Virginia Bañares

Association between the APOE*4 allele and atherosclerosis is age dependent among argentine males

Several studies have shown evidence of an association between the *4 allele of apolipoprotein E (APOE) and coronary heart disease (CHD) in different populations. We determined the APOE genotype and total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDLC) values in 189 patients with angiographically evaluated atherosclerosis. The APOE*4 allele was found to be statistically significantly more frequent (odds ratio, 1.93; 95% confidence interval, 1.12–3.32) among male patients than in a randomly chosen population-based sample. No significant difference was found when female patients were compared to the general population. The APOE*4 allele was found primarily among young (30–45-year-old) male patients (p < 0.04). Despite the ascending linear tendency of the mean TC values for genotypes APOE*2/*3, APOE*3/*3, and APOE*3/*4 reported in our case population, no differences were observed among our patients. We conclude that the APOE*4 allele is associated with an increased risk for atherosclerotic vascular disease, that this association has an age-dependent effect, and that it acts as a genetic factor that increases susceptibility to developing the disease in young to middle-aged male adults in our population.

Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries

BACKGROUND There is little information about familial hypercholesterolemia (FH) epidemiology and care in Ibero-American countries. The Ibero-American FH network aims at reducing the gap on diagnosis and treatment of this disease in the region. OBJECTIVE To describe clinical, molecular, and organizational characteristics of FH diagnosis in Argentina, Brazil, Chile, Colombia, Mexico, Portugal, Spain, and Uruguay. METHODS Descriptive analysis of country data related to FH cascade screening, molecular diagnosis, clinical practice guidelines, and patient organization presence in Ibero-America. RESULTS From a conservative estimation of an FH prevalence of 1 of 500 individuals, there should be 1.2 million heterozygous FH individuals in Ibero-America and roughly 27,400 were diagnosed so far. Only Spain, Brazil, Portugal, and Uruguay have active cascade screening programs. The prevalence of cardiovascular disease ranged from 10% to 42% in member countries, and the highest molecular identification rates are seen in Spain, 8.3%, followed by Portugal, 3.8%, and Uruguay with 2.5%. In the 3 countries with more FH patients identified (Spain, Portugal, and Brazil) between 10 and 15 mutations are responsible for 30% to 47% of all FH cases. Spain and Portugal share 5 of the 10 most common mutations (4 in low density lipoprotein receptor [LDLR] and the APOB3527). Spain and Spanish-speaking Latin American countries share 6 of the most common LDLR mutations and the APOB3527. LDL apheresis is available only in Spain and Portugal and not all countries have specific FH diagnostic and treatment guidelines as well as patient organizations. CONCLUSIONS Ibero-American countries share similar mutations and gaps in FH care.

Tetrasomy 21pter-q22.11: molecular, cytogenetic, and clinical findings

To the Editor: Down’s syndrome (DS) is the most frequent human genetic disorder, occurring in 1/600–800 live births. Although it is usually caused by the presence of an extra chromosome 21, there is minimal understanding of the way in which the additional chromosome causes the disease. To our knowledge, tetrasomy 21 without mosaicism has been reported in only 2 liveborn infants, both with classic dysmorphic signs of DS (1, 2). Here, we describe a new case of a male infant with a partial tetrasomy 21, resulting from an extra pseudodicentric chromosome 21 [psu dic(21)], without DS phenotype. The proband is the fifth child of healthy, nonconsanguineous parents. At birth, the mother was 46 and the father was 52 years old. Birth weight was 3300 g. Referral, at age 9.2 years, was for psychomotor and speech retardation. His physical examination showed brachycephaly, round face, horizontal palpebral fissures, high nasal bridge, prominent lower lip, normal set ears with helix root crossing concha, and macrogenitalism. Dermatoglyphic analysis was normal. The child was examined following the protocol of phenotype– genotype correlation (3). Physical measurements, with the exception of penile length (+4 SD) and testicular volume (6 ml), were all in the normal range. Electrocardiogram (EKG), electroencephalogram (EEG), ophthalmological evaluation, and brain stem auditory evoked potentials were normal. Brain computed tomography (CT) and magnetic resonance imaging (MRI) confirmed brachycephaly, but were otherwise normal. The clinical symptoms in our patient were compared with those on Jackon’s list (4) and only one, brachycephaly, of the ten most discriminating features of DS was present. The phenotypic score was 0,0126 (DS: 0,044-0,127) and, therefore, not consistent with a diagnosis of DS. Idiopathic precocious puberty was diagnosed at age 9.2 years, according to the method of Tanner (5), hormone profiles (6), and MRI of the cranium. Testicular ultrasonography revealed normal testes. At age 11.1 years, the proband has reached pubertal Tanner stage V, with an adult testicular volume (20 ml) and penile length (7). Treatment with gonadotrophin-releasing hormone (GnRH) agonist was initiated. These findings are unusual in healthy male children and have only been observed in 2 DS boys (8), in which primary gonadal deficiency is common (9). At age 10 years, the psychological examination (Terman test) indicated a moderate mental retardation (IQ 37), and his mental level was about 3 years. Visuoconstructive ability and visuomotor skills corresponded to a level of 5 years. Linguistically, he continued to function with pronounced difficulty, his intelligible speech being limited to a few words. The Cu/Zn SOD1 mean concentration in our patient (13090.5 mg/ml erytrocytes) showed an increased of 54.7% with respect to the normal population (84.095.7 mg/ml) and of 6.5% with respect to trisomy 21 patients (125.096.8 mg/ml), suggestive of 50% increased dosage. Karyotype analysis revealed an extra pseudodicentric bisatellited chromosome, which appeared to be of chromosome 21 origin, in all 100 analyzed cells. (Fig. 1a). Fluorescence in situ hybridization (FISH) analysis with probes WCP 21 and D13Z1/ D21Z1 (ONCOR) confirmed its derivation from chromosome 21 over the entire length and its dicentric nature. Hybridization signals were absent on the marker with probes D21S55, 36D3, 8A4/19C7, and 667B10. The size of the hybridization signal on psu dic(21) was larger than on the normal chromosomes 21 with probe 280B1, suggesting the presence of this locus in double dose in the marker chromosome.(Fig. 1b). Thus, according to our cytogenetic, cytomolecular, and SOD1 results, the breakpoint on psu dic(21) was considered to be between the loci SOD1 and D21S404, both in q22.11. In consequence, our patient’s karyotype shows a partial tetrasomy for the region 21pter-q22.11, including the SOD1 locus. The remaining region, from q22.11 to the telomere, is present in the normal diploid copy number. The karyotype was inter-

Unusual genetic variants associated with hypercholesterolemia in Argentina

BACKGROUND AND AIMS Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. METHODS In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300 mg/dL and/or LDL-C≥190 mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. RESULTS In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (n = 20, 2 novel), ABCG5/8 (n = 7, 2 novel), APOB (n = 3, 1 novel), CYP27A1 (n = 3, 1 novel), LIPA (n = 2, 1 novel), APOE (n = 2), LIPC (n = 1, novel), LIPG (n = 1, novel), and SCARB1 (n = 1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. CONCLUSIONS Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy.