[Show abstract][Hide abstract] ABSTRACT: Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underwent ophthalmic examinations and were screened for CYP4V2 mutations by Sanger sequencing and quantitative polymerase chain reaction (qPCR) copy number variation screening. Eight CYP4V2 mutations were found in 10/19 patients, including three patients in whom only monoallelic mutations were detected. Four novel mutations were identified: c.604G>A; p.(Glu202Lys), c.242C>G; p.(Thr81Arg), c.604+4A>G; p.(?), and c.1249dup; p.(Thr417Asnfs*2). In addition, we identified a heterozygous paternally inherited genomic deletion of at least 3.8 Mb, encompassing the complete CYP4V2 gene and several other genes, which is novel. Clinically, patients demonstrated phenotypic variability, predominantly showing choroidal sclerosis, attenuated vessels, and crystalline deposits of varying degrees of severity. To our knowledge, our study reports the first heterozygous CYP4V2 deletion and hence a novel mutational mechanism underlying BCD. Our results emphasize the importance of copy number screening in BCD. Finally, the identification of CYP4V2-negative patients with indistinguishable phenotypes from CYP4V2-positive patients might suggest the presence of mutations outside the coding regions of CYP4V2, or locus heterogeneity, which is unreported so far.
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and Pγ. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for Pγ inhibition. The p.E790K mutant, with an IC₅₀ value of 2.7 nm is 20.7-fold more sensitive for Pγ inhibition, whereas the p.Y323N mutant with an IC₅₀ of 158 nm is 3-fold less sensitive when compared with the wildtype control.
Human Molecular Genetics 02/2011; 20(4):719-30. · 6.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate optic nerve function using the pattern-reversed visual evoked cortical potentials (VECP) before and after bony orbital decompression in dysthyroid optic neuropathy (DON) due to Graves' disease.
A total of 30 eyes of 15 patients (n=14 female) were observed over 30 ± 13 months after bony three-wall orbital decompression. We examined visual acuity (VA), VECP P100 amplitudes and latencies, as well as proptosis using Hertel's exophthalmometry.
Mean logarithm of the minimum angle of resolution (logMAR) VA increased, statistically significantly, by 2.4 lines during 30 ± 13 months (from 0.38 ± 0.25 before surgery to 0.14 ± 0.1 at the end of observation, p=0.0001). All eyes maintained or improved vision by at least one line. Mean postoperative reduction of proptosis was 6.4 ± 3 mm. While VECP P100 amplitudes improved significantly, P100 latencies remained abnormal in 18 eyes (60%) during follow-up of 10 ± 7 months. Nine eyes (30%) with previous latency defects improved in at least one check test, five of which normalised completely. Worsening was evident in seven eyes (23%), and three previously normal eyes developed new pathological latencies. P100 latencies in 14 eyes (47%) remained unchanged.
After decompression surgery, DON remission was observed in all patients regarding vision and VECP amplitudes. New or persistent P100 latency defects were seen in 60% of eyes after surgery. DON is considered to be caused by compressive ischaemic damage, which further underlines the importance of early decompression surgery.
The British journal of ophthalmology 02/2011; 95(2):222-6. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim was to investigate the Essen biopsy forceps as a new instrument and surgical approach for biopsy of intraocular tumours. Biopsy is indicated for assessment of any uncertain intraocular process or confirmation for presumed diagnosis before treatment. There is increasing interest for further genetic and immunocytological information in order to characterise the neoplasm, especially grading and prognosis of micrometastasis in uveal melanoma. The authors have developed a new surgical technique using special intraocular biopsy forceps.
Twenty patients with uncertain intraocular subretinal tumour underwent biopsies carried out using the special Essen biopsy forceps. Biopsies were obtained through sutureless 23-gauge three-port vitrectomy. A small retinotomy tumour specimen was taken by the forceps branches. For further processing, the specimens were flushed out into a sterile tube and then sent to pathologists.
The prebioptical tumour had a mean thickness of 3.48 mm (1.1 to 9.8 mm). In all cases (n=20) biopsies (0.3-2.1 mm in size) were obtained, in 19 cases (95%) allowing precise histological and immunohistochemical typing of the lesions following cytoblock embedding. Uveal melanoma was diagnosed in 50% (n=10), choroidal metastasis in 15% (n=3) and choroidal naevus in 15% (n=3); other diagnoses (n=3) included choroidal haemangioma, B cell lymphoma and old subretinal haemorrhage. Apart from three patients with temporary punctual bleeding on the surface, there were no intra- and postoperative complications.
Biopsy using special forceps is a promising new approach and precise surgical procedure. Especially for small intraocular tumours, this technique has the advantage in providing enough tissue for improved histological examination and presenting a low risk for complications.
The British journal of ophthalmology 01/2011; 95(1):79-82. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinal cone photoreceptors mediate fine visual acuity, daylight vision, and color vision. Congenital hereditary conditions in which there is a lack of cone function in humans cause achromatopsia, an autosomal recessive trait, characterized by low vision, photophobia, and lack of color discrimination. Herein we report the identification of mutations in the PDE6C gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase as a cause of autosomal recessive achromatopsia. Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.
Proceedings of the National Academy of Sciences 11/2009; 106(46):19581-6. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Photodynamic therapy (PDT) in eye disease was approved 10 years ago for age-related macular degeneration (AMD). Thereafter it was approved for choroidal neovascularisation (CNV) in pathological myopia. The treatment regimen is based on two prospective, multicentre trials (TAP and VIP studies).
In the meantime PDT has been successfully used also in several other ocular diseases. PDT is minimally invasive and has an excellent side effect profile. Different diseases and their treatment with PDT are discussed.
The treatments of idiopathic CNV, secondary CNV in inflammatory diseases of the retina and choroid, choroidal haemangioma, vasoproliferative tumours, malignant melanoma of the choroid, and central serous chorioretinopathy with PDT are described. In most patients the disease progression can be stopped and in some the PDT treatment results in visual improvement. The prognosis is better in patients with early disease detection and small lesions.
Several retinal and choroidal diseases can be treated successfully with PDT. Except for AMD and pathological myopia, PDT is an off label treatment.
Klinische Monatsblätter für Augenheilkunde 08/2009; 226(9):725-39. · 0.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Die Therapieoptionen verschiedener vaskulärer Läsionen der Choriokapillaris, der Aderhaut und der Netzhaut wurden durch die
photodynamische Therapie (PDT) erheblich erweitert. Dies gilt auch für die beobachteten Effekte bei der Behandlung choroidaler
Hämangiome mit einer PDT. Verglichen mit den bisherigen Therapieansätzen, stand erstmals ein relativ selektives Verfahren
mit überwiegender Wirksamkeit im Bereich der zu behandelnden Läsion und der Choroidea unter relativer Schonung unmittelbar
benachbarter retinaler Strukturen zur Verfügung. Diese relative Selektivität ist besonders bei der Behandlung subfoveal gelegener
Läsionen von Bedeutung. Während seit der Erstbeschreibung der Behandlung eines choroidalen Hämangioms mit einer PDT  die Wirksamkeit in mehreren klinischen Studien und Fallserien beobachtet wurde, gab es bezüglich des Zeitpunktes und der
Parameter zum Teil unterschiedliche Behandlungsmodalitäten. Im Folgenden soll auf die Effekte der PDT mit Verteporfin bei
der Behandlung des umschriebenen, solitären choroidalen Hämangiomes unter Berücksichtigung der klinischen Merkmale eingegangen
[Show abstract][Hide abstract] ABSTRACT: Vision impairment in children and young adults may derive from choroidal neovascularisation (CNV) related to numerous conditions. The aim of this study is to highlight the applicability of photodynamic therapy using verteporfin (PDT) in these patients.
In 16 eyes of 16 consecutive patients aged 30 years or younger, prospective open-label PDT was performed. Outcomes of visual acuity as well as changes in CNV lesion parameters were evaluated.
The mean patient age at first PDT was 19.7 (SD 8.7) years (range 6-30). 81% of the patients retained stable vision within two lines or exceedingly improved vision during follow-up of 34 (24) months. Significant vision gain was denoted in seven paediatric patients (2.7 (1.4) lines, mean (SD); p = 0.019) as well as in a subgroup of 12 patients not affected by active uveitis (2.6 (2.0) lines, p = 0.0005). Two patients with multifocal choroiditis and panuveitis (MCP) experienced vision losses of five and 11 lines after four PDT sessions despite receiving additional steroidal treatment. Except for one patient with MCP and two patients who dismissed follow-up, a mean of 2.2 (1.3) PDTs per patient sufficiently inactivated CNV lesions during follow-up. In the area of the former PDT spot, alterations of the pigment epithelium increased by 40% without correlation to changes in vision.
The results indicate good PDT efficacy and tolerability most promising in a subgroup of patients with vision-impairing CNV not associated with active uveitis. PDT in young patients with CNV remains a valuable treatment with good risk-benefit profile over the long term.
The British journal of ophthalmology 06/2008; 92(5):655-60. · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To objectively investigate central retinal function in patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) before and after treatment with pegaptanib sodium (PS).
Patients with CNV due to exudative AMD received intravitreal injections of 0.3 mg PS every sixth week if angiographic activity was evident. Longitudinal observation included recordings with multifocal electroretinography (mfERG) before the first treatment and before each injection at follow-up intervals.
During the observation period of 30.5 +/- 8 weeks (mean +/- SD) a mean number of 5.3 +/- 1.3 injections were applied. Final mean log(MAR) visual acuity decreased, statistically nonsignificant, from 0.67 +/- 0.3 at baseline to 0.74 +/- 0.16. mfERG recordings in 12 patients after 25 +/- 9 weeks evinced a decrease in response density which was statistically significant in the central 5 degrees . Mean P1-amplitudes of ring 1, 2, and 3 were reduced by 66%, 39% and 30%, respectively. During follow-up, implicit times of the P1 components remained stable within 4% of baseline. In three of four patients with vision loss of 2 lines or more, P1-response amplitudes decreased substantially at least 6 weeks prior vision loss.
Treatment with PS resulted in a decrease of central retinal function more obvious in mfERG than in VA longitudinal testing. Good correlations were seen between changes in mean vision and changes in mfERG response density components. As a decline in P1-response amplitudes anteceded vision loss in this study, our results indicate a possible role of mfERG to predict vision loss during intravitreal pharmacotherapy.
[Show abstract][Hide abstract] ABSTRACT: The aim of this non-comparative, consecutive case series is to evaluate the short-term results after endoresection of large uveal melanomas in combination with pretreatment with stereotactic gamma knife radiosurgery.
Between March 2000 and November 2002, forty-six patients with large uveal melanomas underwent stereotactic radiosurgery followed by endoresection of the tumour via a standard three-port vitrectomy including laser photocoagulation and silicone oil tamponade. The average tumour height was 9.5 mm. The minimum dose delivered to the tumour volume was 25 Gy.
The median follow-up time was 410 days. In 40 cases (87 %), the eye was retained with a VA of 20/200 or better in 30 cases (65.2 %) and 20/63 or better in ten cases (21.7 %). In 12 eyes with a follow-up of >/= 0.5 years, the median VA was 20/80 after silicone oil removal and cataract surgery had been performed. Six eyes (13 %) were enucleated due to serious complications caused by the radiosurgery (3 cases) or endoresection (3 cases). In 13 patients (28.2 %), additional major surgery was required. Seven patients developed liver metastases during follow-up and six patients died. No local tumour recurrences were observed.
Eyes with large uveal melanomas can be salvaged by stereotactic radiotherapy followed by endoresection.
Klinische Monatsblätter für Augenheilkunde 07/2006; 223(6):513-20. · 0.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the safety and efficacy of beta ray brachytherapy in treatment of vasoproliferative tumours of the retina (VTR).
35 consecutive patients with symptomatic VTR were treated with a ruthenium-106 ((106)Ru) plaque. Three tumours had been treated previously (two with cryotherapy; one with transpupillary thermotherapy). 32 VTR (91.4%) were located in the lower half of the retina and all of them were found between the mid-periphery and the ora serrata. The mean tumour thickness was 2.8 mm. An exudative retinal detachment was present in 25 eyes (71.4%) and in 15 cases (42.9%) hard exudates were found in the macula. The major symptom was loss of vision (77.1%).
Brachytherapy was well tolerated by every patient. The mean applied dose was 416 Gy at the sclera and 108 Gy at the tumour apex. In all but four eyes (88.6%), it was possible to control the VTR activity. The median follow up time was 24 months. Three of the above mentioned four eyes with treatment failure had had secondary glaucoma before therapy. There was no case of radiation induced neuropathy or retinopathy. Cataract surgery was necessary for five patients. The development of epiretinal gliosis was the most common event during follow up (n = 10, 28.6%). The mean visual acuity decreased slightly (0.33 before and 0.29 after brachytherapy). Multivariate analysis showed that the presence of macular pathology before treatment was associated with a 6.1-fold risk of vision of 0.25 or better (p = 0.03).
beta ray brachytherapy with (1106)Ru plaques was able to control the activity of VTR and retain vision. Cases with secondary glaucoma before treatment had a very poor prognosis.
British Journal of Ophthalmology 05/2006; 90(4):447-50. · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the safety and efficacy of photodynamic therapy with verteporfin (PDT) in patients with choroidal neovascularization associated with angioid streaks (CNVAS).
A nonrandomized, prospective clinical investigation of 12 patients with CNVAS was performed. PDT was based on the criteria concerning the treatment of age-related macular degeneration.
The mean follow-up was 41.75 months (range 24-60). The mean number of (re)treatments was 3.3 (range 2-7). Visual acuity improved by at least 1 line in 42%, was stable within +/-2 lines in 33%, decreased by at least 1 line in 58% and by >3 lines in 25% of the patients. The mean visual acuity was 0.30 (range 0.2-0.5) prior to and 0.17 (range 0.03-0.6) after the final PDT. The mean visual acuity of the contralateral eye was 0.1. 75% of contralateral eyes and 25% of the treated eyes had a final visual acuity of < or =0.1 (20/200). At the final follow-up, a significant enlargement of the lesion size was noted in 92% of the cases.
Using the current (re)treatment criteria, PDT does not appear to limit the growth of CNVAS. Compared to the aggressive natural course and to the limited treatment options, PDT may at least in part help to stabilize macular function over a limited period of time.
Ophthalmic Research 02/2006; 38(4):209-17. · 1.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Photodynamic therapy (PDT) with verteporfin has significantly improved the functional outcome in the treatment of choroidal neovascularization (CNV) in various clinical disorders . While CNV due to age-related macular degeneration and pathologic myopia was the primary focus, several studies showed that the treatment effects of PDTwere not only restricted to these two underlying disorders. Recently, several clinical studies observed PDTas a treatment modality of symptomatic choroidal hemangioma [4, 12, 17].
Albrecht von Graæes Archiv für Ophthalmologie 06/2005; 243(5):393-6. · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Achromatopsia is a congenital, autosomal recessively inherited disorder characterized by a lack of color discrimination, low visual acuity (<0.2), photophobia, and nystagmus. Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder. Here, we analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified. A total of 105 achromats carried apparent homozygous mutations, 44 were compound (double) heterozygotes, and 14 patients had only a single mutant allele. The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations. Thus, the majority of mutations in the CNGB3 gene result in significantly altered and/or truncated polypeptides. Several mutations were found recurrently, in particular a 1 bp deletion, c.1148delC, which accounts for over 70% of all CNGB3 mutant alleles. In conclusion, mutations in the CNGB3 gene are responsible for approximately 50% of all patients with achromatopsia. This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent.
European Journal of HumanGenetics 04/2005; 13(3):302-8. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess the long-term effect of acetazolamide treatment on patients with cystoid macular edema (CME) in the course of intermediate or posterior chronic uveitis and to define those patients who may particularly benefit from the drug.
Fifty-two eyes (45 patients) with chronic uveitic CME were treated with acetazolamide at an initial dosage of 500 mg/d. The effect of treatment was assessed by fluorescein angiography, ophthalmoscopy, visual acuity, and Amsler testing. Therapy was withdrawn when CME did not improve at 3 weeks. In cases with CME improvement, the dosage was gradually tapered.
The mean follow-up was 3.1 years (minimum, 1.5 years). Two subgroups were identified: group 1, quiescence of uveitis with acetazolamide as the single therapeutic agent (33 eyes); and group 2, chronically active uveitis requiring additional systemic antiinflammatory drugs (19 eyes). In both groups, visual acuity improvement was statistically significant (group 1, P = 0.012; group 2, P = 0.025). In 12 patients with a stable visual acuity gain, the medication dose could be tapered off completely without any recurrent edema shown by fluorescein angiography after a minimum follow-up of 1 year. Sixteen patients required a maintenance dosage, ranging from 125 to 500 mg daily. No major adverse effects of the medication were observed.
During long-term follow-up, low-dose acetazolamide can be a useful therapeutic option for chronic CME in uveitis. The effect was better in patients with quiescence of uveitis than in those with chronically active uveitis. Permanent therapy is not imperative in every case.
[Show abstract][Hide abstract] ABSTRACT: Ten new and seventeen previously reported Enhanced S Cone Syndrome (ESCS) subjects were used to search for genetic heterogeneity. All subjects were diagnosed with ESCS on the basis of clinical, psychophysical and/or electroretinography testing using published criteria. Mutation analysis was performed on the NR2E3 nuclear receptor gene by single strand conformation analysis and direct sequencing, which revealed either homozygous (N=13) or compound heterozygous (N=11) mutations in 24 subjects (89%), heterozygous mutations in 2 subjects (7%) and no mutations in 1 subject (4%). Fifteen different mutations were identified, including six not previously reported. The subject (Patient A) with no detected NR2E3 mutation had features not usually associated with ESCS, in particular moderate rod photoreceptor function in peripheral retina and an abnormally thick retinal nerve fibre layer. Mutation analysis of the NRL, CRX, NR1D1 and THRB genes in this individual revealed a heterozygous one base-pair insertion in exon 2 of the NRL gene, which results in a predicted truncation of the NRL protein. Loss-of-function NRL alleles have not been described previously in humans, but since the same mutation was present in unaffected family members, it raises the possibility that the abnormal ESCS phenotype in Patient A may result from a digenic mechanism, with a heterozygous NRL mutation and a mutation in another unknown gene.
Human Mutation 12/2004; 24(5):439. · 5.05 Impact Factor