Low-density lipoprotein levels and not mutation status predict intima-media thickness in familial hypercholesterolemia.

BACKGROUND: Intima-media thickness (IMT) is a well-described marker of cardiovascular disease. In this study we aim to determine whether low-density lipoprotein (LDL) levels and disease-related mutation status can predict IMT in patients with severe familial hypercholesterolemia (FH) referred for or on LDL apheresis. METHODS: Genetic screening, lipid profile testing, and IMT measurements were performed on a series of 33 severe FH patients (19 homozygous) on LDL apheresis treatments (LDL 447 ± 151 mg/dL, age range 6-60 years). Data were then compared with literature IMT-LDL data for normal subjects, mild FH patients, and severe FH patients (18, 41, and 6 studies, respectively). RESULTS: Age-adjusted IMT was linearly related to LDL levels over a wide range of values (<500 mg/dL), except for the severe FH no-apheresis cohort. Alternatively, our severe FH population (mostly on apheresis) did follow the mild FH/control age-adjusted IMT-LDL relation. CONCLUSIONS: In severe FH, measuring LDL levels is more predictive of increased IMT than genetic screening.

Homozygous familial hypercholesterolemia in Lebanon: a genotype/phenotype correlation.

Familial hypercholesterolemia (FH) is an inherited disease characterized by the deposition of LDL in tissues causing premature atherosclerosis. Many genes are implicated in FH resulting in a large variability in the phenotype. DNA sequencing of the LDLR gene was done for forty patients clinically diagnosed with homozygous FH and forty family members variably affected. Patients underwent noninvasive heart and vascular studies. Statistical and pedigree analyses were used to correlate the different genotypes with the phenotypes. The prevalence of homozygosity at the Lebanese allele (2043C>A) is 45%. However, 27.5% of the patients have no mutations at all in the LDLR gene, and 27.5% are either heterozygous for the 2043C>A mutation, heterozygous for a mutation in another exon of the LDLR gene, or combined heterozygous for two different mutations. We confirm previous reports on the higher prevalence of FH in Lebanon. Our results do, however contradict previous reports on an assumed higher prevalence among the Christian Lebanese. Mutations in the LDLR especially combined heterozygosity can cause a severe phenotype similar to the homozygous mutation in the Lebanese allele. This information is particularly important in targeting the more prevalent heterozygotes in the general population with early diagnosis and intervention.

Detection of ON1 and novel genotypes of human respiratory syncytial virus and emergence of palivizumab resistance in Lebanon.

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in children and immunocompromised individuals. A multi-center surveillance of the epidemiologic and molecular characteristics of RSV circulating in Lebanon was performed. The attachment (G) and fusion (F) glycoproteins were analyzed and compared to those reported regionally and globally. 16% (83/519) of the nasopharyngeal swabs collected during the 2016/17 season tested positive for RSV; 50% (27/54) were RSV-A and 50% (27/54) were RSV-B. Phylogenetic analysis of the G glycoprotein revealed predominance of the RSVA ON1 genotype, in addition to two novel Lebanese genotype variants, hereby named LBA1 and LBA2, which descended from the ON1 and NA2 RSV-A genotypes, respectively. RSV-B strains belonged to BA9 genotype except for one BA10. Deduced amino acid sequences depicted several unique substitutions, alteration of glycosylation patterns and the emergence of palivizumab resistance among the Lebanese viruses. The emergence of ON1 and other novel genotypes that are resistant to palivizumab highlights the importance of monitoring RSV globally.

Molecular epidemiology and genetic characterization of influenza B virus in Lebanon during 2016-2018.

BACKGROUND: Influenza B viruses are a major cause of serious acute respiratory infections in humans. METHODS: Nasopharyngeal swabs were collected from subjects with influenza-like illness during October 2016-June 2018 and screened for influenza A and B. The hemagglutinin (HA) and neuraminidase (NA) genes of the Lebanese influenza B specimens were sequenced and phylogenetically compared with the vaccine strains and specimens from the Eastern Mediterranean Region and Europe. RESULTS: Influenza A and B viruses co-circulated between October and May and peaked between January and March. During the 2016-2017 season, A/H3N2 (33.4%) and B/Yamagata (29.7%) were the predominantly circulating viruses followed by B/Victoria and A/H1N1pdm09 viruses. During the 2017-2018 season, A/H3N2 (31.5%) and A/H1Npdm09 (29.3%) were most prevalent with co-circulation of B/Yamagata and to a lesser extent B/Victoria viruses. The B/Yamagata specimens belonged to clade-3 while the B/Victoria belonged to clade-1A. None of the analyzed specimens had a mutation known to confer resistance to NA inhibitors (NAIs). CONCLUSION: Multiple subtypes of influenza co-circulate each year in Lebanon with a peak between January and March. The trivalent vaccine included a B/Victoria strain which mismatched the B/Yamagata lineage that predominated during the study period, highlighting the importance of quadrivalent vaccines.

Hereditary vitamin D-resistant rickets in Lebanese patients: the p.R391S and p.H397P variants have different phenotypes.

BACKGROUND: Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder caused by mutations in the vitamin D receptor (VDR) gene. Variable phenotypes have been associated with these mutations, and some of these were linked to the effects they have on the interacting partners of VDR, mainly the retinoic X receptor (RXR). METHODS: We examined four patients with HVDRR from three unrelated Lebanese families. All parents were consanguineous with normal phenotype. We used Sanger sequencing to identify mutations in the coding exons of VDR. RESULTS: Two homozygous mutations (p.R391S and p.H397P), both in exon 9 of the VDR gene, were identified. Phenotype/genotype association was not possible even for the same mutation. Alopecia was seen only with the p.R391S mutation. Despite a comparable rachitic bone disease, the patients showed different responsiveness to large doses of alfacalcidol (1-α-hydroxy vitamin D3) supplementation. CONCLUSIONS: This is the first report of VDR mutations in Lebanon with promising clinical outcomes despite the severity of the phenotypes.

Premature Valvular Heart Disease in Homozygous Familial Hypercholesterolemia.

Valvular heart disease frequently occurs as a consequence of premature atherosclerosis in individuals with familial hypercholesterolemia (FH). Studies have primarily focused on aortic valve calcification in heterozygous FH, but there is paucity of data on the incidence of valvular disease in homozygous FH. We performed echocardiographic studies in 33 relatively young patients (mean age: 26 years) with homozygous FH (mean LDL of 447 mg/dL, 73% on LDL apheresis) to look for subclinical valvulopathy. Twenty-one patients had evidence of valvulopathy of the aortic or mitral valves, while seven subjects showed notable mitral regurgitation. Older patients were more likely to have aortic valve calcification (>21 versus ≤21 years: 59% versus 12.5%; p = 0.01) despite lower LDL levels at the time of the study (385 versus 513 mg/dL; p = 0.016). Patients with valvulopathy were older and had comparable LDL levels and a lower carotid intima-media thickness. Our data suggests that, in homozygous FH patients, valvulopathy (1) is present across a wide age spectrum and LDL levels and (2) is less likely to be influenced by lipid-lowering treatment. Echocardiographic studies that focused on aortic root thickening and stenosis and regurgitation are thus likely an effective modality for serial follow-up of subclinical valvular heart disease.

Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.

BACKGROUND: The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype. METHODS: We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening. RESULTS: We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes. CONCLUSION: The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.