Publications by authors named "Isabelle Drumare"

13 Publications

  • Page 1 of 1

Severe retinitis pigmentosa with posterior staphyloma in a family with c.886C>A p.(Lys296Glu) mutation.

Ophthalmic Genet 2019 08 22;40(4):365-368. Epub 2019 Aug 22.

Biochemistry and Molecular Biology Department - UF Génopathies, Univ Lille , Lille , France.

: Posterior pole staphylomata (PSS) is an outward bulging of ocular wall, rarely reported in association with inherited retinal degenerations. : We report a large French family of Jewish ancestry with a peculiar form of dominant retinitis pigmentosa (RP) and posterior pole staphyloma (PPS). Eight members were clinically and genetically examined. : All affected members complained of night blindness from early childhood and their ERGs were extinguished in the first decade of life. Seven out of eight presented PPS on fundus examination and SD-OCT. The youngest patient did not present PPS at 11 months of age, but the signs of posterior pole bowing became evident at age 8 years. There was no association between the presence of PPS and refraction. Patients with PPS were either hyperopic or myopic, but all have a high with-the-rule astigmatism. A myopic shift was observed for all of them at follow-up. In this family, the disease segregated with the c.886A>G mutation in gene. : A PPS development was observed in initially non-myopic patients of a family with unusually severe dominant RP. The PPS concerned only the area with relatively preserved outer retinal layers (outer nuclear layer and ellipsoid zone). How the outer retina could guide choroid and scleral remodelling remains unclear.
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http://dx.doi.org/10.1080/13816810.2019.1655771DOI Listing
August 2019

Clinical and molecular findings of FRMD7 related congenital nystagmus as adifferential diagnosis of ocular albinism.

Ophthalmic Genet 2019 04 3;40(2):161-164. Epub 2019 Apr 3.

a Service de Génétique Médicale , CHU de Bordeaux , Bordeaux , France.

Background: Congenital nystagmus is one of the most common neuro-ophthalmological disorders. X chromosome-linked forms are associated with pathogenic variants of the GPR143 and FRMD7 genes.

Materials And Methods: Patients' DNA was analyzed using a next-generation sequencing (NGS) panel of genes involved in albinism and related pathologies (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, C10ORF11, GPR143, SLC38A8, HPS 1 to 10, LYST, MITF, FRMD7) Results: We report a 4 generation family with 5 affected members initially referred for molecular diagnosis of ocular albinism. A missense variant of FRMD7 was found in 3 affected cases and one female carrier. We show that the disease in the affected girl is due to skewed inactivation of the X chromosome.

Conclusions: By compiling all the published cases we discuss the variable penetrance among females due to different types of mutation and to X-inactivation.
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http://dx.doi.org/10.1080/13816810.2019.1592201DOI Listing
April 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

Extreme myopia in a family with a missense PAX6 mutation: extended phenotype.

Ophthalmic Genet 2019 02 28;40(1):64-65. Epub 2018 Dec 28.

a Exploration of Vision and Neuro-ophthalmology Department , Lille University Hospital , Lille , France.

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http://dx.doi.org/10.1080/13816810.2018.1558260DOI Listing
February 2019

Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the gene.

Br J Ophthalmol 2019 09 24;103(9):1239-1247. Epub 2018 Nov 24.

Service de génétique médicale, CHU de Bordeaux, Bordeaux, France.

Aim: Oculocutaneous albinism type 1 (OCA1) is due to mutations. c.1205G>A/p.Arg402Gln (R402Q) is a thermosensitive variant of the gene that has been reported to be responsible for mild forms of OCA1. The aim of our study was to define the phenotype associated with this variant.

Methods: In our retrospective series, among 268 patients diagnosed with OCA1, 122 (45.5%) harboured one pathogenic variant of , and the R402Q variant ensured to be in trans by segregation analysis in 69 patients (25.7%), constituting the 'R402Q-OCA1' group. 146 patients harboured two pathogenic variants of the gene other than R402Q. Clinical records were available for 119 of them, constituting the 'Classical-OCA1' group.

Results: Most R402Q-OCA1 patients presented with white or yellow-white hair at birth (71.43%), blond hair later (46.97%), a light phototype but with residual pigmentation (69.64%), and blue eyes (76.56%). Their pigmentation was significantly higher than in the classical-OCA1 group. All patients from the R402Q-OCA1 group presented with ocular features of albinism. However the prevalence of photophobia (78.13%) and iris transillumination (83.87%) and the severity scores of iris transillumination, retinal hypopigmentation and foveal hypoplasia were lower in the R402Q-OCA1 group. Visual acuity was higher in the R402Q-OCA1 group (0.38±0.21 logarithm of the minimum angle of resolution vs 0.76±0.24). Investigations concerning a possible additive effect of the c.575C>A/p.Ser192 (S192Y) variant of in cis with R402Q, suggested by others, showed no significant impact on the phenotype.

Conclusion: The R402Q variant leads to variable but generally mild forms of albinism whose less typical presentation may lead to underdiagnosis.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312729DOI Listing
September 2019

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

Sci Rep 2018 05 1;8(1):6840. Epub 2018 May 1.

Department of Ophtalmology, Amiens University Hospital, Paris, France.

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 2.95/1.10) was lower in Provence-Côte d'Azur with a Mediterranean diet (1.9/1.10), and higher in regions with intensive farming or industrialized activities (5 to 20/1.10). 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.
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http://dx.doi.org/10.1038/s41598-018-25003-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931512PMC
May 2018

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

Sci Rep 2016 09 7;6:32544. Epub 2016 Sep 7.

Institute for Neurosciences of Montpellier U1051, University of Montpellier-University Hospital, Genetics of Sensory Diseases, Montpellier, France.

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.
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http://dx.doi.org/10.1038/srep32544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013278PMC
September 2016

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

Ophthalmology 2016 09 16;123(9):1865-73. Epub 2016 Jun 16.

Eye Clinic, Hôpital Intercommunal, Créteil, France.

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.
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http://dx.doi.org/10.1016/j.ophtha.2016.05.018DOI Listing
September 2016

Long-term follow-up of two patients with oligocone trichromacy.

Doc Ophthalmol 2015 Oct 3;131(2):149-58. Epub 2015 Jul 3.

Exploration of Visual Function and Neuro-Ophthalmology Department, Lille University Hospital, Rue Emilie Laine, 59037, Lille Cedex, France.

Introduction: Oligocone trichromacy (OT) is an uncommon cone dysfunction disorder, the mechanism of which remains poorly understood. OT has been thought to be non-progressive, but its long-term visual outcome has been seldom reported in the literature. Our aim was to present two OT patients followed at our institution over 18 years.

Materials And Methods: Complete ocular examination, color vision, visual fields, and full-field electroretinography (ERG) were performed at initial presentation and follow-up. Spectral-domain optical coherence tomography (OCT) was performed during follow-up when available at our institution.

Results: Initial ocular examination showed satisfactory visual acuities with normal fundus examination and near-to-normal color vision. However, computerized perimetry demonstrated a ring-shaped scotoma around fixation, and ERG showed a profound cone dysfunction. The discrepancy between preserved color vision and profound cone dysfunction leads to the diagnosis of OT. Subsequent follow-ups over 18 years showed subtle degradation of visual acuities along with progression of the myopia in both patients and slight worsening of color vision in one patient. Initial OCT revealed a focal interruption of the ellipsoid line along with decreased thickness of the perifoveal macula. Subsequent OCT imaging performed 2 years later did not show any macular changes.

Conclusion: Although OT is known to be a non-progressive cone dysfunction, our results suggest that subtle degradation of the visual function might happen over time.
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http://dx.doi.org/10.1007/s10633-015-9508-8DOI Listing
October 2015

Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome.

Am J Ophthalmol 2015 Aug 15;160(2):364-372.e1. Epub 2015 May 15.

Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Strasbourg, France; Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. Electronic address:

Purpose: To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association.

Design: Retrospective observational case series.

Methods: Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing.

Results: All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident.

Conclusions: Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.
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http://dx.doi.org/10.1016/j.ajo.2015.05.007DOI Listing
August 2015

Further delineation of eye manifestations in homozygous 15q13.3 microdeletions including TRPM1: a differential diagnosis of ceroid lipofuscinosis.

Am J Med Genet A 2014 Jun 25;164A(6):1537-44. Epub 2014 Mar 25.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, France.

The 15q13.3 heterozygous microdeletion is a fairly common microdeletion syndrome with marked clinical variability and incomplete penetrance. The average size of the deletion, which comprises six genes including CHRNA7, is 1.5 Mb. CHRNA7 has been identified as the gene responsible for the neurological phenotype in this microdeletion syndrome. Only seven patients with a homozygous microdeletion that includes at least CHRNA7, and is inherited from both parents have been described in the literature. The aim of this study was to further describe the distinctive eye manifestations from the analysis in the three French patients diagnosed with the classical 1.5 Mb homozygous microdeletion. Patients' ages ranged from 30 months to 9 years, and included one sib pair. They all displayed a remarkably severe identifiable clinical phenotype that included congenital blindness and convulsive encephalopathy with inconstant abnormal movements. The ophthalmological examination revealed a lack of eye tracking, optic nerve pallor, an immature response with increased latencies with no response to the checkerboard stimulations at the visual evoked potential examination, and a distinctive retina dystrophy with a negative electroretinogram in which the "b" wave was smaller than the "a" wave after a dark adapted pupil and bright flash in all patients. Clear genotype-phenotype correlations emerged, showing that this eye phenotype was secondary to homozygous deletion of TRPM1, the gene responsible for autosomal recessive congenital stationary night blindness. The main differential diagnosis is ceroid lipofuscinosis.
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http://dx.doi.org/10.1002/ajmg.a.36471DOI Listing
June 2014

Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.

Am J Hum Genet 2012 Feb;90(2):321-30

Institut National de la Santé et de la Recherche Médicale, Paris, France.

Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.
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http://dx.doi.org/10.1016/j.ajhg.2011.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276675PMC
February 2012

TRPM1 is mutated in patients with autosomal-recessive complete congenital stationary night blindness.

Am J Hum Genet 2009 Nov 5;85(5):720-9. Epub 2009 Nov 5.

INSERM, UMR_S968, F-75012, Paris, France.

Night vision requires signaling from rod photoreceptors to adjacent bipolar cells in the retina. Mutations in the genes NYX and GRM6, expressed in ON bipolar cells, lead to a disruption of the ON bipolar cell response. This dysfunction is present in patients with complete X-linked and autosomal-recessive congenital stationary night blindness (CSNB) and can be assessed by standard full-field electroretinography (ERG), showing severely reduced rod b-wave amplitude and slightly altered cone responses. Although many cases of complete CSNB (cCSNB) are caused by mutations in NYX and GRM6, in approximately 60% of the patients the gene defect remains unknown. Animal models of human diseases are a good source for candidate genes, and we noted that a cCSNB phenotype present in homozygous Appaloosa horses is associated with downregulation of TRPM1. TRPM1, belonging to the family of transient receptor potential channels, is expressed in ON bipolar cells and therefore qualifies as an excellent candidate. Indeed, mutation analysis of 38 patients with CSNB identified ten unrelated cCSNB patients with 14 different mutations in this gene. The mutation spectrum comprises missense, splice-site, deletion, and nonsense mutations. We propose that the cCSNB phenotype in these patients is due to the absence of functional TRPM1 in retinal ON bipolar cells.
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http://dx.doi.org/10.1016/j.ajhg.2009.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775830PMC
November 2009