Abstracts, XXIII National Congress of the Italian Society for the Study of Atherosclerosis (SISA) with e2e2 genotype and 2 were carriers of the R136S ...

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Abstracts, XXIII National Congress of the Italian Society for the Study of Atherosclerosis (SISA) with e2e2 genotype and 2 were carriers of the R136S mutation associated with e2 allele in one case previously published (Nutr Metab Cardiovas Dis 2003; 13: 93 99) and with e4 allele in the other case (the patient described here). The first case with R136S mutation (previously described by our group) belonged to a four-generation kindred from Genoa with a high rate of mortality for coronary artery disease: the proband was a 51 year-old female with previous myocardial infarction and residual angina, severe carotid atherosclerosis, arterial disease at lower limbs and arterial hypertension. Another case with R136S, previously published (see above), was identified in Palermo: the proband was an overweight 62 year-old male with a mixed hyperlipidemia; the second allele in this patient was e4. The R136S mutation co-segregated with the same haplotype at the APOE locus in the three Italian families ( 491 T, 219 G and 2440 G), thus suggesting a common ancestor. APOE R136S associated with e4 allele seems to be less deleterious on the arterial wall than associated with e2 allele. 89 PREDICTIVE FACTORS OF CAROTID ARTERIES STENOSIS IN GENETICALLY CHARACTERIZED HETEROZYGOUS FH PATIENTS L. Pisciotta1 , E. Pino1 , E. Pastorino1 , S. Calandra2 , S. Bertolini1 . 1 Internal Medicine, University of Genoa, 2 Department of Biomedical Science, University of Modena and Reggio Emilia, Italy E-mail: [email protected] We searched for elements predicting for the development of carotid arteries stenosis (>25%) in 354 genetically characterized FH patients (178 males and 176 females, over 30 years of age; TC 10.08±1.77, LDL-C 8.14±1.72, HDL-C 1.30±0.36, TG 1.51±0.70 mmol/L). Multiple logistic regression analysis showed that the presence of carotid plaques was independently associated with male gender (OR 3.09, 1.45 6.58, P 0.003), five-year increase of age (OR 1.92, 1.62 2.28, P 0.0001), arterial hypertension (OR 5.14, 2.07 12.7, P 0.0001), 1 mmol/L increase of LDL-C (OR 1.35, 1.12 1.64, P 0.002) and the presence of coronary artery disease (OR 4.10, 1.99 8.43, P 0.0001). No association were found with smoking, HDL-C and TG levels, and with LDL receptor mutational class (defective vs negative). We then analysed factors related to the severity of carotid lesions in this group of patients (stenosis between 25 and 50%, between 51 and 75% and over 75%, which were present in 43.2%, 4.8% and 2.2% of the patients, respectively). The severity of the lesions was also significantly related with some of the above mentioned parameters: five-year increase of age (P 0.0001), arterial hypertension (P 0.0001), LDL-C level (P 0.02) and the presence of coronary artery disease (P 0.0001). The LDL receptor mutational class was marginally associated with the severity of carotid stenosis (P 0.05). 90 A MODERATE PHENOTYPIC EXPRESSION IN A PATIENT HOMOZYGOUS FOR D200G MUTATION OF LDLR GENE L. Pisciotta1 , S. Martini2 , R. Fresa1 , A. Bellocchio1 , S. Airaldi1 , S. Calandra3 , S. Bertolini1 . 1 Department of Internal Medicine, University of Genoa, Genoa; 2 O.U. of Medicine, Piove di Sacco Hospital, Padua, 3 Deparment of Biomedical Science, University of Modena and Reggio Emilia, Italy E-mail: [email protected] We have genetically characterized four patients homozygous for the c.662 A>G mutation of LDLR gene (D200G, p.D221G). The clinical and biochemical features of these patients are reported in the Table. Patient





Sex Age (years) Smoking habits TC (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) TG (mmol/L) APOE genotype Receptor activity in fibroblasts PCSK9 gene CAD

M 49 no 17.84 16.81 0.64 0.85 e3e3 8% normal 3V, BP43y

M 50 no 12.59 10.86 1.29 0.94 e3e4 8% p.R97H Silent, 2V, BP54y

M 50 yes 16.29 14.58 0.77 2.03 e2e3 ND normal Angina

F 40 No 14.95 13.06 0.98 1.95 e3e3 ND normal No

The patient B.F., in comparison to the other homozygous patients, appears to have a less severe clinical phenotype. He underwent BP surgery at 54 and was treated with LDL apheresis every 15 days and simvastatin 40 mg/day (more recently with ezetimibe/simvastatin 10/40 mg/day). During the last five years LDL-C levels before apheresis ranged from 5.43 to 6.07 mmol/L (mean 5.71±0.15). The SPECT performed in 2009 (at 59 years of age) showed a normal myocardial perfusion. By sequencing PCSK9 gene we found a c.290 G>A mutation in exon 2 (p.R97H). R97 appears to be highly conserved during evolution (even in Zebrafish) and seems to be crucial for a correct folding and autocatalytic clevage of the peptide necessary to exit the ER. In silico analysis with PolyPhen predicts this mutation as possibly damaging. We have collected data from 122 heterozygous patients with D200G mutation (mean LDL-C levels adj. for gender and age resulted 6.67±1.49, median 6.47 mmol/L). Two heterozygous relatives of


proband B.F. were carriers of the PCSK9 p.R97H mutation; their LDL-C levels were 4.62 and 4.78 mmol/L (both below the 10th percentile of the distribution in heterozygous subjects with D200G). These observations suggest that p.R97H might be a loss of function (LOF) mutation, thus explaining the less severe phenotype of the patient (i.e. preservation of the residual LDL receptors). Obviously, functional analysis of the mutant PCSK9 in transfected cells is necessary to confirm this hypothesis. 91 MOLECULAR CHARACTERIZATION OF A CLINICALLY HOMOZYGOUS FH PATIENT FROM BOLIVIA L. Pisciotta, V. Guido, A. Bellocchio, R. Fresa, S. Bertolini. Department of Internal Medicine, University of Genoa, Italy E-mail: [email protected] The patient was a 10 year-old female from Bolivia, with xanthomas in the Achilles tendons and in the extensor tendons of the hands of big sizes, enormous tuberous xanthomas over the elbows, planar xanthomas in the gluteal region and in interdigital web of the hands between the first and second fingers. The plasma lipid profile of the patient was: TC 16.26, LDL-C 15.49, HDL-C 0.41 and TG 0.78 mmol/L. The proband’s father, 31 year-old, was free of cardiovascular symptoms and ultrasound examination of the carotid arteries revealed a max-IMT of 0.7 mm; his plasma lipid profile was: TC 6.90, LDL-C 5.00, HDL-C 1.29 and TG 1.33 mmol/L. The proband’s mother, 29 yearold, was not clinically evaluated but her reported plasma lipid profile was: TC 7.27, LDL-C 6.36, HDL-C 0.54 and TG 1.78 mmol/L. The reported lipid profile of the 4 year-old proband’s brother was: TC 8.12, LDL-C 7.22, HDL-C 0.75 and TG 0.32 mmol/L. By sequencing LDLR gene in the proband we identified the following mutations: c.535 G>A in exon 4 (E158K, p.E179K) and c.1472 C>A in exon 10 (T470N, p.T491N). The proband has inherited the first mutation from the mother and the second mutation from the father. The DNA sample from the proband’s brother was not available. Both mutations were never described before. Computational analysis of the two missense mutations was performed using Poly-Phen (http://genetics.bwh.harvard.edu/pph), PANTHER (http:// www.pantherdb.org/) and SIFT programmes (http://blocks.fhcrc.org/sift/ SIFT.html). The two mutations were predicted to be pathogenic by all three programmes. Mutation Poly-Phen



SupPSEC 5.054 P deleterious Not tolerated 0.886 P substituted 0.03 SupPSEC 7.045 P deleterious Not tolerated 0.982 P substituted 0.004


Probably damaging PSIC score 2.319 Probably damaging PSIC score 2.210


92 MOLECULAR CHARACTERIZATION OF TWO NOVEL PATIENTS WITH CHOLESTERYL ESTER STORAGE DISEASE (CESD) L. Pisciotta1 , S. Decarlis2 , H. Michelakakis3 , R. Fresa1 , S. Calandra4 , S. Bertolini1 . 1 Department of Internal Medicine, University of Genoa, 2 Deparment of Pediatrics, University of Milan,3 Department of Enzymology, Institute of Child Health, Athens, 4 Deparment of Biomedical Science, University of Modena and Reggio Emilia, Italy and Greece E-mail: [email protected] CESD is a recessive disorder characterized by hepato- or hepatosplenomegaly, chronic liver disease (fibrosis and nodular cirrhosis), increase of liver enzymes in plasma, mixed hyperlipidemia with low HDL and premature atherosclerosis. The disease is caused by cholesteryl esters (CE) accumulation in tissues, mainly in the liver, and variable accumulation of triglycerides (TG). The genetic defect consists in homozygous or compound heterozygous mutations of the LIPA gene (10q23.2-q23.3) encoding the lysosomal acid lipase (LAL), which hydrolizes CE and TG internalised via receptor-mediated endocytosis of plasma lipoprotein particles. Mutations that completely abolish LAL activity cause the severe Wolman’s disease, while mutations allowing a residual LAL activity (2 8% of controls in leukocytes) cause CESD. We have recently characterized two novel patients with CESD. Case 1. Italian female, 11 year-old, with hepatosplenomegaly, increased plasma levels of liver enzymes, mixed hyperlipidemia (TC 8.35 and TG 2.93 mmol/L) and residual LAL activity (3% in leukocytes, 10% in fibroblasts). Case 2. Greek male, 22 year-old, with hepatomegaly, hepatic fibrosis with accumulation of macrophages, moderate hypercholesterolemia (TC 5.58 mmol/L) and low HDL, increased plasma levels of liver enzymes and residual LAL activity (2% in leukocytes, 6% in fibroblasts). By sequencing the LIPA gene both patients resulted to be homozygous for the c.894 G>A mutation in exon 8 (del c.823_894, del p.S275_Q298). Up to now 41 patients with CESD (including the present cases) have been genetically characterized. Among these patients the c.894 G>A mutation, which allows 3 5% normal splicing of the LIPA pre-mRNA, resulted to be the most frequent mutation found in CESD patients (11 homozygotes, 24 compound heterozygotes), accounting for 56% of the mutant alleles.