Increased steroidogenesis promotes early-onset and severe vision loss in females with OPA1 dominant optic atrophy.

OPA1 mutations are responsible for autosomal dominant optic atrophy (ADOA), a progressive blinding disease characterized by retinal ganglion cell (RGC) degeneration and large phenotypic variations, the underlying mechanisms of which are poorly understood. OPA1 encodes a mitochondrial protein with essential biological functions, its main roles residing in the control of mitochondrial membrane dynamics as a pro-fusion protein and prevention of apoptosis. Considering recent findings showing the importance of the mitochondrial fusion process and the involvement of OPA1 in controlling steroidogenesis, we tested the hypothesis of deregulated steroid production in retina due to a disease-causing OPA1 mutation and its contribution to the visual phenotypic variations. Using the mouse model carrying the human recurrent OPA1 mutation, we disclosed that Opa1 haploinsufficiency leads to very high circulating levels of steroid precursor pregnenolone in females, causing an early-onset vision loss, abolished by ovariectomy. In addition, steroid production in retina is also increased which, in conjunction with high circulating levels, impairs estrogen receptor expression and mitochondrial respiratory complex IV activity, promoting RGC apoptosis in females. We further demonstrate the involvement of Muller glial cells as increased pregnenolone production in female cells is noxious and compromises their role in supporting RGC survival. In parallel, we analyzed ophthalmological data of a multicentre OPA1 patient cohort and found that women undergo more severe visual loss at adolescence and greater progressive thinning of the retinal nerve fibres than males. Thus, we disclosed a gender-dependent effect on ADOA severity, involving for the first time steroids and Müller glial cells, responsible for RGC degeneration.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

PURPOSE: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. DESIGN: A national matched case-control study. PARTICIPANTS: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). METHODS: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. MAIN OUTCOME MEASURES: Extensive macular atrophy with pseudodrusen status (cases vs. controls). RESULTS: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP. CONCLUSIONS: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

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.

Nutrient intake in an elderly population in southern France (POLANUT): deficiency in some vitamins, minerals and omega-3 PUFA.

OBJECTIVE: Evaluation of the nutritional status of an elderly cohort from a French Mediterranean area. DESIGN: Cross-sectional nutritional assessment in the framework of the population-based POLA cohort. SUBJECTS AND METHODS: 832 subjects aged 70 years or older answered a 165-item, semi-quantitative food frequency questionnaire. Mean Nutritional Need (MNN) was defined as 77% of the French Recommended Daily Allowance (RDA). The risk for clinical deficiency (CD) was defined as intakes lower than the Limit Threshold Intake (70% of the MNN). RESULTS: Consumption was characterized by an excess of saturated fatty acids (SFA) (95.4% of subjects above the RDA) and a deficit of omega-3 polyunsaturated fatty acids (PUFA) (60.1% and 46.9% of subjects at risk for CD for alpha-linolenic (ALA) and long-chain omega-3 PUFA, respectively). Median intakes of fiber, vitamins B6, B9, and D, calcium, and magnesium were below the RDA. Dairy products were the first providers of SFA, nuts of ALA, and fish of long-chain omega-3 PUFA and vitamin D. CONCLUSION: The study identified an unbalanced food intake, with an excess of mammal animal products, mainly of dairy products, and a deficit of fish and vegetal foods. This resulted in a deficiency in some vitamins, minerals, and omega-3 PUFA.

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.

Albumin and transthyretin as risk factors for cataract: the POLA study.

OBJECTIVE: To assess the associations of markers of protein nutrition (plasma albumin and transthyretin) with cataract. METHODS: The Pathologies Oculaires Liées à l'Age (POLA) Study (1995-1997) is a population-based study on age-related eye diseases, performed in 2584 residents of Sète (South of France), aged 60 to 95 years. Cataract classification was based on a standardized lens examination at slitlamp according to Lens Opacities Classification System III. RESULTS: After multivariate adjustment, the risk for cataract (any type) was increased by about 50% in the lowest quintile of plasma albumin concentration (<38.28 g/L) and transthyretin concentration (<0.21 g/L) (odds ratio [OR], 1.49 [95% confidence interval (CI), 1.04-2.14]) and OR, 1.48 [95% CI, 1.03-2.13], respectively). The associations were stronger with mixed cataract (OR, 1.87 [95% CI, 0.95-3.68] and OR, 2.37 [95% CI, 1.22-4.59] for albumin and transthyretin levels, respectively) and nuclear cataract (OR, 2.39 [95% CI, 1.20-4.76] for low transthyretin levels). There were no significant associations with the other types of cataract. There were no associations of cataracts with high-sensitivity C-reactive protein and orosomucoid levels. CONCLUSIONS: This study is suggestive of an association of protein undernutrition with increased risk of cataract. Low protein intake may induce deficiencies of specific amino acids that are needed to maintain the health of the lens, or other nutritional deficiencies, particularly niacin, thiamin, and riboflavin.

The three-year incidence of age-related macular degeneration: the "Pathologies Oculaires Liées à l'Age" (POLA) prospective study.

PURPOSE: To assess the 3-year incidence of age-related macular degeneration (AMD) in a French population. DESIGN: The "Pathologies Oculaires Liées à l'Age" (POLA) Study, a population-based prospective cohort study. METHODS: Retinal photographs were graded according to the international classification. Early age-related maculopathy (ARM) was defined by the presence of (1) soft indistinct drusen (>125 microm) and/or (2) soft distinct drusen (>125 microm) associated with pigmentary abnormalities. RESULTS: The 3-year incidence of AMD was 0.49% (95% confidence interval [CI]: 0.13 to 0.85) and increased significantly with age, reaching 3.41% (95% CI: 0 to 7.2) in participants aged 80 years or more. After adjustment for age, eyes with early ARM at baseline were 78 times more at risk of developing AMD than eyes without early ARM (OR = 78.4, 95% CI: 14.6 to 420.1). CONCLUSIONS: This study confirms that AMD develops mainly in subjects aged 80 years or older, and in subjects with early ARM.

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.

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

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.

Strategies to prevent iron deficiency and improve reproductive health.

Anemia and iron deficiency affect billions of people worldwide, especially women of reproductive age, pregnant women, and young children. Many countries have iron and folic acid supplementation programs for pregnant women. However, the impact of these programs is uncertain. Multiple-micronutrient supplementation during pregnancy has been advocated; however, it is unclear whether this has additional advantages. Overall, programs have shown only modest impact on increasing birth weight. This review discusses the present state of knowledge on interventions to improve iron status during pregnancy and reproductive health, and investigates other possibilities such as supplementation prior to conception to improve maternal and child health.

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. DESIGN: Population-based study, prospective cohort. SETTING: Sète, on the French Mediterranean coast. PARTICIPANTS: Five hundred and fifty-three men and 888 women aged 60 and older from the Pathologies Oculaires Liées à l'Age cohort free of known comorbidities. MEASUREMENTS: Plasma levels of cholesterol, albumin, transthyretin (TTR), C-reactive protein (CRP), and alpha 1-acid glycoprotein (AAG) were measured at baseline. To investigate the risks of 5-year (early) and 5- to 9-year (late) mortality, hazard ratios (HR) were evaluated using Cox models. RESULTS: In men, early death was associated with high CRP and AAG and low albumin and TTR. In women, early death was associated with high AAG, low TTR and low cholesterol. For late death, the only significant association was with CRP in men. A synergistic effect was observed between biomarkers of inflammation and malnutrition. In men, the adjusted HR of early death was 4.98 (95% confidence interval (CI)=2.25-11.01) for both CRP in the highest quartile and albumin in the lowest. In men, this risk was greatest for both AAG in the highest quartile and TTR in the lowest (HR=6.86, 95% CI=3.20-14.71). In women, this risk was greatest for both AAG in the highest quartile and TTR in the lowest (HR=4.64, 95% CI=1.79-12.05). Cancer mortality was greater for high CRP and AAG and for low albumin and TTR in men but not in women. CONCLUSION: Biomarkers of inflammation and malnutrition together predict early mortality. In healthy elderly subjects, TTR and AAG could be helpful in identifying elderly subjects at higher risk of death.