Corneal arcus as the presenting sign of familial hypercholesterolemia in a young child.

A 2.6-year-old boy presented with prominent corneal arcus. This clinical sign is rarely seen at such a young age and led to the diagnosis of familial hypercholesterolemia (FH). Genetic analysis detected biallelic pathogenic sequence variants c.1069G>A and c.2034C>A in the LDLR gene. There is significant cardiovascular morbidity and mortality associated with FH, hence early diagnosis and treatment is imperative.

Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil.

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.

Association Between Cholesterol Efflux Capacity and Atherosclerotic Cardiovascular Disease in Patients With Familial Hypercholesterolemia.

OBJECTIVE: Patients with familial hypercholesterolemia (FH) are at high risk for premature atherosclerotic cardiovascular disease (ASCVD), especially because of long-term exposure to high low-density lipoprotein cholesterol levels. It has been reported that low-density lipoprotein-lowering therapy delays the onset of ASCVD. However, it still remains difficult to prevent it. Therefore, novel biomarkers and therapeutic targets are necessary to evaluate and prevent atherosclerosis in FH. The aim of this study was to investigate associations of cholesterol efflux capacity with the presence of ASCVD and clinical features in patients with heterozygous FH. APPROACH AND RESULTS: We measured cholesterol efflux capacity in 227 patients with heterozygous FH under pharmaceutical treatment. Seventy-six (33.5%) of them were known to have ASCVD. In a logistic-regression analysis adjusted for risk factors, increased efflux capacity was associated with decreased risk of ASCVD even after the addition of high-density lipoprotein cholesterol level as a covariate (odds ratio per 1-SD increase, 0.95; 95% confidence interval, 0.90-0.99; P<0.05). Decreased cholesterol efflux capacity was associated with the presence of corneal arcus after adjusting for age and sex. In addition, inverse relationships between cholesterol efflux capacity and Achilles tendon thickness, as well as carotid intima-media thickness, were observed after adjustment for age, sex, and traditional cardiovascular risk factors. CONCLUSIONS: Cholesterol efflux capacity was independently and inversely associated with the presence of ASCVD in heterozygous FH. In view of residual risks after treatment with statins, cholesterol efflux capacity might be a novel biomarker and a therapeutic target for preventing atherosclerosis in patients with FH.

Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy.

PURPOSE: Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed. METHODS: DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5' untranslated region (UTR) exons. RESULTS: No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes). CONCLUSIONS: Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.

Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor-like domain of jagged 1.

In the present study, we report a kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Six of seven available affected patients manifested mild-to-severe combined hearing loss, predominantly affecting middle frequencies. Two patients were diagnosed with vestibular pathology. All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. No individual in this family met diagnostic criteria for any previously described clinical syndrome. A candidate-gene approach was undertaken and culminated in the identification of a novel Jagged 1 (JAG1) missense mutation (C234Y) in the first cysteine of the first epidermal-growth-factor-like repeat domain of the protein. JAG1 is a cell-surface ligand in the Notch signaling pathway. Mutations in JAG1 have been identified in patients with Alagille syndrome. Our findings revealed a unique phenotype with highly penetrant deafness, posterior embryotoxon, and congenital heart defects but with variable expressivity in a large kindred, which demonstrates that mutation in JAG1 can cause hearing loss.

A novel single base deletion in the LDLR gene (211delG): Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes.

A single base deletion (211delG) in the low density lipoprotein receptor (LDLR) gene was shown to cause familial hypercholesterolaemia (FH) in a large family from Northern Ireland. Twenty-four of 52 family members tested had this mutation, 13 of which were newly diagnosed. Mutation-positive individuals had significantly higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without 211delG. LDL-C was a more accurate indicator of disease status than TC. When TC levels alone were considered, in individuals over 16 years, a false negative rate (TC < 7.5 mmol/l) of 40% was found; however this fell to 13% based on inclusion of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly higher TC levels than those without CAD and tended to have tendinous xanthomas (TX) and corneal arcus (CA). Generic polymorphisms in the angiotensin converting enzyme (ACE) and apolipoprotein (apo) B genes did not appear to be associated with lipid levels or with the clinical severity of the disease; however, the apo E epsilon4 allele did show a lipid-raising effect in individuals with the mutation.

[Arcus juvenilis and lecithin:cholesterol acyltransferase functions. Report of a case of familial fish-eye-disease]. / L'arcus juvenilis et les fonctions de la lécithine: cholestérol acyltransférase. A propos d'un cas familial de "fish-eye-disease".

A Fish-Eye Disease family has been recently discovered in Bordeaux, being made up 3 homozygous and 3 heterozygous patients for a recessive hereditary anomaly of LCAT. The influence of the enzyme on the plasma lipoprotein composition and its role in cholesterol efflux explain, at least for a part, the pathophysiology of the lipidic corneal clouding which is the single symptom in the homozygous patients. The comparison of the molecular biology data resulting from the analysis of the patient's LCAT gene with those which have been obtained in other FED patients as in patients with classic LCAT deficiency allows to differenciate biochemically both pathologies. It allows too the differentiation between primary and secondary (Tangier disease, apo A-I deficiency, A-I and C-III deficiency) LCAT deficiencies, which may be all associated with a Corneal arcus. The profile of the lipidic parameters most often measured in plasma (Total cholesterol, HDL-cholesterol, cholesterol esterification rate, lipidogramme, apo A-I, apo A-II, LCAT mass and activity) is practically pathognomonic of this affection and consequently authorizes its differential diagnosis. In spite of the striking deficiency of HDL as of their atherogenesis preventing markers these patients do not show any sign of early cardio vascular disease.

[Diagnostic and functional significance of arcus lipoides in hypercholesterolemia]. / Diagnostische und funktionelle Bedeutung des Arcus lipoides bei Hypercholesterinämie.

Twenty-eight patients were studied who required treatment for hypercholesterolemia type IIa. Familial hypercholesterolemia was found in 53%. Sixty percent of all patients had arcus senilis. When familial and non-familial hypercholesterolemia were compared the incidence of arcus senilis was 80% and 38%, respectively. The gradation of the condition was minor (n = 9), moderate (n = 4), or pronounced (n = 4); all patients with a strong degree and 7 of 8 patients with either moderate or pronounced arcus senilis had familial hypercholesterolemia. The mean cholesterol level was 345 +/- 82 in patients with familial hypercholesterolemia and 353 +/- 120 mg/dl in patients with non-familial hypercholesterolemia. Although the correlation between the cholesterol level and the degree of arcus senilis was higher in patients with familial hypercholesterolemia than in those with non-familial hypercholesterolemia (r = 0.45 versus r = 0.17), neither had clinical relevance. There was no connection between the cholesterol level, refraction or visual acuity. The mean contrast sensitivity measured for five different spatial frequencies in all patients was normal. In comparison with patients without arcus senilis, the mean values in patients with severe arcus senilis showed lower contrast sensitivity for the higher spatial frequencies.

Conjunctival xerosis, arcus lipoides and Rieger's disease.

Three generations of a family with conjunctival xerosis, Rieger's anomaly (complete or incomplete) and arcus lipoides are described. The xerosis was found always to be accompanied by a Rieger anomaly, which had sometimes, but not always, been detected before. Independent heredity was not observed. In a number of cases the xerosis was bilateral and localised both temporally and nasally. The combination appears to be a stigma malformationis oculi. Correlation with a temporary vitamin A deficiency in early youth appears possible. At this age in such families caution is advisable in the administration of vitamin A inhibiting medicines such as steroids and neomycine.

Granular corneal dystrophy with late manifestation.

Ninety-two cases of granular corneal dystrophy, most of them belonging to 5 pedigrees are described. The age of manifestation in this Finnish type of granular dystrophy is first in the end of the second decade, and visual acuity is in mean normal through the whole life. An autopsy study showed no changes outside cornea elsewhere in the eyeball. In one family with granular dystrophy, another type of dystrophy, hereditary fleck dystrophy of the cornea, was accidentally found.

[Crystalline corneal dystrophy (Schnyder) in the presence of familial type IIa hyperlipoproteinaemia (author's transl)]. / Kristalline Hornhautdystrophie (Schnyder) bei familiärer Typ II a-Hyperlipoproteinämie.

A family with dominant autosomal hyperlipoproteinaemia typ IIa is reported. One sibling, a 19-year-old man, showed in addition to the hyperlipoproteinaemia typical corneal signs of crystalline corneal dystrophy of Schnyder. From 1964 to 1976 these corneal deposits increased. The problems of hyperlipoproteinaemia combined with corneal crystalline dystrophy are discussed.