Outcome of Cataract Surgery in Patients With Retinitis Pigmentosa.

PURPOSE: To assess the visual outcome of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, noncomparative clinical study. METHODS: Preoperative, intraoperative, and postoperative data of patients with RP who were undergoing cataract surgery were collected from several expertise centers across Europe. RESULTS: In total, 295 eyes of 226 patients were included in the study. The mean age at surgery of the first eye was 56.1 ± 17.9 years. Following surgery, best-corrected visual acuity (BCVA) improved significantly from 1.03 to 0.81 logMAR (ie, 20/214 to 20/129 Snellen) in the first treated eye (-0.22 logMAR; 95% CI = -0.31 to -0.13; P < .001) and from 0.80 to 0.56 logMAR (ie, 20/126 to 20/73 Snellen) in the second treated eye (-0.24 logMAR; 95% CI = -0.32 to -0.15; P < .001). Marked BCVA improvements (postoperative change in BCVA of ≥0.3 logMAR) were observed in 87 of 226 patients (39%). Greater odds for marked visual improvements were observed in patients with moderate visual impairment or worse. The most common complications were zonular dialysis (n = 15; 5%) and (exacerbation of) cystoid macular edema (n = 14; 5%), respectively. Postoperative posterior capsular opacifications were present in 111 of 295 eyes (38%). CONCLUSION: Significant improvements in BCVA are observed in most patients with RP following cataract surgery. Baseline BCVA is a predictor of visual outcome. Preoperative evaluation should include the assessment of potential zonular insufficiency and the presence of CME, as they are relatively common and may increase the risk of complications.

Clinical outcomes of treatment with idebenone in Leber's hereditary optic neuropathy in the Netherlands: A national cohort study.

PURPOSE: The purpose of the study was to present results from a national Dutch cohort of patients with Leber's Hereditary Optic Neuropathy (LHON) treated with idebenone. METHODS: The multicentre, open-label, retrospective evaluation of the long-term outcome of idebenone treatment of Dutch LHON patients on visual function and on thickness of the retinal ganglion cell layer. Patients included in the analysis had a confirmed mutation in their mitochondrial DNA encoding either of the seven subunits of complex I, had a reported loss of vision in at least one eye and had a follow-up of more than 6 months after their treatment was started. Control visits involved routine clinical examinations of visual function and retinal structure at (1) the start of treatment, (2) nadir (time of lowest visual acuity), (3) the time of recovery (if any), (4) the time of termination of treatment and (5) more than 6 months after termination of the treatment. RESULTS: Data from 72 patients were analysed. Treatment duration was 23.8 ± 14.4 (mean ± SD) months. A positive response, that is either a clinically relevant recovery (CRR) or a clinically relevant stabilization (CRS), occurred in 53% and 11% of the patients, respectively. The magnitude of CRR was 0.41 ± 1.54 logMAR. CRR of visual acuity is associated with recovery of colour discrimination. The thickness of both the ganglion cell complex (GCC) and the retinal nerve fibre layer (RNFL) is irreversibly reduced. CONCLUSION: Our results confirm that idebenone may help to restore or maintain visual function. Whether this effect will persist is still unknown. Thinning of retinal neural tissue appears to be permanent.

Stargardt disease: monitoring incidence and diagnostic trends in the Netherlands using a nationwide disease registry.

PURPOSE: To assess the incidence of Stargardt disease (STGD1) and to evaluate demographics of incident cases. METHODS: For this retrospective cohort study, demographic, clinical and genetic data of patients with a clinical diagnosis of STGD1 were registered between September 2010 and January 2020 in a nationwide disease registry. Annual incidence (2014-2018) and point prevalence (2018) were assessed on the basis of this registry. RESULTS: A total of 800 patients were registered, 56% were female and 83% were of European ancestry. The incidence was 1.67-1.95:1,000,000 per year and the point prevalence in 2018 was approximately 1:22,000-1:19,000 (with and without 10% of potentially unregistered cases). Age at onset was associated with sex (p = 0.027, Fisher's exact); 1.9x more women than men were observed (140 versus 74) amongst patients with an age at onset between 10 and 19 years, while the sex ratio in other age-at-onset categories approximated one. Late-onset STGD1 (≥45 years) constituted 33% of the diagnoses in 2014-2018 compared to 19% in 2004-2008. Diagnostic delay (≥2 years between the first documentation of macular abnormalities and diagnosis) was associated with older age of onset (p = 0.001, Mann-Whitney). Misdiagnosis for age-related macular degeneration (22%) and incidental STGD1 findings (14%) was common in patients with late-onset STGD1. CONCLUSION: The observed prevalence of STGD1 in real-world data was lower than expected on the basis of population ABCA4 allele frequencies. Late-onset STGD1 was more frequently diagnosed in recent years, likely due to higher awareness of its phenotype. In this pretherapeutic era, mis- and underdiagnosis of especially late-onset STGD1 and the role of sex in STGD1 should receive special attention.

Impact of upper blepharoplasty, with or without orbicularis oculi muscle removal, on tear film dynamics and dry eye symptoms: A randomized controlled trial.

PURPOSE: Upper blepharoplasty may be related to dry eye symptoms since the function of the orbicularis oculi muscle may affect the tear film. We aimed to assess the effect of blepharoplasty with or without the removal of a strip of orbicularis oculi muscle on tear film dynamics and dry eye symptoms. METHODS: A double-blind, randomized, controlled trial comparing upper blepharoplasty without (group A) or with (group B) orbicularis oculi muscle excision was performed on 54 healthy Caucasian patients. Tear film dynamics and dry eye symptoms were evaluated using multiple dry eye parameters, i.e. tear osmolarity, Schirmer test I, corneal/conjunctival staining, tear break-up time (TBUT), Oxford Scheme, Sicca Ocular Staining Score and Ocular Surface Disease Index questionnaire. All the parameters were assessed preoperatively and 6 and 12 months after upper blepharoplasty. All the groups' outcomes were compared. RESULTS: The differences were not significant between the two upper blepharoplasty techniques regarding most of the above-mentioned outcomes. Subjective symptoms of ocular irritation, consistent with dry eye disease and vision-related impairment, were reduced after upper blepharoplasty independent of the type of the technique applied, while the pre and postoperative outcomes of the objective tear dynamics did not differ 12 months after surgery. However, group B demonstrated a significant increase in tear osmolarity and TBUT at the 6-month follow-up visit. CONCLUSION: An upper blepharoplasty alleviates subjective dry eye complaints in the long term, while not changing the tear dynamics. The improvement was independent of the blepharoplasty technique used.

[New treatment option for Leber hereditary optic neuropathy: early diagnosis is required]. / Nieuwe therapie voor hereditaire opticusneuropathie van Leber.

BACKGROUND: Leber hereditary optic neuropathy (LHON) is an orphan disease which leads to painless subacute loss of central vision in both eyes. It develops mainly in young adults and is more common in males. It most often leads to lifelong blindness. Idebenone has shown to have a favourable effect in promoting vision recovery in LHON-patients with recent visual impairement. CASE DESCRIPTION: Two male LHON patients, aged 27 and 54 years of age were misdiagnosed during one year with optic neuritis and conversion disorder. The delay caused unnecessary emotional suffering and took away the opportunity of idebenone treatment. This can be prevented by greater awareness of disease characteristcs and OCT-scanning. CONCLUSION: Therapy for LHON requires a timely diagnosis.

Recognizing differentiating clinical signs of CLN3 disease (Batten disease) at presentation.

PURPOSE: To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation. METHODS: Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients). RESULTS: Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5-10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG. CONCLUSION: Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease.

Late-Onset Stargardt Disease Due to Mild, Deep-Intronic ABCA4 Alleles.

Purpose: To investigate the role of two deep-intronic ABCA4 variants, that showed a mild splice defect in vitro and can occur on the same allele as the low penetrant c.5603A>T, in Stargardt disease (STGD1). Methods: Ophthalmic data were assessed of 18 STGD1 patients who harbored c.769-784C>T or c.4253+43G>A in combination with a severe ABCA4 variant. Subjects carrying c.[769-784C>T; 5603A>T] were clinically compared with a STGD1 cohort previously published carrying c.5603A>T noncomplex. We calculated the penetrances of the intronic variants using ABCA4 allele frequency data of the general population and investigated the effect of c.769-784C>T on splicing in photoreceptor progenitor cells (PPCs). Results: Mostly, late-onset, foveal-sparing STGD1 was observed among subjects harboring c.769-784C>T or c.4253+43G>A (median age of onset, 54.5 and 52.0 years, respectively). However, ages of onset, phenotypes in fundo, and visual acuity courses varied widely. No significant clinical differences were observed between the c.[769-784C>T; 5603A>T] cohort and the c.4253+43G>A or the c.5603A>T cohort. The penetrances of c.769-784C>T (20.5%-39.6%) and c.4253+43G>A (35.8%-43.1%) were reduced, when not considering the effect of yet unidentified or known factors in cis, such as c.5603A>T (identified in 7/7 probands with c.769-784C>T; 1/8 probands with c.4253+43G>A). Variant c.769-784C>T resulted in a pseudo-exon insertion in 15% of the total mRNA (i.e., ∼30% of the c.769-784C>T allele alone). Conclusions: Two mild intronic ABCA4 variants could further explain missing heritability in late-onset STGD1, distinguishing it from AMD. The observed clinical variability and calculated reduced penetrance urge research into modifiers within and outside of the ABCA4 gene.

Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides.

PURPOSE: Using exome sequencing, the underlying variants in many persons with autosomal recessive diseases remain undetected. We explored autosomal recessive Stargardt disease (STGD1) as a model to identify the missing heritability. METHODS: Sequencing of ABCA4 was performed in 8 STGD1 cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and 3 cases with no ABCA4 variant. The effect of intronic variants was analyzed using in vitro splice assays in HEK293T cells and patient-derived fibroblasts. Antisense oligonucleotides were used to correct splice defects. RESULTS: In 24 of the probands (67%), one known and five novel deep-intronic variants were found. The five novel variants resulted in messenger RNA pseudoexon inclusions, due to strengthening of cryptic splice sites or by disrupting a splicing silencer motif. Variant c.769-784C>T showed partial insertion of a pseudoexon and was found in cis with c.5603A>T (p.Asn1868Ile), so its causal role could not be fully established. Variant c.4253+43G>A resulted in partial skipping of exon 28. Remarkably, antisense oligonucleotides targeting the aberrant splice processes resulted in (partial) correction of all splicing defects. CONCLUSION: Our data demonstrate the importance of assessing noncoding variants in genetic diseases, and show the great potential of splice modulation therapy for deep-intronic variants.

Clinical Characterization of 66 Patients With Congenital Retinal Disease Due to the Deep-Intronic c.2991+1655A>G Mutation in CEP290.

Purpose: To describe the phenotypic spectrum of retinal disease caused by the c.2991+1655A>G mutation in CEP290 and to compare disease severity between homozygous and compound heterozygous patients. Methods: Medical records were reviewed for best-corrected visual acuity (BCVA), age of onset, fundoscopy descriptions. Foveal outer nuclear layer (ONL) and ellipsoid zone (EZ) presence was assessed using spectral-domain optical coherence tomography (SD-OCT). Differences between compound heterozygous and homozygous patients were analyzed based on visual performance and visual development. Results: A total of 66 patients were included. The majority of patients had either light perception or no light perception. In the remaining group of 14 patients, median BCVA was 20/195 Snellen (0.99 LogMAR; range 0.12-1.90) for the right eye, and 20/148 Snellen (0.87 LogMAR; range 0.22-1.90) for the left. Homozygous patients tended to be more likely to develop light perception compared to more severely affected compound heterozygous patients (P = 0.080) and are more likely to improve from no light perception to light perception (P = 0.022) before the age of 6 years. OCT data were available in 12 patients, 11 of whom had retained foveal ONL and EZ integrity up to 48 years (median 23 years) of age. Conclusions: Homozygous patients seem less severely affected compared to their compound-heterozygous peers. Improvement of visual function may occur in the early years of life, suggesting a time window for therapeutic intervention up to the approximate age of 17 years. This period may be extended by an intact foveal ONL and EZ on OCT.

The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants.

Purpose: To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. Methods: The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospectively. Two asymptomatic siblings carrying the same ABCA4 variants as their probands were clinically examined. The penetrance of p.Asn1868Ile was calculated using allele frequency data of ABCA4 variants in non-Finnish European individuals. Results: The p.Asn1868Ile variant was found in cis with known variants in 14/67 probands. In 27/67 probands, we identified p.Asn1868Ile without additional variants in cis, in combination with known, mainly severe ABCA4 variants. In 23/27 probands, the trans configuration was established. Among 27 probands and 6/7 STGD1 siblings carrying p.Asn1868Ile, 42% manifested late-onset disease (>44 years). We additionally identified four asymptomatic relatives carrying a combination of a severe variant and p.Asn1868Ile; ophthalmologic examination in two persons did not reveal STGD1. Based on ABCA4 allele frequency data, we conservatively estimated the penetrance of p.Asn1868Ile, when present in trans with a severe variant, to be below 5%. Conclusions: A significant fraction of genetically unexplained STGD1 cases carries p.Asn1868Ile as a second variant. Our findings suggest exceptional differences in disease expression or even nonpenetrance of this ABCA4 variant, pointing toward an important role for genetic or environmental modifiers in STGD1.

International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.

De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in Blue Cone Monochromacy.

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. 'LIAVA', 'LVAVA') with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the 'LIAVA' haplotype derived from an ancestral less deleterious 'LIAVS' haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.

A Nonsense Mutation in FAM161A Is a Recurrent Founder Allele in Dutch and Belgian Individuals With Autosomal Recessive Retinitis Pigmentosa.

PURPOSE: To identify mutations in FAM161A underlying autosomal recessive retinitis pigmentosa (arRP) in the Dutch and Belgian populations and to investigate whether common FAM161A-associated phenotypic features could be identified. METHODS: Homozygosity mapping, amplification-refractory mutation system (ARMS) analysis, and Sanger sequencing were performed to identify mutations in FAM161A. Microsatellite and SNP markers were genotyped for haplotype analysis. Patients with biallelic mutations underwent detailed ophthalmologic examinations, including measuring best-corrected visual acuity, extensive fundus photography with reflectance and autofluorescence imaging, and optical coherence tomography. RESULTS: Homozygosity mapping in 230 Dutch individuals with suspected arRP yielded five individuals with a homozygous region harboring FAM161A. Sanger sequencing revealed a homozygous nonsense mutation (c.1309A>T; p.[Arg437*]) in one individual. Subsequent ARMS analysis and Sanger sequencing in Dutch and Belgian arRP patients resulted in the identification of seven additional individuals carrying the p.(Arg437*) mutation, either homozygously or compound heterozygously with another mutation. Haplotype analysis identified a shared haplotype block of 409 kb surrounding the p.(Arg437*) mutation in all patients, suggesting a founder effect. Although the age of onset was variable among patients, all eight developed pronounced outer retinal loss with severe visual field defects and a bull's eye-like maculopathy, followed by loss of central vision within 2 decades after the initial diagnosis in five subjects. CONCLUSIONS: A founder mutation in FAM161A p.(Arg437*) underlies approximately 2% of arRP cases in the Dutch and Belgian populations. The age of onset of the retinal dystrophy appears variable, but progression can be steep, with almost complete loss of central vision later in life.

Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds.

PURPOSE: We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds. METHODS: Ophthalmological examination, general paediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings. RESULTS: Clinical analysis showed high hyperopia (+11 D and +12 D), short axial lengths (15 mm) and the presence of macular folds and optic nerve head drusen. Autofluorescence of the retina was generally normal with subtle macular abnormalities. Sequence analysis showed compound heterozygosity for severe MFRP mutations in both sisters: a previously reported p.Asn167fs (c.498dupC) and a novel stop codon mutation p.Gln91X (c.271C>T). CONCLUSION: These are the youngest nanophthalmos patients in the literature identified with severe loss of MFRP function, showing already the known structural abnormalities for this disease. Adult patients affected by homozygous or compound heterozygous MFRP mutations generally show signs of retinal dystrophy, with ERG disturbances and RPE abnormalities on autofluorescence imaging. ERG examination could not be performed in these children, but extensive RPE abnormalities were not seen at this young age.

Ocular and extra-ocular features of patients with Leber congenital amaurosis and mutations in CEP290.

PURPOSE: This study investigated the centrosomal protein, 290-KD (CEP290) associated genotype and ocular and extra-ocular phenotype in 18 patients with Leber congenital amaurosis (LCA). METHODS: Eighteen patients with LCA from 14 families with mutations in the CEP290 gene were identified with sequencing or with heteroduplex analysis. Ophthalmic examinations were performed on all patients. Scans of the central nervous system were reassessed in three patients and obtained in two. Renal function was evaluated in all patients. Ultrasonography of the kidneys was performed in six patients. RESULTS: Eight patients (from five families) carried the c.2991+1655A>G mutation homozygously. Nine solitary patients carried this variant combined with a nonsense, frameshift, or splice site mutation on the second allele. One new nonsense mutation was identified: c.1078C>T. Fourteen patients (from 12 families) had been completely blind from birth or had light perception. The best-recorded visual acuity was 20/200. Peripheral fundus changes appeared to be progressive with a relatively preserved posterior pole. Novel ophthalmic features for the CEP290 phenotype were Coats-like exudative vasculopathy in two patients, a small chorioretinal coloboma in one patient, and well defined, small, atrophic spots at the level of the retinal pigment epithelium causing a dot-like appearance in five patients. Some CEP290 patients exhibited systemic abnormalities. We found abnormal proprioception in two patients and mild mental retardation in one. One patient was infertile due to immobile spermatozoa. No renal abnormalities were detected. CONCLUSIONS: CEP290-associated LCA has a severe, progressive, and clinically identifiable phenotype. Distinct extra-ocular findings were noted, which may be attributed to ciliary dysfunction.

Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy.

OBJECTIVE: To evaluate the clinical course, genetic etiology, and visual prognosis in patients with cone dystrophy (CD) and cone-rod dystrophy (CRD). DESIGN: Clinic-based, longitudinal, multicenter study. PARTICIPANTS: Consecutive probands with CD (N = 98), CRD (N = 83), and affected relatives (N = 41 and N = 17, respectively) from various ophthalmogenetic clinics in The Netherlands, Belgium, and the United Kingdom. METHODS: Data on best-corrected Snellen visual acuity, color vision, ophthalmoscopy, fundus photography, Goldmann perimetry, and full-field standard electroretinogram (ERG) from all patients were registered from medical charts over a mean follow-up of 19 years. The ABCA4, CNGB3, KCNV2, PDE6C, and RPGR genes were analyzed by direct sequencing in autosomal recessive (AR) and X-linked (XL), respectively. Genotyping was not undertaken for autosomal-dominant cases. MAIN OUTCOME MEASURES: The 10-year progression of all clinical parameters and cumulative lifetime risk of low vision and legal blindness were assessed. RESULTS: The mean age onset for CD was 16 years (standard deviation, 11), and of CRD 12 years (standard deviation, 11; P = 0.02). The pattern of inheritance was AR in 92% of CD and 90% of CRD. Ten years after diagnosis, 35% of CD and 51% of CRD had a bull's eye maculopathy; 70% of CRD showed absolute peripheral visual field defects and 37% of CD developed rod involvement on ERG. The mean age of legal blindness was 48 (standard error [SE], 3.1) years in CD, and 35 (SE, 1.1; P<0.001) years in CRD. ABCA4 mutations were found in 8 of 90 (9%) of AR-CD, and in 17 of 65 (26%) of AR-CRD. Other mutations were detected in CNGB3 (3/90; 3%), KCNV2 (4/90; 4%), and in PDE6C (1/90; 1%). The RPGR gene was mutated in the 2 XL-CD and in 4 of 5 (80%) of XL-CRD. ABCA4 mutations as well as age of onset <20 years were significantly associated with a faster progression to legal blindness (P<0.001). CONCLUSIONS: Although CD had a slightly more favorable clinical course than CRD, both disorders progressed to legal blindness in the majority of patients. Mutations in the ABCA4 gene and early onset of disease were independent prognostic parameters for visual loss. Our data may serve as an aid in counseling patients with progressive cone disorders.

Intermediate uveitis and alopecia areata: is there a relationship? Report of 3 pediatric cases.

Three previously healthy children, aged 5, 8, and 15 years, with idiopathic intermediate uveitis (IU) and alopecia areata (AA) are described. These are the first 3 cases of which we are aware with this coexistence. The results of extensive diagnostic evaluations were negative in all 3 cases. AA preceded the diagnosis of bilateral IU in 1 child and followed within several months after IU diagnosis in 2 children. The severity of uveitis ranged from mild to sight-threatening, and hair loss ranged from local lesions in 2 cases to total alopecia in 1 case. Pathogenesis of both diseases is discussed. Theoretically, the coexistence of IU and AA might be based on the similarities in their complex pathogenesis. However, more research is needed to evaluate if the coexistence is based on an association between 2 autoimmune disorders or is a coincidence.

A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.

PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.