dx.doi.org/10.1016/j.jpeds.2009.02.022
[6] Fouchier, S.W., Defesche, J.C., Kastelein, J.J. and Sijbrands, E.J. (2004) Familial Defective Apolipoprotein B versus Familial Hypercholesterolemia: An Assessment of Risk. Seminars in Vascular Medicine, 4, 259-264.
http://dx.doi.org/10.1055/s-2004-861493
[7] Garcia-Alvarez, I., Castillo, S., Mozas, P. and Grupo de Estudio de la Hipercolesterolemia Familiar (2003) Differences in Clinical Presentation between Subjects with a Phenotype of Familial Hypercholesterolemia Determined by Defects in the LDL-Receptor and Defects in Apo B-100. Revista Española de Cardiología, 56, 769-774.
[8] Harada-Shiba, M., Arai, H., Oikawa, S., Ohta, T., Okada, T., Okamura, T., Nohara, A., Bujo, H., Yokote, K., Wakatsuki, A., Ishibashi, S. and Yamashita, S. (2012) Guidelines for the Management of Familial Hypercholesterolemia. Journal of Atherosclerosis and Thrombosis, 19, 1043-1060.
http://dx.doi.org/10.5551/jat.14621
[9] Rodendurg, J., Vissers, M.N., Wiegman, A., Trip, M.D., Bakker, H.D. and Kastelein, J.J. (2004) Familial Hypercholesterolemia in Children. Current Opinion in Lipidology, 15, 405-411.
http://dx.doi.org/10.1097/01.mol.0000137228.92396.f3
[10] Wiegman, A., de Groot, E., Hutten, B.A., Rodenburg, J., Gort, J., Bakker, H.D., Sijbrands, E.J. and Kastelein, J.J. (2004) Arterial Intima-Media Thickness in Children Heterozygous for Familial Hypercholesterolaemia. Lancet, 363, 342-343.
http://dx.doi.org/10.1016/S0140-6736(04)15467-6
[11] Marks, D., Thorogood, M., Neil, H.A. and Humphries, S.E. (2003) A Review on the Diagnosis, Natural History, and Treatment of Familial Hypercholesterolaemia. Atherosclerosis, 168, 1-14.
http://dx.doi.org/10.1016/S0021-9150(02)00330-1
[12] Defesche, J.C., Lansberg, P.J., Umans-Eckenhausen, M.A. and Kastelein, J.J. (2004) Advanced Method for the Identification of Patients with Inherited Hypercholesterolemia. Seminars in Vascular Medicine, 4, 59-65.
http://dx.doi.org/10.1055/s-2004-822987
[13] Lind, S., Rudling, M., Ericsson, S., Olivecrona, H., Eriksson, M., Borgström, B., Eggertsen, G., Berglund, L. and Angelin, B. (2004) Growth Hormone Induces Low-Density Lipoprotein Clearance but Not Bile Acid Synthesis in Humans. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 349-356.
http://dx.doi.org/10.1161/01.ATV.0000110657.67317.90
[14] Humphries, S.E., Cranston, T., Allen, M., Middleton-Price, H., Fernandez, M.C., Senior, V., Hawe, E., Iversen, A., Wray, R., Crook, M.A. and Wierzbicki, A.S. (2006) Mutational Analysis in UK Patients with a Clinical Diagnosis of Familial Hypercholesterolaemia: Relationship with Plasma Lipid Traits, Heart Disease Risk and Utility in Relative Tracing. Journal of Molecular Medicine, 84, 203-214.
http://dx.doi.org/10.1007/s00109-005-0019-z
[15] Fouchier, S.W., Kastelein, J.J. and Defesche, J.C. (2005) Update of the Molecular Basis of Familial Hypercholesterolemia in the Netherlands. Human Mutation, 26, 550-556.
http://dx.doi.org/10.1002/humu.20256
[16] Leren, T.P. (2004) Cascade Genetic Screening for Familial Hypercholesterolemia. Clinical Genetics, 66, 483-487.
http://dx.doi.org/10.1111/j.1399-0004.2004.00320.x
[17] Watts, G.F., Gidding, S., Wierzbicki, A.S., Toth, P.P., Alonso, R., Brown, W.V., Bruckert, E., Defesche, J., Lin, K.K., Livingston, M., Mata, P., Parhofer, K.G., Raal, F.J., Santos, R.D., Sijbrands, E.J., Simpson, W.G., Sullivan, D.R., Susekov, A.V., Tomlinson, B., Wiegman, A., Yamashita, S. and Kastelein, J.J. (2014) Integrated Guidance on the Care of Familial Hypercholesterolaemia from the International FH Foundation. International Journal of Cardiology, 171, 309-325.
http://dx.doi.org/10.1016/j.ijcard.2013.11.025
[18] Alves, A.C., Medeiros, A.M., Francisco, V., Gaspar, I.M., Rato, Q. and Bourbon, M. (2010) Molecular Diagnosis of Familial Hypercholesterolemia: An Important Tool for Cardiovascular Risk Stratification. Revista Portuguesa de Cardiologia, 29, 907-921.
[19] Leigh, S.E., Foster, A.H., Whittall, R.A., Hubbart, C.S. and Humphries, S.E. (2008) Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database. Annals of Human Genetics, 72, 485-498.
http://dx.doi.org/10.1111/j.1469-1809.2008.00436.x
[20] Garcia-Garcia, A.B., Ivorra, C., Martinez-Hervas, S., Blesa, S., Fuentes, M.J., Puig, O., Martín-de-Llano, J.J., Carmena, R., Real, J.T. and Chaves, F.J. (2011) Reduced Penetrance of Autosomal Dominant Hypercholesterolemia in a High Percentage of Families: Importance of Genetic Testing in the Entire Family. Atherosclerosis, 218, 423-430.
http://dx.doi.org/10.1016/j.atherosclerosis.2011.07.106
[21] Kotze, M.J., Davis, H.J., Bissbort, S., Langenhoven, E., Brusnicky, J. and Oosthuizen, C.J. (1993) Intrafamilial Variability in the Clinical Expression of Familial Hypercholesterolemia: Importance of Risk Factor Determination for Genetic Counselling. Clinical Genetics, 43, 295-299.
http://dx.doi.org/10.1111/j.1399-0004.1993.tb03821.x
[22] Medeiros, A.M., Alves, A.C., Francisco, V., Bourbon, M. and investigators of the Portuguese FH Study (2010) Update of the Portuguese Familial Hypercholesterolaemia Study. Atherosclerosis, 212, 553-558.
http://dx.doi.org/10.1016/j.atherosclerosis.2010.07.012
[23] Vuorio, A., Kuoppala, J., Kovanen, P.T., Humphries, S.E., Strandberg, T., Tonstad, S. and Gylling, H. (2010) Statins for Children with Familial Hypercholesterolemia. Cochrane Database of Systematic Reviews, 7, Article ID: CD006401.
[24] Vuorio, A., Docherty, K., Humphries, S., Kuoppala, J. and Kovanen, P. (2013) Statin Treatment of Children with Familial Hypercholesterolemia—Trying to Balance Incomplete Evidence of Long-Term Safety and Clinical Accountability: Are We Approaching a Consensus? Atherosclerosis, 226, 315-320.
http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.032
[25] Braamskamp, M.J., Wijburg, F.A. and Wiegman, A. (2012) Drug Therapy of Hypercholesterolaemia in Children and Adolescents. Drugs, 72, 759-772.
http://dx.doi.org/10.2165/11632810-000000000-00000
[26] Araujo, M.B., Botto, P.M. and Mazza, C.S. (2012) Use of Ezetimibe in the Treatment of Familial Hypercholesterolemia in Children and Adolescents. Anales de Pediatría, 77, 37-42.
http://dx.doi.org/10.1016/j.anpedi.2011.11.007
[27] Avis, H.J., Kusters, M., Vissers, M.N., Huijgen, R., Janssen, T.H., Wiegman, A., Kindt, I., Kastelein, J.J., Wijburg, F.A. and Hutten, B.A. (2012) Follow-Up of Children Diagnosed with Familial Hypercholesterolemia in National Genetic Screening Program. Journal of Pediatrics, 161, 99-103.
http://dx.doi.org/10.1016/j.jpeds.2011.12.037

  
comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.