María José Ariza1, José Rioja2, Daiana Ibarretxe3, Ana Camacho4, José Luis Díaz-Díaz5, Alipio Mangas6, Julio A Carbayo-Herencia7, Pablo Ruiz-Ocaña8, Itziar Lamíquiz-Moneo9, Daniel Mosquera10, Pedro Sáenz11, Luis Masana3, Ovidio Muñiz-Grijalvo4, Sofía Pérez-Calahorra9, Pedro Valdivielso12. 1. Department of Medicine and Dermatology, Lipids and Atherosclerosis Laboratory, Centro de Investigaciones Médico Sanitarias (CIMES), Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Spain. Electronic address: mariza@uma.es. 2. Department of Medicine and Dermatology, Lipids and Atherosclerosis Laboratory, Centro de Investigaciones Médico Sanitarias (CIMES), Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Spain. 3. Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira i Virgili, Reus, Spain. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Institut d'Investigació Sanitaria Pere Virgili. 4. UCERV-UCAMI, Internal Medicine Department, University Hospital Virgen del Rocío, Sevilla, Spain. 5. Lipid and Cardiovascular Risk Unit, Internal Medicine Service, Complejo Hospitalario Universitario A Coruña, Spain. 6. Internal Medicine Department, University Hospital Puerta del Mar, School of Medicine, University of Cadiz, Institute of Research and Innovation in Biomedical Sciences (INiBICA), Cádiz, Spain. 7. Lipid Unit, Hospital Quirón Salud, Albacete, Spain, and Department of Clinical Medicine, University Miguel Hernández, San Juan de Alicante, Alicante, Spain. 8. Diabetes and Metabolism Unit, Department of Pediatrics, University Hospital Puerta del Mar, Cádiz, Spain. 9. Lipid Unit, University Hospital Miguel Servet, IIS Aragón, CIBERCV, Zaragoza, Spain. 10. Department of Internal Medicine, Hospital de San Pedro, Logroño, Spain. 11. Lipid Clinic, Internal Medicine Department, Hospital de Mérida, Mérida, Spain. 12. Department of Medicine and Dermatology, Lipids and Atherosclerosis Laboratory, Centro de Investigaciones Médico Sanitarias (CIMES), Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Spain; Internal Medicine Unit, University Hospital Virgen de la Victoria, Málaga, Spain.
Abstract
BACKGROUND: Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. OBJECTIVE: This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. METHODS: Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). RESULTS: Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326_327insC; p.Tyr110Leufs*158). CONCLUSION: We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS.
BACKGROUND:Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. OBJECTIVE: This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. METHODS: Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). RESULTS: Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326_327insC; p.Tyr110Leufs*158). CONCLUSION: We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS.