Rosa María Sánchez-Hernández1, Pablo Prieto-Matos2, Fernando Civeira3, Eduardo Esteve Lafuente4, Manuel Frías Vargas5, José T Real6, Fernando Goñi Goicoechea7, Francisco J Fuentes8, Miguel Pocovi9, Mauro Boronat10, Ana María Wägner10, Luis Masana11. 1. Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno Infantil de Gran Canaria, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. Electronic address: rosamariasanher@gmail.com. 2. Unidad de Endocrinología Pediátrica, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Spain. 3. Unidad Clínica y de Investigación en Lípidos y Arterioesclerosis, Hospital Universitario Miguel Servet, IIS Aragón, Centro de Investigación Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Universidad de Zaragoza, Zaragoza, Spain. 4. Servicio Endocrinología y Nutrición, Hospital Universitari de Girona Dr. Josep Trueta, Spain. 5. Centro de Salud San Andrés, Madrid, Spain. 6. Servicio de Endocrinología y Nutrición, Hospital Clínico Valencia, Departamento de Medicina, Universidad de Valencia, INCLIVA, Centro de Investigación Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Spain. 7. Servicio Endocrinología y Nutrición, Hospital Universitario de Basurto, Bilbao, Spain. 8. Hospital Universitario Reina Sofía, Universidad de Córdoba, Centro de Investigación Biomédica en Red de Fisiopatolgía de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Instituto Maimónedes de Investigación Biomédica de Córdoba (IMIBIC), Spain. 9. Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, IIS Aragón, CIBERCV, Zaragoza, Spain. 10. Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno Infantil de Gran Canaria, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain. 11. Unidad de Medicina Vascular y Metabolica, Unidad de Investigación en Lipidos y Arterioesclerosis, Hospital Universitario "Sant Joan", Universitat Rovira i Virgili, IISPV, CIBERDEM, Reus, Madrid, Spain.
Abstract
BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in LDL protein receptor adaptor 1 (LDLRAP1). It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. We aimed to characterize ARH in Spain. METHODS: Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia of Spain were reviewed. RESULTS: Seven patients with ARH were identified, 6 true homozygous and one compound heterozygous with a novel mutation: c.[863C>T];p.[Ser288Leu]. High genetic heterogeneity was found in this cohort. True homozygous subjects for LDLRAP1 have more severe phenotypes than the compound heterozygous patient, but similar to patients with homozygous familial hypercholesterolemia (HoFH). Cardiovascular disease was present in 14% of the ARH patients. LDL-C under treatment was above 185 mg/dl and the response to PCSK9 inhibitors was heterogeneous. Finally, the estimated prevalence in Spain is very low, with just 1 case per 6.5 million people. CONCLUSIONS: ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of ASCVD than HoFH.
BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in LDL protein receptor adaptor 1 (LDLRAP1). It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. We aimed to characterize ARH in Spain. METHODS: Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia of Spain were reviewed. RESULTS: Seven patients with ARH were identified, 6 true homozygous and one compound heterozygous with a novel mutation: c.[863C>T];p.[Ser288Leu]. High genetic heterogeneity was found in this cohort. True homozygous subjects for LDLRAP1 have more severe phenotypes than the compound heterozygous patient, but similar to patients with homozygous familial hypercholesterolemia (HoFH). Cardiovascular disease was present in 14% of the ARHpatients. LDL-C under treatment was above 185 mg/dl and the response to PCSK9 inhibitors was heterogeneous. Finally, the estimated prevalence in Spain is very low, with just 1 case per 6.5 million people. CONCLUSIONS:ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of ASCVD than HoFH.