Publications by authors named "Francesca Simonelli"

115 Publications

Nephroplex: a kidney-focused NGS panel highlights the challenges of PKD1 sequencing and identifies a founder BBS4 mutation.

J Nephrol 2021 May 8. Epub 2021 May 8.

Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Genetic testing of patients with inherited kidney diseases has emerged as a tool of clinical utility by improving the patients' diagnosis, prognosis, surveillance and therapy.

Methods: The present study applied a Next Generation Sequencing (NGS)-based panel, named NephroPlex, testing 115 genes causing renal diseases, to 119 individuals, including 107 probands and 12 relatives. Thirty-five (poly)cystic and 72 non (poly)cystic individuals were enrolled. The latter subgroup of patients included Bardet-Biedl syndrome (BBS) patients, as major components.

Results: Disease-causing mutations were identified in 51.5 and 40% of polycystic and non-polycystic individuals, respectively. Autosomal dominant polycystic kidney disease (ADPKD) patients with truncating PKD1 variants showed a trend towards a greater slope of the age-estimated glomerular filtration rate (eGFR) regression line than patients with (i) missense variants, (ii) any PKD2 mutations and (iii) no detected mutations, according to previous findings. The analysis of BBS individuals showed a similar frequency of BBS4,9,10 and 12 mutations. Of note, all BBS4-mutated patients harbored the novel c.332+1G>GTT variant, which was absent in public databases, however, in our internal database, an additional heterozygote carrier was found. All BBS4-mutated individuals originated from the same geographical area encompassing the coastal provinces of Naples.

Discussion: In conclusion, these findings indicate the potential for a genetic panel to provide useful information at both clinical and epidemiological levels.
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http://dx.doi.org/10.1007/s40620-021-01048-4DOI Listing
May 2021

Evaluation of Donor and Recipient Characteristics Involved in Descemet Stripping Automated Endothelial Keratoplasty Outcomes.

Front Med (Lausanne) 2021 12;8:605160. Epub 2021 Apr 12.

Multidisciplinary Department of Medical, Surgical, and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.

To evaluate both donor and recipient features involved in visual acuity restoring and complication insurgence in eyes that have undergone Descemet stripping automated endothelial keratoplasty (DSAEK). In this retrospective study, charts of 111 eyes of 96 patients (mean age 70.25 ± 8.58 years) that underwent DSAEK were evaluated. Only Fuch's Distrophy (FD) or Bullous Keratopathy (BK) due to cataract surgery eyes were included. A complete ophthalmic check with endothelial cell density (ECD) and central corneal thickness (CCT) measurement was performed before surgery and at 1, 3, 6, and 12 months follow-up. Each DSAEK was performed by the same well-trained surgeon; only pre-cut lenticules, provided by same Eye Bank, were implanted. A total of 48 (43%) complications have been observed (most of them were 22 partial graft detachments and 17 IOP spikes). At the last follow-up (mean: 8.58 ± 4.09 months), a significant increase ( < 0.05) of best corrected visual acuity (BCVA) was detected. Overall mean BCVA of the eyes evaluated was 0.40 ± 0.43 LogMAR with BK eyes showing a significantly higher improvement ( < 0.05) compared to FD eyes. The only factor showing a significant correlation ( < 0.05) with visual acuity enhancement was the implant of a lenticule thinner than 100 μm. Recipient features significantly ( < 0.05) associated with complications observed after surgery were glaucoma and diabetes mellitus. The use of a graft thinner than 100 μm can provide better visual acuity recovery while recipients affected by glaucoma or diabetes mellitus are more prone to develop complications after surgery.
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http://dx.doi.org/10.3389/fmed.2021.605160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072002PMC
April 2021

Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 Years and 4 Years.

Ophthalmology 2021 Mar 30. Epub 2021 Mar 30.

Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Objective: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; LUXTURNA®, Spark Therapeutics, Inc.) administration in subjects with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3-4 years, and to review safety outcomes.

Design: Open-label, randomized, controlled phase 3 trial.

Subjects: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n=21) or control (n=10). One subject from each group withdrew before, or at, randomization.

Methods: Subjects in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) subjects served as controls for 1 year, then received VN.

Main Outcome Measures: Change from injection baseline in bilateral performance on the multi-luminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold (FST) white light, visual field (VF), and visual acuity (VA).

Results: Mean bilateral MLMT change scores at Year 4 for OI subjects and at Year 3 for DI subjects were 1.7 and 2.4 respectively, with 71% of subjects with a Year 3 visit able to pass MLMT at the lowest light level. Mean change in FST white light, averaged over both eyes at Year 4 for OI subjects, and at Year 3 for DI subjects, was -1.90 log(cd.s/m) and -2.91 log(cd.s/m), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at Year 4 for OI subjects and 157.9 at Year 3 for DI subjects. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logMAR at Year 4 for OI subjects and -0.06 logMAR at Year 3 for DI subjects. One OI subject had a retinal detachment around Year 4, which impacted VA for the OI group. No product-related serious adverse events (SAEs) occurred, and there were no deleterious immune responses.

Conclusions: Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3-4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure, and was similar between intervention groups, with no product-related SAEs reported.
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http://dx.doi.org/10.1016/j.ophtha.2021.03.031DOI Listing
March 2021

Choroidal Vascularity Features in Patients with Choroideremia and Cystoid Spaces.

Diagnostics (Basel) 2021 Feb 24;11(3). Epub 2021 Feb 24.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania 'Luigi Vanvitelli', via Pansini 5, 80131 Naples, Italy.

Cystoid spaces (CSs) are a common retinal finding in choroideremia (CHM) patients. The aim of this study was to analyze the vascular features of the choroid associated with the presence of CSs in patients with confirmed genetic diagnosis of CHM. A total of 33 patients (33 eyes) were enrolled in this retrospective cross-sectional study and divided into two groups based on the presence (17 eyes) or absence (16 eyes) of CSs. Choroidal features were evaluated on spectral-domain optical coherence tomography including subfoveal choroidal thickness (CT), total choroidal area (TCA), luminal choroidal area (LCA), and stromal choroidal area (SCA). The choroidal vascularity index (CVI) was then calculated in all study eyes. All structural choroidal parameters were calculated both on the entire length of the B-scan and in the central subfoveal 1500 μm. The average age was 37.3 ± 11.6 and 31.4 ± 16.7 years ( = 0.25) and mean logMAR best-corrected visual acuity was 0.11 ± 0.20 and 0.20 ± 0.57 ( = 0.54) in the CHM groups with and without CSs, respectively. There were no significant differences in subfoveal CT, and TCA, LCA, SCA, and CVI evaluated on either the entire scan or in the central 1500 μm (all > 0.05). All choroidal vasculature parameters exhibited no significant differences between CHM eyes with and without CSs. Our results suggest that the choroid may not be involved in the development of CSs in patients with CHM.
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http://dx.doi.org/10.3390/diagnostics11030382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996232PMC
February 2021

Circulating miRNAs in diabetic retinopathy patients: Prognostic markers or pharmacological targets?

Biochem Pharmacol 2021 Apr 16;186:114473. Epub 2021 Feb 16.

Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

In this study we analyzed the expression of circulating miRNAs, in the serum of diabetic retinopathy (DR) patients. Five miRNAs (hsa-miR-195-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-27b-3p and hsa-miR-451a) were validated as biomarkers for stratification of DR stages, from the early non-proliferative (NPDR) to the late proliferative (PDR) phase. Furthermore, circulating levels of these miRNAs correlated with retinal hyper-reflective spots (HRS), assessed by optical coherence tomography (OCT). The number of HRS increased with worsening of DR stages. On the contrary, no significant vascular density differences between NPDR and PDR patients were detected by angio-OCT (OCTA). A post-hoc bioinformatics analysis associated these five miRNAs to target genes belonging to the "Tumor Necrosis Factor alfa signaling" pathway, and several molecules were predicted to modify miRNAs expression. In conclusion, correlation between specific circulating miRNAs and intraretinal hyper-reflective spots was demonstrated, confirming that these miRNAs were validated as prognostic biomarkers, and also as potential pharmacological targets, warranting further clinical evaluation to explore novel therapeutics for diabetic retinopathy.
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http://dx.doi.org/10.1016/j.bcp.2021.114473DOI Listing
April 2021

Clinical and Molecular Characterization of Achromatopsia Patients: A Longitudinal Study.

Int J Mol Sci 2021 Feb 7;22(4). Epub 2021 Feb 7.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania "Luigi Vanvitelli", via Pansini 5, 80131 Naples, Italy.

Achromatopsia (ACHM) is a rare genetic disorder of infantile onset affecting cone photoreceptors. To determine the extent of progressive retinal changes in achromatopsia, we performed a detailed longitudinal phenotyping and genetic characterization of an Italian cohort comprising 21 ACHM patients (17 unrelated families). Molecular genetic testing identified biallelic pathogenic mutations in known ACHM genes, including four novel variants. At baseline, the patients presented a reduced best corrected visual acuity (BCVA), reduced macular sensitivity (MS), normal dark-adapted electroretinogram (ERG) responses and undetectable or severely reduced light-adapted ERG. The longitudinal analysis of 16 patients (mean follow-up: 5.4 ± 1.0 years) showed a significant decline of BCVA (0.012 logMAR/year) and MS (-0.16 dB/year). Light-adapted and flicker ERG responses decreased below noise level in three and two patients, respectively. Only two patients (12.5%) progressed to a worst OCT grading during the follow-up. Our findings corroborate the notion that ACHM is a progressive disease in terms of BCVA, MS and ERG responses, and affects slowly the structural integrity of the retina. These observations can serve towards the development of guidelines for patient selection and intervention timing in forthcoming gene replacement therapies.
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http://dx.doi.org/10.3390/ijms22041681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914547PMC
February 2021

Analysis of Corneal Distortion after Myopic PRK.

J Clin Med 2020 Dec 28;10(1). Epub 2020 Dec 28.

Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, 80132 Napoli, Italy.

The purpose of the study is to evaluate the corneal biomechanical properties (CBP) and their behaviors after myopic refractive surgery both with Ocular Response Analyzer (ORA) and Corvis ST (CST). This retrospective study included 145 eyes of 145 patients with a mean age of 33.13 ± 9.24 years, who underwent myopic photorefractive keratectomy (PRK) for a refractive defect, measured as spherical equivalent, of mean -4.69 ± 2.04 D and have been evaluated before surgery and at 1, 3 and 6 months follow-up. Corneal hysteresis (CH) and corneal resistance factor (CRF) values significantly decreased after 1 month and remained statistically stable during further follow-ups. CST parameters had a different evolution: only second applanation time (AT2) differences showed a significant variation after 1 month that did not statistically change over time. Highest concavity deformation amplitude (HCDA), highest concavity peak distance (HCPD), first applanation time (AT1) and velocity (AV1) showed continuous significant differences both after 3 and after 6 months. This study suggests that after central surface ablation surgery, such as myopic PRK, corneal shape is remodeling, and its deformation parameters are going to change even at 6 months follow-up. This indicates that it should be important to evaluate refractive surgery patients during a longer follow-up because this could allow earlier diagnosis and better management of late-onset complications.
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http://dx.doi.org/10.3390/jcm10010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794860PMC
December 2020

Spectrum of Disease Severity in Patients With X-Linked Retinitis Pigmentosa Due to RPGR Mutations.

Invest Ophthalmol Vis Sci 2020 12;61(14):36

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania "Luigi Vanvitelli," Naples, Italy.

Purpose: The purpose of this study was to perform a detailed longitudinal phenotyping of X-linked retinitis pigmentosa (RP) caused by mutations in the RPGR gene during a long follow-up period.

Methods: An Italian cohort of 48 male patients (from 31 unrelated families) with RPGR-associated RP was clinically assessed at a single center (mean follow-up = 6.5 years), including measurements of best-corrected visual acuity (BCVA), Goldmann visual field (GVF), optical coherence tomography (OCT), fundus autofluorescence (FAF), microperimetry, and full-field electroretinography (ERG).

Results: Patients (29.6 ± 15.2 years) showed a mean BCVA of 0.6 ± 0.7 logMAR, mostly with myopic refraction (79.2%). Thirty patients (62.5%) presented a typical RP fundus, while the remaining sine pigmento RP. Over the follow-up, BCVA significantly declined at a mean rate of 0.025 logMAR/year. Typical RP and high myopia were associated with a significantly faster decline of BCVA. Blindness was driven primarily by GVF loss. ERG responses with a rod-cone pattern of dysfunction were detectable in patients (50%) that were significantly younger and more frequently presented sine pigmento RP. Thirteen patients (27.1%) had macular abnormalities without cystoid macular edema. Patients (50%) with a perimacular hyper-FAF ring were significantly younger, had a higher BCVA and a better-preserved ellipsoid zone band than those with markedly decreased FAF. Patients harboring pathogenic variants in exons 1 to 14 showed a milder phenotype compared to those with ORF15 mutations.

Conclusions: Our monocentric, longitudinal retrospective study revealed a spectrum disease progression in male patients with RPGR-associated RP. Slow disease progression correlated with sine pigmento RP, absence of high myopia, and mutations in RPGR exons 1 to 14.
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http://dx.doi.org/10.1167/iovs.61.14.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774109PMC
December 2020

Application of Artificial Intelligence in the Analysis of Features Affecting Cataract Surgery Complications in a Teaching Hospital.

Front Med (Lausanne) 2020 11;7:607870. Epub 2020 Dec 11.

Multidisciplinary Department of Medical, Surgical and Dental Specialities, University of Campania Luigi Vanvitelli, Naples, Italy.

To evaluate the ocular and systemic factors involved in cataract surgery complications in a teaching hospital using artificial intelligence. One eye of 1,229 patients with a mean age of 70.2 ± 10.3 years old that underwent cataract surgery was selected for this study. Ocular and systemic details of the patients were recorded and then analyzed by means of artificial intelligence. A total of 1.25 billion simulations of artificial intelligence learning and testing were conducted on several variables and a customized model of analysis was developed. A total of 73 complications were recorded in this study. According to the analysis performed, the main factors involved in cataract surgery complications were: a surgeon in training, axial length and intraocular lens power. The model predicted how long surgery would last with an error of <6 min compared to the effective time needed. According to the data here obtained, artificial intelligence could be an interesting option to build customized models able to prevent complications and to predict actual surgery time. The customized algorithm option allows the development of better models adaptable to different units as well as the possibility to be calibrated for the same unit along time.
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http://dx.doi.org/10.3389/fmed.2020.607870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759659PMC
December 2020

Two-year macular volume assessment in multiple sclerosis patients treated with fingolimod.

Neurol Sci 2021 Feb 8;42(2):731-733. Epub 2020 Oct 8.

Multiple Sclerosis Center, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: Fingolimod (FNG) is associated with the development of symptomatic macular edema (ME) in a small subset of multiple sclerosis (MS) patients. By using spectral domain optical coherence tomography (SD-OCT), an increase in the total macular volume (TMV) was rarely detected during the first months of treatment.

Objectives: The objective of this study is to assess whether FNG treatment leads to long-term macular changes in a real-life setting.

Methods: Sixty RRMS patients starting FNG, according to therapeutic indication, were enrolled at three Italian MS centers and followed for 2 years.

Results: The mean TMV did not change between baseline and the follow-up. No patients experienced visual acuity drop during the follow-up.

Conclusions: Initiation of FNG in MS is associated with a modest, not significant, increase in macular volume followed by no further significant changes over 2 years, highlighting the good safety profile of such treatment in MS.
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http://dx.doi.org/10.1007/s10072-020-04802-xDOI Listing
February 2021

Bergmeister's papilla in a young patient with type 1 sialidosis: case report.

BMC Ophthalmol 2020 Aug 31;20(1):356. Epub 2020 Aug 31.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania L. Vanvitelli, 80131, Naples, Italy.

Background: Sialidosis is a rare genetic lysosomal storage disorder caused by a deficit of neuraminidase enzyme activity. Patients with sialidosis present various neurological disorders such as: myoclonic epilepsy and hypotonia, often associated with visual impairment. A typical aspect of sialidosis is the finding of a macular cherry-red spot on ocular fundus examination. In this paper we describe a unilateral case of Bergmeister's papilla (BP) in a young female patient suffering from type 1 sialidosis.

Case Presentation: A 28-year-old young woman suffering from type 1 sialidosis, confirmed by previously described compound heterozigosity Leu91Arg and Gly328Ser on N-acetyl-alpha-neuraminidase - 1 (NEU1) gene, underwent an opthalmological examination at the Eye Clinic of the University of Campania L. Vanvitelli, for bilateral visual deterioration. The patient was suffering from myoclonic epilepsy with hypotonia and severe motor disability. Fundoscopic examination showed a typical macular cherry-red spot with retinal pigment epithelium dystrophy in the middle periphery, in both eyes. Furthermore, in the left eye (OS), a vitreous thickening was observed in the nasal sector of the optic disc, remnant of fetal vasculature on the optic disc (Bergmeister's papilla). Optical coherence tomography (OCT) showed, in both eyes, a thickening of the ganglion cell layer (GCL) with a hyperreflective opacity as a cap on the left optic disc.

Conclusions: In our paper we have described, for the first time in literature, a case of BP in a patient with type 1 sialidosis. The detection of BP with thickening of the peripapillary vitreous by SD-OCT is useful in monitoring any vitreo-retinal change that could cause future visual deterioration.
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http://dx.doi.org/10.1186/s12886-020-01628-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460740PMC
August 2020

Long-term refractive results of posterior iris-claw fixation implants in aphakic eyes after complicated cataract surgery.

Eye (Lond) 2020 Aug 25. Epub 2020 Aug 25.

Multidisciplinary Department of Medical, Surgical and Dental Specialities, Università della Campania Luigi Vanvitelli, Napoli, Italy.

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http://dx.doi.org/10.1038/s41433-020-01156-8DOI Listing
August 2020

Biofeedback Rehabilitation and Visual Cortex Response in Stargardt's Disease: A Randomized Controlled Trial.

Transl Vis Sci Technol 2020 05 11;9(6). Epub 2020 May 11.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.

Purpose: to evaluate the effect of biofeedback (BF) rehabilitation on the visual function and on the activity of primary visual cortex (PVC) in patients with Stargardt's disease owing to mutations in the gene (STGD1).

Methods: This was a single-center, controlled, randomized study. Twenty-four patients with STGD1 were randomized into two groups: a treatment group (TG) undergoing BF rehabilitation and a control group (CG). Treatment with BF consisted of a 10-minute session per eye performed weekly for 12 weeks. The subjects underwent a baseline and 3-month follow-up visits, including best-corrected visual acuity (BCVA), reading test, microperimetry, and functional magnetic resonance imaging (fMRI). The fMRI studies were acquired sequentially using a passive viewing condition and an active reading task. The primary outcomes were the change in the fMRI activation of primary visual cortex and the change in reading ability.

Results: After treatment, the patients in the TG were able to read smaller characters ( = 0.002) with a greater reading speed ( = 0.014) compared with patients in the CG. The fMRI studies showed a significant effect ( < 0.001) of BF on primary visual cortex activation in the TG compared with the CG. Finally, we observed significant ( < 0.05) improvements of best-corrected visual acuity, macular sensitivity, and fixation stability parameters in the TG compared with the CG.

Conclusions: Our study showed that visual rehabilitation using BF improved the usage of residual visual function in patients with STGD1.

Translational Relevance: Our findings show that the BF treatment compared with no treatment at all resulted in benefits. The specificity of the treatment could be examined to determine whether BF can be included in clinical practice.
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http://dx.doi.org/10.1167/tvst.9.6.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409294PMC
May 2020

Diagnosis and Management of Type 1 Sialidosis: Clinical Insights from Long-Term Care of Four Unrelated Patients.

Brain Sci 2020 Aug 1;10(8). Epub 2020 Aug 1.

Department of Neuroscience, Reproductive and Odontostomatological Sciences, Federico II University, 80131 Naples, Italy.

: Sialidosis is a rare autosomal recessive disease caused by mutations, leading to neuraminidase deficiency and accumulation of sialic acid-containing oligosaccharides and glycopeptides into the tissues. Sialidosis is divided into two clinical entities, depending on residual enzyme activity, and can be distinguished according to age of onset, clinical features, and progression. Type 1 sialidosis is the milder, late-onset form, also known as non-dysmorphic sialidosis. It is commonly characterized by progressive myoclonus, ataxia, and a macular cherry-red spot. As a rare condition, the diagnosis is often only made after few years from onset, and the clinical management might prove difficult. Furthermore, the information in the literature on the long-term course is scarce. : We describe a comprehensive clinical, neuroradiological, ophthalmological, and electrophysiological history of four unrelated patients affected by type 1 sialidosis. The long-term care and novel clinical and neuroradiological insights are discussed. : We report the longest follow-up (up to 30 years) ever described in patients with type 1 sialidosis. During the course, we observed a high degree of motor and speech disability with preserved cognitive functions. Among the newest antiseizure medication, perampanel (PER) was proven to be effective in controlling myoclonus and tonic-clonic seizures, confirming it is a valid therapeutic option for these patients. Brain magnetic resonance imaging (MRI) disclosed new findings, including bilateral gliosis of cerebellar folia and of the occipital white matter. In addition, a newly reported variant (c.914G > A) is described.
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http://dx.doi.org/10.3390/brainsci10080506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465165PMC
August 2020

Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in : Detailed clinical investigation in a 9-years-old female.

Mol Genet Metab Rep 2020 Sep 20;24:100615. Epub 2020 Jun 20.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Via Pansini 5, 80131 Naples, Italy.

Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in : the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes genes.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306489PMC
September 2020

An Alu-mediated duplication in NMNAT1, involved in NAD biosynthesis, causes a novel syndrome, SHILCA, affecting multiple tissues and organs.

Hum Mol Genet 2020 08;29(13):2250-2260

Department of Genetics and Genome Biology, University of LE1 7RH Leicester, Leicester, UK.

We investigated the genetic origin of the phenotype displayed by three children from two unrelated Italian families, presenting with a previously unrecognized autosomal recessive disorder that included a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and Leber congenital amaurosis (SHILCA), as well as some brain anomalies that were visible at the MRI. Autozygome-based analysis showed that these children shared a 4.76 Mb region of homozygosity on chromosome 1, with an identical haplotype. Nonetheless, whole-exome sequencing failed to identify any shared rare coding variants, in this region or elsewhere. We then determined the transcriptome of patients' fibroblasts by RNA sequencing, followed by additional whole-genome sequencing experiments. Gene expression analysis revealed a 4-fold downregulation of the gene NMNAT1, residing indeed in the shared autozygous interval. Short- and long-read whole-genome sequencing highlighted a duplication involving 2 out of the 5 exons of NMNAT1 main isoform (NM_022787.3), leading to the production of aberrant mRNAs. Pathogenic variants in NMNAT1 have been previously shown to cause non-syndromic Leber congenital amaurosis (LCA). However, no patient with null biallelic mutations has ever been described, and murine Nmnat1 knockouts show embryonic lethality, indicating that complete absence of NMNAT1 activity is probably not compatible with life. The rearrangement found in our cases, presumably causing a strong but not complete reduction of enzymatic activity, may therefore result in an intermediate syndromic phenotype with respect to LCA and lethality.
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http://dx.doi.org/10.1093/hmg/ddaa112DOI Listing
August 2020

Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.

Genet Med 2020 07 20;22(7):1235-1246. Epub 2020 Apr 20.

Bartiméus Diagnostic Center for Complex Visual Disorders, Zeist, The Netherlands.

Purpose: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands.

Methods: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays.

Results: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband.

Conclusion: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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http://dx.doi.org/10.1038/s41436-020-0787-4DOI Listing
July 2020

Clinical and Genetic Analysis of a European Cohort with Pericentral Retinitis Pigmentosa.

Int J Mol Sci 2019 Dec 20;21(1). Epub 2019 Dec 20.

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', via Pansini 5, 80131 Naples, Italy.

Retinitis pigmentosa (RP) is a clinically heterogenous disease that comprises a wide range of phenotypic and genetic subtypes. Pericentral RP is an atypical form of RP characterized by bone-spicule pigmentation and/or atrophy confined in the near mid-periphery of the retina. In contrast to classic RP, the far periphery is better preserved in pericentral RP. The aim of this study was to perform the first detailed clinical and genetic analysis of a cohort of European subjects with pericentral RP to determine the phenotypic features and the genetic bases of the disease. A total of 54 subjects from 48 independent families with pericentral RP, non-syndromic and syndromic, were evaluated through a full ophthalmological examination and underwent clinical exome or retinopathy gene panel sequencing. Disease-causative variants were identified in 22 of the 35 families (63%) in 10 different genes, four of which are also responsible for syndromic RP. Thirteen of the 34 likely pathogenic variants were novel. Intra-familiar variability was also observed. The current study confirms the mild phenotype of pericentral RP and extends the spectrum of genes associated with this condition.
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http://dx.doi.org/10.3390/ijms21010086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982348PMC
December 2019

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials.

Ophthalmology 2019 09 22;126(9):1273-1285. Epub 2019 Jun 22.

Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector-based gene therapy for RPE65 mutation-associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2.

Design: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial.

Participants: Forty subjects who received 1.5×10 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]).

Methods: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects.

Main Outcome Measures: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing.

Results: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log(cd.s/m) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred.

Conclusions: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation-associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.
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http://dx.doi.org/10.1016/j.ophtha.2019.06.017DOI Listing
September 2019

Atrial natriuretic peptide predicts disease progression and digital ulcers development in systemic sclerosis patients.

J Cardiovasc Med (Hagerstown) 2019 Nov;20(11):771-779

Department of Translational and Precision Medicine.

Aims: Systemic sclerosis (SSc) is an autoimmune disease characterized by micro/macrovascular damage due to the underlying fibrosis. Markers able to predict the progression of cardiovascular damage, including digital ulcers, in SSc are warranted. We aimed at characterizing the relevance of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide plasma levels in relation to cardiovascular damage and digital ulcers in a cohort of Italian SSc patients.

Methods: Seventy patients were enrolled (64 women and six men; mean age 56.7 ± 14 years) with a disease duration of 11.1 ± 8.3 years. Clinical, instrumental (nailfold videocapillaroscopy, ECG, transthoracic echocardiography, pulmonary function test with diffusion lung CO), NT-proANP and N-terminal probrain natriuretic peptide plasma levels measurement were performed at baseline. The clinical follow-up lasted 24 months. The statistical approach used to achieve the study objectives included multivariate analysis, receiver operating characteristic curve, Kaplan-Meier and Cox regression analyses.

Results: Both NT-proNPs levels correlated with systolic pulmonary arterial pressure, but only the NT-proANP level correlated with right heart dimension. Both NT-proNPs levels were higher in patients experiencing events at follow-up but only the NT-proANP level significantly predicted the progression of cardiovascular damage, including development of pulmonary arterial hypertension (PAH). NT-proANP levels were higher in patients with digital ulcers and strongly predicted their development.

Conclusion: Our results show that the NT-proANP plasma level significantly correlates with disease progression such as new onset of PAH, worsening of pulmonary hypertension and development of digital ulcers in a cohort of SSc Italian patients. If future studies will confirm our findings, the plasma NT-proANP level could be used in clinical practice as a novel sensitive marker for PAH and digital ulcers development in SSc.
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http://dx.doi.org/10.2459/JCM.0000000000000852DOI Listing
November 2019

Full-field electroretinography, visual acuity and visual fields in Usher syndrome: a multicentre European study.

Doc Ophthalmol 2019 10 2;139(2):151-160. Epub 2019 Jul 2.

Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Elfriede-Aulhorn-Str. 7, 72076, Tuebingen, Germany.

Purpose: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH).

Methods: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age.

Results: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes.

Conclusions: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages.
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http://dx.doi.org/10.1007/s10633-019-09704-8DOI Listing
October 2019

Carbonic anhydrase inhibitors in patients with X-linked retinoschisis: effects on macular morphology and function.

Ophthalmic Genet 2019 06 31;40(3):207-212. Epub 2019 May 31.

a Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences , University of Campania Luigi Vanvitelli , Naples , Italy.

: Currently there is no medical treatment for X-linked retinoschisis (XLRS). In many retinal dystrophies, carbonic anhydrase inhibitors (CAIs) are effectively used to reduce cystoid macular edema. Prospective studies investigating the effect of CAIs in patients with XLRS are needed for the evaluation of their efficacy in this disease. The purpose of our work is to investigate the effects on macular morphology and function of oral CAIs used for the treatment of foveal lesions in patients with XLRS. : Nineteen patients with a clinical diagnosis of XLRS were enrolled and prescribed oral CAIs for six months. We evaluated the therapeutic effect of CAIs with: best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography, microperimetry (MP) and multifocal electroretinography (mfERG). : We observed a significant improvement of BCVA (p-value = 0.013), central retinal thickness (p-value = 0.004) and macular sensitivity (p-value<0.001). Moreover, in regards to mfERG responses, an increase of P1 wave amplitude was observed in three of the six rings. : Our data supports the efficacy of oral CAIs for the treatment of macular cyst-like lesions in XLRS patients. The recovery of a normal retinal anatomy by means of oral CAIs could be useful to create the optimal circumstances for gene therapy. The increase in macular sensitivity and in P1 wave amplitude confirmed that MP and mfERG provide with an unbiased and more sensitive understanding of how macular function may respond to the use of CAIs. Therefore, we recommend the use of MP and mfERG to assess the effect of therapy in XLRS.
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http://dx.doi.org/10.1080/13816810.2019.1616303DOI Listing
June 2019

Intein-mediated protein trans-splicing expands adeno-associated virus transfer capacity in the retina.

Sci Transl Med 2019 05;11(492)

Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.

Retinal gene therapy with adeno-associated viral (AAV) vectors holds promises for treating inherited and noninherited diseases of the eye. Although clinical data suggest that retinal gene therapy is safe and effective, delivery of large genes is hindered by the limited AAV cargo capacity. Protein trans-splicing mediated by split inteins is used by single-cell organisms to reconstitute proteins. Here, we show that delivery of multiple AAV vectors each encoding one of the fragments of target proteins flanked by short split inteins results in protein trans-splicing and full-length protein reconstitution in the retina of mice and pigs and in human retinal organoids. The reconstitution of large therapeutic proteins using this approach improved the phenotype of two mouse models of inherited retinal diseases. Our data support the use of split intein-mediated protein trans-splicing in combination with AAV subretinal delivery for gene therapy of inherited blindness due to mutations in large genes.
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http://dx.doi.org/10.1126/scitranslmed.aav4523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863751PMC
May 2019

CHM/REP1 Transcript Expression and Loss of Visual Function in Patients Affected by Choroideremia.

Invest Ophthalmol Vis Sci 2019 04;60(5):1547-1555

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.

Purpose: To evaluate the disease progression in patients with clinical and genetic diagnoses of choroideremia during a long-term follow-up and to investigate the relationship between pathogenic variants in the CHM/REP1 gene and disease phenotypes.

Methods: We performed a retrospective longitudinal study on 51 affected men by reviewing medical charts at baseline and follow-up visits to extract the following ocular findings: best-corrected visual acuity, Goldmann visual field, optical coherence tomography, microperimetry. Data obtained from the analysis of DNA and mRNA were reevaluated for genetic classification of patients.

Results: The longitudinal analysis showed a significant (P < 0.001) worsening of best-corrected visual acuity with a mean rate of 0.011 logMar per year before 50 years and 0.025 logMar per year after 50 years. Similarly, V4e Goldmann visual field area significantly (P ≤ 0.01) decreased at a mean rate of 2.7% per year before 40 years and 5.7% after 40 years. Moreover, we observed a significant (P < 0.05) decrease of macular sensitivity with a mean rate of 5.0% per year and a decrease of mean macular thickness with a mean rate of 0.8% per year. We classified our patients into two groups according to the expression of the CHM/REP1 gene transcript and observed that mutations leading to mRNA absence are associated with an earlier best-corrected visual acuity and Goldmann visual field loss.

Conclusions: Our analysis of morphological and functional parameters in choroideremia patients showed a slow disease progression, particularly in the first decades of life. Overall, reevaluation of clinical and molecular data suggests exploring the genotype-phenotype relationship based on CHM/REP1 transcript expression.
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http://dx.doi.org/10.1167/iovs.18-25501DOI Listing
April 2019

Retinal dystrophy in an individual carrying a de novo missense variant of SMARCA4.

Mol Genet Genomic Med 2019 06 11;7(6):e682. Epub 2019 Apr 11.

Department of Translational Medicine, Federico II University, Naples, Italy.

Background: Coffin-Siris syndrome (CSS) is characterized by intellectual disability, dysmorphic facial features, growth deficiency, microcephaly, and abnormalities of the fifth fingers/toes. CSS is caused by mutations in several genes of the BRG1-associated factor pathway including SMARCA4.

Methods: Whole-exome sequencing was performed on a 14-year-old female individual who presented with mild intellectual disability and dysmorphic features, tooth abnormalities, and short stature. She had brachydactyly but no aplasia or hypoplasia of the distal phalanx or nail of the fifth digit. She was also found to have retinal dystrophy that has not been previously reported in CSS.

Results: The individual presented herein was found to harbor a previously unreported de novo variant in SMARCA4.

Conclusion: This case expands the phenotypic spectrum of CSS manifestations.
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http://dx.doi.org/10.1002/mgg3.682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565552PMC
June 2019

Correction: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 04;21(4):1028

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

The original version of this Article contained an incorrect version of Fig. 3, which included two variants initially shown in black text in Fig. 3a that the authors removed from the final manuscript. The correct version of Fig. 3 without the two variants now appears in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0392-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752296PMC
April 2019

Early posterior vitreous detachment is associated with LAMA5 dominant mutation.

Ophthalmic Genet 2019 02 27;40(1):39-42. Epub 2018 Dec 27.

a Neurology Clinic II, Department of Medical Sciences, Surgery, Neurology, Metabolic Diseases and Geriatrics , University of Campania Luigi Vanvitelli , Naples , Italy.

Background: Extracellular matrix molecular components, previously linked to multisystem syndromes include collagens, fibrillins and laminins. Recently, we described a novel multisystem syndrome caused by the c.9418G>A p.(V3140M) mutation in the laminin alpha-5 (LAMA5) gene, which affects connective tissues of all organs and apparatus in a three generation family. In the same family, we have also reported a myopic trait, which, however, was linked to the Prolyl 4-hydroxylase subunit alpha-2 (P4HA2) gene. Results of investigation on vitreous changes and their pathogenesis are reported in the present study.

Materials And Methods: Nineteen family individuals underwent complete ophthalmic examination including best-corrected visual acuity (BCVA), fundus examination, fundus photography, intraocular pressure measurement, axial length measurement using ocular biometry, Goldmann visual field examination, standard electroretinogram, SD-OCT. Segregation analysis of LAMA5 and P4HA2 mutations was performed in enrolled members.

Results: The vitreous alterations fully segregated with LAMA5 mutation in both young and adult family members. Slight reduction of retinal thickness and peripheral retinal degeneration in only two patients were reported.

Conclusions: In this work we showed that PVD is a common trait of LAMA5 multisystem syndrome, therefore occurring as an age-unrelated trait. We hypothesize that the p.(V3140M) mutation results in a reduction of retinal inner limiting membrane (ILM) stability, leading to a derangement in the macromolecular structure of the vitreous gel, and PVD. Further investigations will be necessary to elucidate the role of wild type and mutated LAMA5 in the pathogenesis of PVD.
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http://dx.doi.org/10.1080/13816810.2018.1558261DOI Listing
February 2019

Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease.

Genet Med 2019 06 31;21(6):1319-1329. Epub 2018 Oct 31.

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

Purpose: RAX2 encodes a homeobox-containing transcription factor, in which four monoallelic pathogenic variants have been described in autosomal dominant cone-dominated retinal disease.

Methods: Exome sequencing in a European cohort with inherited retinal disease (IRD) (n = 2086) was combined with protein structure modeling of RAX2 missense variants, bioinformatics analysis of deletion breakpoints, haplotyping of RAX2 variant c.335dup, and clinical assessment of biallelic RAX2-positive cases and carrier family members.

Results: Biallelic RAX2 sequence and structural variants were found in five unrelated European index cases, displaying nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) with an age of onset ranging from childhood to the mid-40s (average mid-30s). Protein structure modeling points to loss of function of the novel recessive missense variants and to a dominant-negative effect of the reported dominant RAX2 alleles. Structural variants were fine-mapped to disentangle their underlying mechanisms. Haplotyping of c.335dup in two cases suggests a common ancestry.

Conclusion: This study supports a role for RAX2 as a novel disease gene for recessive IRD, broadening the mutation spectrum from sequence to structural variants and revealing a founder effect. The identification of biallelic RAX2 pathogenic variants in five unrelated families shows that RAX2 loss of function may be a nonnegligible cause of IRD in unsolved ARRP cases.
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http://dx.doi.org/10.1038/s41436-018-0345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752271PMC
June 2019

Nocturnal blood pressure patterns and cardiovascular outcomes in patients with masked hypertension.

J Clin Hypertens (Greenwich) 2018 09 29;20(9):1238-1246. Epub 2018 Jul 29.

Hypertension Unit, Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sant'Andrea Hospital, University of Rome Sapienza, Rome, Italy.

Masked hypertension (MHT) is characterized by normal clinic and above normal 24-hour ambulatory blood pressure (BP) levels. We evaluated clinical characteristics and CV outcomes of different nocturnal patterns of MHT. We analyzed data derived from a large cohort of adult individuals, who consecutively underwent home, clinic, and ambulatory BP monitoring at our Hypertension Unit between January 2007 and December 2016. MHT was defined as clinic BP <140/90 mm Hg and 24-hour BP ≥ 130/80 mm Hg, and stratified into three groups according to dipping status: (a) dippers, (b) nondippers, and (c) reverse dippers. From an overall sample of 6695 individuals, we selected 2628 (46.2%) adult untreated individuals, among whom 153 (5.0%) had MHT. In this group, 67 (43.8%) were nondippers, 65 (42.5%) dippers, and 21 (13.7%) reverse dippers. No significant differences were found among groups regarding demographics, clinical characteristics, and prevalence of risk factors, excluding older age in reverse dippers compared to other groups (P < 0.001). Systolic BP levels were significantly higher in reverse dippers than in other groups at both 24-hour (135.6 ± 8.5 vs 130.4 ± 6.0 vs 128.2 ± 6.8 mm Hg, respectively; P < 0.001) and nighttime periods (138.2 ± 9.1 vs 125.0 ± 6.3 vs 114.5 ± 7.7 mm Hg; P < 0.001). Reverse dipping was associated with a significantly higher risk of stroke, even after correction for age, gender, BMI, dyslipidemia, and diabetes (OR 18.660; 95% IC [1.056-33.813]; P = 0.046). MHT with reverse dipping status was associated with higher burden of BP and relatively high risk of stroke compared to both dipping and nondipping profiles, although a limited number of CV outcomes have been recorded during the follow-up.
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http://dx.doi.org/10.1111/jch.13361DOI Listing
September 2018

Usher Syndrome and Color Vision.

Curr Eye Res 2018 10 30;43(10):1295-1301. Epub 2018 Jul 30.

a Centre for Ophthalmology, Institute for Ophthalmic Research , University of Tuebingen , Tuebingen , Germany.

Purpose: The aim of this study is to report on the results of color vision testing in a European cohort of patients with Usher syndrome (USH). We describe the results in relation to Usher type (USH1 and USH2), age and visual acuity.

Methods And Methods: The color vision of 220 genetically confirmed adult USH patients, aged 18-70 years, was analyzed with one of three methods: the Farnsworth D-15 Dichotomous test (D-15) along with the Lanthony desaturated 15 Hue tests (D-15d), the Roth 28-Hue test, or the Ishihara 14-plate test. Visual acuity was measured with either the ETDRS or the SNELLEN charts. The Confusion index, the Selectivity index and the Confusion angle were calculated for the panel tests and used for analysis. The numbers of plates that could not be read were analyzed for the Ishihara test.

Results: For the panel tests, the degree of color loss (Confusion index) is similar in both subtypes of USH, but the polarization of error scores (Selectivity index) is significantly lower in USH1 than USH2, showing more diffuse errors than those found in USH2. There is no significant correlation between logMAR visual acuity and the Confusion or the Selectivity indices. Additionally, we find a significant correlation between patient age and the degree and the polarity of the loss only in USH2. There was no difference between USH1 and USH2 in the results of the Ishihara test.

Conclusions: The examination of color vision in patients with USH shows a significant difference in the pattern of color vision loss in USH1 and USH2 patients, but not in the severity of the loss. In USH2, we find a correlation between patient age and the degree and the polarity of the loss. These results may be due to differences in the pathogenesis of retinal dystrophy in USH1 and USH2.
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http://dx.doi.org/10.1080/02713683.2018.1501804DOI Listing
October 2018