ABB  Vol.5 No.8 , July 2014
Familial Hypercholesterolemia in an Azorean Family: A Novel Mutation in the Low-Density Lipoprotein Receptor Gene
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. &#73n the affected cases, an intronic heterozygous point mutation (c.818-3C > G) causing a premature termination of transcription (stop codon) was identified.


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

 
 
Top