Pseudoxanthoma elasticum and retinitis pigmentosa in a patient with a novel mutation in the ABCC6 gene.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP). CASE: A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified. CONCLUSION: We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype.

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks.

This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 years) were enrolled and followed for a median of 3.2 years. Four asymptomatic patients were significantly younger than three symptomatic patients with decreased visual acuity at presentation (mean age; 38.1 vs. 61.5 years, p = 0.020). The asymptomatic patients maintained good vision (20/32 or better) and had no choroidal neovascularization (CNV) over the observation period. The symptomatic patients showed additional reduction in visual acuity and bilateral CNV occurrence during the longitudinal follow-up. Pathogenic ABCC6 variants were identified in all patients, leading to a diagnosis of PXE. Heterozygous monoallelic variants were identified in four patients and compound heterozygous variants were detected in three patients. Nine ABCC6 variants were identified, including one novel variant, c.2035G>T [p.Glu679Ter]. This is the first genetic study of Korean patients with PXE.

Angioid Streaks in Types I and II Congenital Dyserythropoietic Anaemia (CDA).

Background. Angioid streaks (AS) are visible irregular breaks in Bruch's membrane, extending radially from the optic nerve head and with overlaying atrophic retinal pigment epithelium. In 50 % of patients, AS are associated with Pseudoxanthoma elasticum, Ehlers-Danlos syndrome, sickle cell anaemia or Paget's disease. In 50 % of patients, AS are idiopathic. Congenital Dyserythropoietic Anaemia (CDA) is a rare, inherited disorder of ineffective erythropoiesis with morphologically abnormal erythroblasts. CDA was first recognised as a separate entity in 1968 and classified into three main groups. CDA demographics have identified 614 known families and > 700 cases worldwide. A few case reports of AS in CDA I and III have been published, but there is no report of AS in CDA II, the most frequent of the CDAs, as well no follow-up. History and Signs. 8 eyes of 4 CDA patients were examined. The CDA I patients were a 46 year old man and a 52 year old woman. They were first seen in 2009 and followed up for 9 and 11 months, respectively. The 2 female CDA II patients were seen in 2010 and were aged 35 and 42 years at first presentation. Vision, Amsler grid, optical coherence tomography (OCT), fundus pictures and fluorescent angiography were performed. Blood was drawn for neutrophil elastase determination (ELA2). Therapy and Outcome. All patients showed bilateral AS. Mean best corrected visual acuity was 20/20 without metamorphopsia and with normal OCT. During the follow-up period, no progression occurred. No choroidal neovascularisation (CNV) was detected. ELA2 serum levels were normal. Conclusions. This is the first report of AS in CDA II and the first follow-up in CDA I. No evidence of progression was seen within this period of time. Longer follow-up is needed to detect whether AS progresses. All patients with AS should be seen by an ophthalmologist on a regular basis. The risk of CNV is given. Therapy is possible and the outcome is best if the CNV is recognised and treated early.

Pseudoxanthoma elasticum associated with vitelliform macular lesion.

The authors describe an uncommon association between pseudoxanthoma elasticum with typical fundus lesions and positive testing for mutation in the ABCC6 gene and the concomitant presence of a large subfoveal vitelliform lesion.

[Choroidal neovascularization secondary to angioid streaks: A familial case report]. / Neovascularización coroidea secundaria a estrías angioides: un caso familiar.

CASE REPORT: We report a familial case of 2 brothers that suffered choroidal neovascularization (CNV) secondary to angioid streaks. They were both treated with a monthly intravitreal injection of ranibizumab (Lucentis(®)) for 3 months. Visual acuity was stabilized and fluorescein angiography revealed complete resolution of CNV. Neither recurrent CNV lesion nor new hemorrhages were reported during the follow-up period. DISCUSSION: The use of intravitreal ranibizumab for the treatment of CNV in patients with angioid streaks has shown favorable results. However, further studies with a longer follow-up and larger number of patients are necessary to more precisely determine the results of this therapy.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

Ocular manifestations of juvenile Paget disease.

OBJECTIVES: To determine the prevalence and spectrum of retinal changes in juvenile Paget disease. METHODS: Observational case series and literature review with analysis. Patients with clinical and molecular evidence of juvenile Paget disease were recruited by members of the International Hyperphosphatasia Collaborative Group. Participants underwent ophthalmic examinations consisting of at least best-corrected Snellen visual acuity and dilated fundal examination or color fundus photography. A MEDLINE literature search was performed, and all identified case reports were reviewed for information regarding ocular phenotype. RESULTS: Fourteen eyes from 7 patients were examined. The mean (SD) patient age was 22 (8) years, and 4 patients were female. Retinal abnormalities were evident in 12 of 14 eyes and were reported among an additional 12 patients in the literature. Retinal abnormalities included mottling of the retinal pigment epithelium, peripapillary atrophy, angioid streaks, and choroidal neovascularization. Cumulative number of retinal abnormalities was strongly associated with increasing age. CONCLUSIONS: Juvenile Paget disease is associated with progressive retinopathy characterized by the development of angioid streaks, which may be complicated by choroidal neovascularization, the predominant cause of visual loss. Osteoprotegerin or its signaling pathway may have a role in calcification of Bruch membrane and in the pathogenesis of angioid streaks. Retinopathy in patients with juvenile Paget disease may be a sign of a more generalized vascular disorder.

Fundus autofluorescence in Pseudoxanthoma elasticum.

PURPOSE: Pseudoxanthoma elasticum (PXE) is an inherited multisystem disorder of the elastic tissue. Typical ocular manifestations include angioid streaks, peau d'orange, salmon spots, and choroidal neovascularization (CNV). Changes in Bruch membrane lead to progressive atrophy of the retinal pigment epithelium (RPE), secondary CNVs, and visual loss. The RPE-photoreceptor complex was studied in vivo using fundus autofluorescence (FAF) imaging. METHODS: Forty-six patients (92 eyes) with PXE were investigated using digital fundus photography, fluorescein angiography (FA), and FAF imaging. The diagnosis was confirmed by multisystem clinical examination, mutation analysis of the ABCC6 gene, and skin biopsy. RESULTS: The mean age of the patient cohort was 50 years (range, 13-74 years), and mean visual acuity was 20/125. Fundus changes typical for PXE were observed in all eyes. Angioid streaks were detected in all but six eyes. Peau d'orange was hardly detectable on FAF, whereas comet tail lesions were apparent. Retinal pigment epithelium atrophy typically was widespread and heterogeneous, located mostly adjacent to angioid streaks or CNVs. Pattern dystrophy-like changes were only found in patients with previous CNV formation in the same or the contralateral eye. CONCLUSION: Abnormalities of the RPE-photoreceptor complex detected by FAF imaging were more diverse and widespread than expected from conventional fundus imaging. The exhibition of pattern dystrophy-like changes may be a transitional state toward a neovascular event in a subgroup of patients. The extensive alteration of the RPE suggests an important role of pathologic RPE changes in the evolution of visual loss in PXE.

Novel mutations of ABCC6 gene in Japanese patients with Angioid streaks.

Angioid streaks (AS) are eye abnormalities caused by breaks in Bruch's membrane. The condition is often associated with pseudoxanthoma elasticum (PXE). The ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6) is reported to be the causal gene for PXE, although there have been no reports on whether the ABCC6 gene is the causal gene for AS. The aims of this study are to isolate the causal mutations for AS using a haplotype-based case-control study. We genotyped 54 Japanese AS patients and 150 controls for 5 single-nucleotide polymorphisms (SNPs). A simple association study using each SNP and a haplotype-based case-control study were performed. Twelve patients with special haplotypes for AS were selected, and were then subjected to gene sequencing. Six variants were successfully identified as causal mutations for AS (p.R419Q, p.E422K, c.2542delG, Del_Exon23, c.3774-3775insC and p.E1427K), and 4 of these were novel. This method can be applied to both identifying susceptibility variants of multifactorial diseases and isolating mutations in single-gene diseases.

Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches.

Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vascular walls, and Bruch's membrane in the eye. Clinically, patients exhibit characteristic lesions of the posterior segment of the eye including peau d'orange, angioid streaks, and choroidal neovascularisations, of the skin including soft, ivory-colored papules in a reticular pattern that predominantly affect the neck and large flexor surfaces, and of the cardiovascular system with peripheral and coronary arterial occlusive disease as well as gastrointestinal bleedings. There is yet no definitive therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. Very recently, the ABCC6 gene on chromosome 16p13.1 was found to be associated with the disease. Mutations within ABCC6 cause reduced or absent transmembraneous transport that leads to accumulation of extracellular material. Presumably, this mechanism causes calcification of elastic fibers. Despite the characteristic clinical features, the variability in phenotypic expressions, and the low prevalence may be responsible for the disease being underdiagnosed. This review compiles and summarizes current knowledge of PXE pathogenesis and clinical findings. Furthermore, different therapeutic strategies to treat retinal manifestations are discussed, including thermal laser coagulation, photodynamic therapy, and intravitreal injections of drugs inhibiting vascular endothelial growth factor.

Congenital dyserythropoietic anaemia, type I, in a Caucasian patient with retinal angioid streaks (homozygous Arg1042Trp mutation in codanin-1).

A congenital dyserythropoietic anaemia (CDA) was recognised in a French Caucasian male patient. Blood smears showed a pronounced aniso-poikilocytosis. Bone marrow light microscopy showed signs of dyserythropoesis, but no internuclear chromatin bridges. Electron microscopy disclosed erythroblast nuclei with the Swiss cheese aspect and the presence of cytoplasmic organelles, assessing the diagnosis of CDA I. The presence of internuclear chromatin bridges may thus be missing in CDA I. The patient proved to be homozygous for the Arg1042Trp mutation in codanin-1 (the 'Bedouin mutation'). By the age of 25, the patient's vision started to deteriorate as a result of retinal angioid streaks and macular abnormalities. Evolution was controlled and the patient, being nearly 50 yr old now, still has a partial use of his eyes. This second case of retinal angioid streaks reported in CDA I adds to the non-haematological features likely to be associated with this condition.

Novel mutation in ABCC6 gene in a Japanese pedigree with pseudoxanthoma elasticum and retinitis pigmentosa.

PURPOSE: To report a novel mutation of the ABCC6 gene in a Japanese family that had a case of pseudoxanthoma elasticum (PXE) another with PXE and retinitis pigmentosa. METHODS: Ophthalmologic examinations were performed, and the ABCC6 gene was analysed by direct genomic sequencing. RESULTS: Fundus examinations of the 48-year-old proband disclosed angioid streaks and a peud'orange appearance of the retina of the both eyes, whereas both of his 25- and 20-year-old daughters had pigmentary degeneration and angioid streaks. In the sibilings, the mixed cone-rod ERG was almost nondetectable, whereas that of the proband was well-preserved. Molecular genetic analysis revealed that the proband has a homozygous nonsense mutation at the 595 bp in the ABCC6, and the siblings were heterozygous for the same mutation. This mutation was not detected in Japanese subjects in the JSNP database (http://snp.ims.u-tokyo.ac.jp/). CONCLUSIONS: Our results demonstrated an association between a novel mutation in the ABCC6 gene and PXE in a Japanese family.

Optic disc drusen, angioid streaks, and mottled fundus in various combinations in a Sicilian family.

BACKGROUND: We describe a Sicilian family in which optic disc drusen, angioid streaks, and mottled fundus--without dermatological signs of pseudoxanthoma elasticum (PXE)--are present in various combinations and segregate as an autosomal dominant trait. Since these ocular manifestations can be part of the clinical signs of PXE, we examined the possible involvement of a mutation in the ABCC6 gene, which is known to be responsible for PXE. METHODS: Linkage analysis was performed with both intragenic and flanking markers. We used marker D16B9722 and a single-nucleotide polymorphism located in exon 15 of the ABCC6 gene. LOD score values were calculated on the assumption of a gene frequency of 0.0001 and both complete penetrance and reduced penetrance (90%), with theta values between 0.0 and 0.4. RESULTS: LOD score values excluded the involvement of the ABCC6 gene. CONCLUSIONS: The dominant transmission of optic disc drusen, mottled fundus, and angioid streaks in this family is not due to alterations in the ABCC6 gene.

Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III).

Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22. In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.