Annie Lacroux

Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study

The POLA study (June 1995 through July 1997) is a population-based study on cataract and age-related macular degeneration (AMD) and their risk factors in 2584 residents of Séte (South of France), aged 60–95 years. Classification of AMD was performed on 50° fundus photographs, according to an international classification. The presence of cardiovascular disease and its risk factors was determined by interviewer-based questionnaire, clinical examination (anthropometry, blood pressure) and fasting plasma measurements. Using a logistic model adjusted for age and gender, late AMD was not significantly associated with a history of cardiovascular disease, diabetes, use of hypocholesterolemic drugs, hypertension, blood pressure or plasma lipids. Obese subjects (body mass index greater than 30 kg/m 2 ) had a 2.29-fold (95% confidence interval (CI): 1.00–5.23) and 1.54-fold (CI: 1.05–2.26) increased risk of late AMD and pigmentary abnormalities in comparison with lean subjects. Finally, the risk of soft drusen was decreased in those subjects with a history of cardiovascular disease (odds-ratio (OR) = 0.72, CI: 0.54–0.97), and increased with increasing levels of HDL-cholesterol (OR = 1.52, CI: 1.14–2.02). None of these results were modified by further adjustments for smoking, educational level and plasma alpha-tocopherol. These results need to be confirmed by other studies, which ideally should be longitudinal and prospective.

Biomarkers of inflammation and malnutrition associated with early death in healthy elderly people.

OBJECTIVES: To determine whether malnutrition and biomarkers of inflammation predict all‐cause, cancer, and cardiovascular mortality in healthy elderly subjects.

Dietary fat and the risk of age-related maculopathy: the POLANUT Study

This study aimed at assessing the associations of dietary fat with the risk of age-related maculopathy (ARM), in the framework of a population-based study from southern France. Nutritional data were collected using a dietitian-administered food-frequency questionnaire. ARM was classified from retinal photographs using the international classification and included neovascular age-related macular degeneration, geographic atrophy, soft indistinct drusen, soft distinct drusen associated with pigmentary abnormalities. After multivariate adjustment, high total, saturated and monounsaturated fat intake were associated with increased risk for ARM (odds ratio (OR)=4.74, P=0.007; OR=2.70, P=0.04; and OR= 3.50, P=0.03, respectively). Total polyunsaturated fatty acid was not significantly associated with ARM. Total and white fish intake was not significantly associated with ARM, but fatty fish intake (more than once a month versus less than once a month) was associated with a 60% reduction in risk for ARM (OR=0.42, P=0.01).

Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management.

ABSTRACT Purpose: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. Methods: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. Results: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. Conclusions: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.

Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia.

Objective To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. Methods Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1 mutation, 8 and 33 had X-linked RP (xlRP) with RP2 and RPGR mutations, respectively, 198 and 93 had Usher syndrome and arRP without RP1 mutations, respectively. The median of the spherical equivalent (SE) and the IQR (Q25–Q75) was determined and multiple comparisons were performed. Results arRP patients with RP1 mutations had SE median at −4.0 dioptres (D) OD (Ocula Dextra); −3.88 D OS (Ocula Sinistra), whereas arRP patients without RP1 mutations (−0.50 D OD; −0.75 D OS) and Usher syndrome patients (−0.50 D OD; −0.38 D OS) were significantly less myopic (p<0.0001). Conversely, myopia of xlRP patients with either an RPGR mutation (−4.50 D OD; −5.25 D OS) or an RP2 mutation (−6.25 D OD; −6.88 D OS) was not significantly different from the arRP group with RP1 mutations. arRP without RP1 mutations, Usher syndrome and adRP with RP1 mutation had a narrow IQR (−9.06 to −1.13 D), whereas arRP with RP1 mutations and xlRP with RP2 or RPGR mutations had a larger range (−9.06; −1.13 D). Conclusions arRP patients with RP1 mutations have myopia not different from patients with xlRP with RP2 or RPGR mutations, while RP patients from other genetic subgroups were emmetropic or mildly myopic. We suggest that arRP patients with high myopic refractive error should be preferentially analysed for RP1 mutations.

Clinical Evaluation and Cone Alterations in Choroideremia

Choroideremia is a rare retinal dystrophy (OMIM #303100; prevalence 1/50 000) with progressive atrophy of the retinal pigment epithelium, choriocapillaris, and concomitant loss of photoreceptors. As development of therapies highlights the need for fine markers in this disease, we have investigated a large patient series by examining the cone density and progression of the atrophy in the central islet through adaptive optics and retinal autofluorescence, respectively. Briefly, 44 male patients (mean age, 35 years; range, 2e69) from the database of the national referral center Maolya (Montpellier University Hospital, study authorization no. 11018S, France) were included. Most patients (92%; 36/39) complained of night blindness; 28% had night blindness onset after the age of 20. They had myopic refractive error (91%; SE 3.02 3.01; right eye, 3.20 3.13 OS), different from 681 eyes of patients with various retinal dystrophies (SE 1.23 2.91; P < 0.0001; Fig S1A available at www.aaojournal.org). Visual acuity (decimal Snellen chart), varying from 1.0 to light perception, was correlated with age (r 1⁄4 0.59; P < 0.0001), mainly declining after 40 (Fig S1B), with 42% of patients having a 0.2 to 0.6 difference between the 2 eyes. Visual field reduction by Goldmann perimetry correlated with age (r 1⁄4 0.74; P < 0.0001; Fig S1C) as rod (r 1⁄4 0.51; P < 0.0001), and cone (r 1⁄4 0.57; P < 0.0001) electroretinogram amplitudes correlated with age as well. (Fig S1D, E). By fundus autofluorescence with the Heidelberg retinal confocal angiograph (Heidelberg Engineering, Dossenheim, Germany), using the “draw region” tool, we measured the surface of the central islet at several time points. Before 17 years (mean, 15.1), the mean surface was 25.7 mm, decreasing by 6.05 mm/y. After 17 years (mean, 24.9), it was 5.4 mm, decreasing by 1.23 mm/y (Fig 1A). Spectral domain OCT (Heidelberg Engineering) showed disorganized structures of the retina (tubulations, cysts, interlaminar bridges) that we compared with images obtained by adaptive optics-based infrared fundus ophthalmoscopy using the RTX-1 camera (Imagine eyes, Orsay, France). In the fovea, small pigment clumps at the level of the retinal pigment epithelium were seen (Fig 1B), even though the structure and thickness of the photoreceptor layers (outer nuclear layer, outer limiting membrane, ellipsoid zone) looked normal (Fig 1C). Atrophy of the temporal side of the fovea was frequent; the interpapillary macula zone was preserved. We measured cone density using adaptive optics-based infrared fundus ophthalmoscopy in 2 groups of patients younger than 25 who still had a reliably observable cone mosaic around the fovea, in 100-mm windows between 300 and 600 mm eccentricity, and compared it with normal controls. In the 6to 15-year-old group (mean, 11.7) the patients had fewer cones (20 206 2731 cones/mm; 6 individuals; 12 eyes) than controls (mean age, 8.3; 29 339 1368 cones/mm; 4 individuals, 8 eyes; P < 2 10 ; Fig S2 available at www.aaojournal.org). In the 16to 25-year-old group (mean, 18), patients also had fewer cones (18 678 1796 cones/mm; 3 individuals, 5 eyes) than controls (mean age, 22; 26 41

A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene.

To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations.

Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.106) was lower in Provence-Côte d’Azur with a Mediterranean diet (1.9/1.106), and higher in regions with intensive farming or industrialized activities (5 to 20/1.106). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.