-
Atherosclerosis May 2021Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable...
BACKGROUND AND AIMS
Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs.
METHODS
ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association.
RESULTS
158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found.
CONCLUSIONS
PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.
Topics: Genetic Association Studies; Genotype; Humans; Middle Aged; Peripheral Arterial Disease; Phenotype; Pseudoxanthoma Elasticum
PubMed: 33812167
DOI: 10.1016/j.atherosclerosis.2021.03.012 -
Vision (Basel, Switzerland) Mar 2021The aim of this study was to report unusual progression of type 2 macular neovascularization (MNV) associated with age-related macular degeneration (AMD), high myopia or...
The aim of this study was to report unusual progression of type 2 macular neovascularization (MNV) associated with age-related macular degeneration (AMD), high myopia or angioid streaks. Retrospective multicentric observational case series data were used. Eyes that progressed from type 2 MNV secondary to AMD, high myopia or angioid streaks to fibrovascular pigment epithelial detachment (PED) were included. A total of 29 treatment-naive eyes from 29 patients with type 2 MNV secondary to AMD ( = 14), high myopia ( = 10) or angioid streaks ( = 5) that progressed to a fibrovascular PED on Spectral Domain-Optical Coherence Tomography were used. This progression occurred within 3 months after anti-VEGF therapy initiation. Logarithm of minimum angle of resolution (LogMAR) visual acuity improved significantly after anti-VEGF therapy, from 0.55 (SD ± 0.30) (20/63-20/80) at baseline to 0.30 (20/40) at 3 months, and 0.33 (20/40) at the final follow-up (mean follow up: 3.68 years). Mean number of intravitreal injections per year for patients with a total follow-up ≥ 12 months ( = 24) was 4.3 ± 2.1 per year. Progression from type 2 MNV to a fibrovascular PED may occur in patients suffering from AMD, high myopia or angioid streaks. This progression appears early after initiation of anti-VEGF therapy and is associated with a favorable visual and anatomical outcome, at least on a short follow up basis.
PubMed: 33805868
DOI: 10.3390/vision5020016 -
Hippokratia 2021Ocular involvement in patients with transfusion-dependent β-thalassemia is quite common, and its frequency differs among studies. This case series aimed to describe the...
BACKGROUND
Ocular involvement in patients with transfusion-dependent β-thalassemia is quite common, and its frequency differs among studies. This case series aimed to describe the ocular abnormalities occurring in β-thalassemia patients who need regular blood transfusions and receive iron chelation therapy.
CASE SERIES
This is a case series prospectively studied 32 β-thalassemia patients from Northern Greece receiving regular blood transfusions and iron-chelating therapy. Patients' average age was 35.5 years. Eighteen patients with major phenotypes and fourteen patients with intermedia type underwent comprehensive ophthalmic examination at the time of enrolment, including visual acuity evaluation, refraction and color vision tests, Amsler grid test, slit-lamp, and dilated-pupil fundus examination. Additionally, we performed visual field testing and optical coherence tomography in all patients and fluorescein angiography only in selected cases. After six months, patients' complete ophthalmic examination was repeated for any new ocular findings due to the disease process and iron chelation therapy. Ocular involvement was detected in 46.87 % of the patients. Lesions were most frequently seen in elderly patients with thalassemia major. Lens opacities were present in 21.8 %, and degeneration of the retinal pigment epithelium was described in 15.6 % of the patients, representing the commonest fundus alteration observed, followed by fundus atrophy. The most severe and vision-threatening condition described in this study was the presence of angioid streaks with choroidal neovascularisation. Six months follow-up of patients did not reveal any new ocular findings.
CONCLUSION
Early detection of severe ocular abnormalities is important in patients with thalassemia; thus, an ophthalmologic examination should be included at regular check-ups. An annual examination is currently indicated for asymptomatic patients, while in symptomatic and complicated cases, patients should be closely followed-up. HIPPOKRATIA 2021, 25 (2):79-82.
PubMed: 35937508
DOI: No ID Found -
Arquivos Brasileiros de Oftalmologia 2020A 65-year-old female patient was referred to our hospital for evaluation for cataract surgery. Her past medical history included corrective jaw surgeries for facial...
A 65-year-old female patient was referred to our hospital for evaluation for cataract surgery. Her past medical history included corrective jaw surgeries for facial deformities that developed during infancy and persisted through early adulthood. A complete ophthalmological examination revealed bilateral angioid streaks, drusen in both optic disc areas, and a subretinal neovascular membrane in the left macula. Genetic analysis revealed a mutation in the SH3BP2 gene compatible with the diagnosis of cherubism. Clinical and laboratory evaluation revealed no additional systemic disorders. Cherubism is a rare disease characterized by the development of painless fibro-osseous lesions in the jaws and the maxilla in early childhood. Ophthalmologic findings in this disease are primarily related to orbital bone involvement. This is the first report of AS and optic disc drusen in a patient diagnosed with cherubism. Our findings suggest that angioid streaks and optic disk drusen should be included in the differential diagnosis of ophthalmic disorders identified in patients with this genetic abnormality.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Angioid Streaks; Cherubism; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Optic Disk; Optic Disk Drusen
PubMed: 33470282
DOI: 10.5935/0004-2749.20200097 -
Ophthalmology Science Mar 2021To describe the natural history of Bruch's membrane (BM) calcification in patients with pseudoxanthoma elasticum (PXE).
PURPOSE
To describe the natural history of Bruch's membrane (BM) calcification in patients with pseudoxanthoma elasticum (PXE).
DESIGN
Retrospective cohort study.
PARTICIPANTS
Both eyes of 120 PXE patients younger than 50 years, 78 of whom had follow-up imaging after more than 1 year.
METHODS
All patients underwent multimodal imaging, including color fundus photography, near-infrared reflectance (NIR) imaging, and late phase indocyanine green angiography (ICGA). We determined the distance from the optic disc to the central and temporal border of peau d'orange on NIR, expressed in horizontal optic disc diameter (ODD). The length of the longest angioid streak was classified into 5 zones.
MAIN OUTCOME MEASURES
Age-specific changes of peau d'orange, angioid streaks, and ICGA hypofluorescence as surrogate markers for the extent of BM calcification.
RESULTS
In cross-sectional analysis, longer angioid streaks were associated with increasing age ( < 0.001 for trend). The temporal border of peau d'orange showed a weak association with increasing age (β = 0.02; 95% confidence interval [CI], 0.00-0.04), whereas the central border showed a strong association (β = 0.12; 95% CI, 0.09-0.15). Longitudinal analysis revealed a median shift of the central border to the periphery of 0.08 ODD per year (interquartile range [IQR], 0.00-0.17; < 0.001). This shift was more pronounced in patients younger than 20 years (0.12 ODD per year [IQR, 0.08-0.28]) than in patients older than 40 years (0.07 ODD per year [IQR, -0.05 to 0.15]). The temporal border did not shift during follow-up ( = 0.69). New or growing angioid streaks were detected in 39 of 156 eyes (25%). The hypofluorescent area on ICGA was visible only in the fourth or fifth decade and correlated with longer angioid streaks.
CONCLUSIONS
In PXE patients, the speckled BM calcification slowly confluences during life. The location of the temporal border of peau d'orange remains rather constant, whereas the central border shifts to the periphery. This suggests the presence of a predetermined area for BM calcification. A larger ICGA hypofluorescent area correlates with older age and longer angioid streaks, which implies that it depends on the degree of BM calcification.
PubMed: 37487136
DOI: 10.1016/j.xops.2020.100001 -
The Pan African Medical Journal 2020This case series illustrates clinical features and treatment outcomes of angioid streak associated CNV (AS-CNV) in 3 consecutive patients. Mean age of patients was 43.2...
This case series illustrates clinical features and treatment outcomes of angioid streak associated CNV (AS-CNV) in 3 consecutive patients. Mean age of patients was 43.2 years with one female patient. Bilateral CNV was present in one patient. Comet-tail lesions were present in all cases. No underlying systemic association was found in any of the patients. All patients were treated with 3 loading doses of anti-VEGF injections (ranibizumab in two and aflibercept was used in one case). Subretinal fluid resolved in all cases with no recurrence of CNV activity at mean follow-up of 10.75 months. AS-CNV in Zambian eyes responds favourably to anti-VEGF injections.
Topics: Adult; Angiogenesis Inhibitors; Angioid Streaks; Choroidal Neovascularization; Female; Follow-Up Studies; Humans; Male; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome; Zambia
PubMed: 33117488
DOI: 10.11604/pamj.2020.36.294.25065 -
Journal of Internal Medicine May 2021Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of...
PURPOSE
Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients.
METHODS
First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients.
RESULTS
6.4% of ABCC6-negative PXE patients (n = 3) harboured biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE.
CONCLUSION
CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.
Topics: Calcinosis; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Eye; HEK293 Cells; Humans; Multidrug Resistance-Associated Proteins; Mutation, Missense; Phenotype; Pseudoxanthoma Elasticum; Retrospective Studies; Skin; Spastic Paraplegia, Hereditary
PubMed: 33107650
DOI: 10.1111/joim.13193 -
The British Journal of Dermatology Jun 2021Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and...
Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19-year-old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene-targeted panel of next-generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ-glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ-glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K-dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate-to-severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE-like phenotypes.
Topics: Adult; Cutis Laxa; Heterozygote; Humans; Multidrug Resistance-Associated Proteins; Mutation; Phenotype; Pseudoxanthoma Elasticum; Young Adult
PubMed: 33000479
DOI: 10.1111/bjd.19576 -
GMS Ophthalmology Cases 2020Angioid streaks (AS) are irregular crack-like dehiscences in Bruch's membrane that are often associated with atrophic degeneration of the overlying retinal pigment...
Angioid streaks (AS) are irregular crack-like dehiscences in Bruch's membrane that are often associated with atrophic degeneration of the overlying retinal pigment epithelium. We herein report multimodal imaging of AS. Multicolor imaging highlighted AS in dark orange color. AS were better visualized in infrared reflectance as compared to green reflectance and blue reflectance. Peau d'orange appearance was seen as alternating dark and bright patches on color fundus photography with corresponding hyporeflective and hyperreflective patches on infrared reflectance. Comet lesions showed increased signal on infrared reflectance and hyperautofluorescence. Multicolor imaging is a non-invasive imaging modality which helps in clearly delineating these lesions.
PubMed: 32884892
DOI: 10.3205/oc000165 -
F1000Research 2020Pseudoxanthoma elasticum (PXE) is a rare inherited disorder, characterised by a progressive mineralization and fragmentation of elastic fibres of the skin, retina and...
Pseudoxanthoma elasticum (PXE) is a rare inherited disorder, characterised by a progressive mineralization and fragmentation of elastic fibres of the skin, retina and cardiovascular system. At an initial stage, the skin usually exhibits distinctive lesions and subsequently extra-dermal manifestations. The diagnosis is based on clinical manifestations, histological analysis of the lesions and genetic analysis. This is a case report of a 12-year-old child complaining of painless, mildly itchy yellow papules in the cervical region with 1 year of evolution. PXE is currently an incurable disease and has a favourable prognosis when cardiovascular and retinal complications are prevented and monitored.
Topics: Biopsy; Cardiovascular System; Child; Female; Humans; Pseudoxanthoma Elasticum; Retina; Skin; Ultrasonography
PubMed: 32742638
DOI: 10.12688/f1000research.21431.1