Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Letnik:
66
Journal Article
Recenzirano
Odprti dostop
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy ...(VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.
Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional
variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen
possible pathogenic role.
Exome sequencing of a family with RP revealed a splice variant in
. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in
. In addition, the clinical diagnosis of the
retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of
and its paralog
in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.
This study discusses a previously unreported association between monoallelic or biallelic
variants and RP. Notably, similar observations have been reported for
.
Purpose
Serum eye drops (SEDs) are used to treat a variety of ocular surface defects. Serum eye drops (SEDs) are normally produced from the patient’s blood. However, not all patients can donate ...sufficient or suitable blood, and logistics can be challenging. Allogeneic blood from voluntary blood donors does not have these disadvantages. Our aim was to evaluate whether autologous and allogeneic SEDs have comparable efficacy and tolerability.
Methods
In a prospective, double‐blind crossover trial, patients with severe dry eyes were randomized to first receive autologous SEDs for one month, followed by one‐month washout, before receiving allogeneic SEDs for 1 month; or receive the SED preparations in reverse order. The Ocular Surface Disease Index (OSDI) was the primary endpoint, and various secondary endpoints were determined. A linear mixed model with random intercept for each patient was applied per treatment group to compare the pre‐ and postoutcome measurements.
Results
Nineteen patients were enrolled, of whom 15 completed the trial. When autologous SEDs were used, the mean ± SD OSDI improved from 62 ± 19 to 57 ± 18. For allogeneic SEDs, the OSDI changed from 59 ± 20 to 56 ± 23. The estimated mean difference (95% confidence interval) was −4.2 (−9.5 to 1.2) for autologous and −4.5 (−9.8 to 0.9) for allogeneic SEDs (both, not significant). Adverse events were mild and resolved completely.
Conclusion
Autologous and allogeneic SEDs have comparable efficacy and tolerability for use in patients with severe dry eyes. Allogeneic SEDs are therefore an attractive alternative for patients who need SEDs but are clinically or logistically unable to donate blood.
Age-related macular degeneration (AMD) is a multifactorial disease, in which complement-mediated inflammation plays a pivotal role. A positive family history is an important risk factor for ...developing AMD. Certain lifestyle factors are shown to be significantly associated with AMD in non-familial cases, but not in familial cases. This study aimed to investigate whether the contribution of common genetic variants and complement activation levels differs between familial and sporadic cases with AMD.
1216 AMD patients (281 familial and 935 sporadic) and 1043 controls (143 unaffected members with a family history of AMD and 900 unrelated controls without a family history of AMD) were included in this study. Ophthalmic examinations were performed, and lifestyle and family history were documented with a questionnaire. Nine single nucleotide polymorphisms (SNPs) known to be associated with AMD were genotyped, and serum concentrations of complement components C3 and C3d were measured. Associations were assessed in familial and sporadic individuals. The association with risk alleles of the age-related maculopathy susceptibility 2 (ARMS2) gene was significantly stronger in sporadic AMD patients compared to familial cases (p = 0.017 for all AMD stages and p = 0.003 for advanced AMD, respectively). ARMS2 risk alleles had the largest effect in sporadic cases but were not significantly associated with AMD in densely affected families. The C3d/C3 ratio was a significant risk factor for AMD in sporadic cases and may also be associated with familial cases. In patients with a densely affected family this effect was particularly strong with ORs of 5.37 and 4.99 for all AMD and advanced AMD respectively.
This study suggests that in familial AMD patients, the common genetic risk variant in ARMS2 is less important compared to sporadic AMD. In contrast, factors leading to increased complement activation appear to play a larger role in patients with a positive family history compared to sporadic patients. A better understanding of the different contributions of risk factors in familial compared to non-familial AMD will aid the development of reliable prediction models for AMD, and may provide individuals with more accurate information regarding their individual risk for AMD. This information is especially important for individuals who have a positive family history for AMD.
To describe the clinical and genetic spectrum of RP1-associated retinal dystrophies.
In this multicenter case series, we included 22 patients with RP1-associated retinal dystrophies from 19 families ...from The Netherlands and Japan. Data on clinical characteristics, visual acuity, visual field, ERG, and retinal imaging were extracted from medical records over a mean follow-up of 8.1 years.
Eleven patients were diagnosed with autosomal recessive macular dystrophy (arMD) or autosomal recessive cone-rod dystrophy (arCRD), five with autosomal recessive retinitis pigmentosa (arRP), and six with autosomal dominant RP (adRP). The mean age of onset was 40.3 years (range 14-56) in the patients with arMD/arCRD, 26.2 years (range 18-40) in adRP, and 8.8 years (range 5-12) in arRP patients. All patients with arMD/arCRD carried either the hypomorphic p.Arg1933* variant positioned close to the C-terminus (8 of 11 patients) or a missense variant in exon 2 (3 of 11 patients), compound heterozygous with a likely deleterious frameshift or nonsense mutation, or the p.Gln1916* variant. In contrast, all mutations identified in adRP and arRP patients were frameshift and/or nonsense variants located far from the C-terminus.
Mutations in the RP1 gene are associated with a broad spectrum of progressive retinal dystrophies. In addition to adRP and arRP, our study provides further evidence that arCRD and arMD are RP1-associated phenotypes as well. The macular involvement in patients with the hypomorphic RP1 variant suggests that macular function may remain compromised if expression levels of RP1 do not reach adequate levels after gene augmentation therapy.
Retinitis pigmentosa (RP) shows substantial genetic heterogeneity. It has been estimated that in approximately 60%-80% of RP cases, the genetic diagnosis can be found using whole exome sequencing ...(WES). In this study, the purpose was to identify causative variants in individuals with genetically unexplained retinal disease, which included one consanguineous family with two affected siblings and one case with RP.
To identify the genetic defect, WES was performed in both probands, and clinical analysis was performed. To obtain insight into the function of KIAA1549 in photoreceptors, mRNA expression, knockdown and protein localisation studies were performed.
Through analysis of WES data, based on population allele frequencies, and in silico prediction tools, we identified a homozygous missense variant and a homozygous frameshift variant in
that segregate in two unrelated families. Kiaa1549 was found to localise at the connecting cilium of the photoreceptor cells and the synapses of the mouse retina. Both variants affect the long transcript of
, which encodes a 1950 amino acid protein and shows prominent brain expression. The shorter transcript encodes a 734 amino acid protein with a high retinal expression and is affected by the identified missense variant. Strikingly, knockdown of the long transcript also leads to decreased expression of the short transcript likely explaining the non-syndromic retinal phenotype caused by the two variants targeting different transcripts.
In conclusion, our results underscore the causality of segregating variants in
for autosomal recessive RP. Moreover, our data indicate that KIAA1549 plays a role in photoreceptor function.
Little is known regarding the therapeutic effect of carbonic anhydrase inhibitors (CAIs) in the management of cystic macular lesions in children with X-linked juvenile retinoschisis (XLRS) despite ...the fact that this disease often manifests during childhood. Therefore, our goal was to determine the efficacy of CAIs in the treatment of cystic macular lesions in children with XLRS.
We used CAIs to treat cystic macular lesions in 18 eyes of nine children with XLRS. We evaluated the therapeutic effect of CAI treatment with the best-corrected visual acuity and foveal zone thickness (FZT) with spectral-domain optical coherence tomography. A reduction of at least 22.4% in FZT was defined as objective evidence of response.
Five of nine (55.6%) XLRS patients showed a significant reduction of FZT in both eyes over a median treatment interval of 6.8 months (range, 1-23). In four of five (80.0%) patients, this reduction was already apparent after 1 month of treatment. An improvement of visual acuity was observed in five eyes (27.8%) of three patients (33.3%). Six patients (66.6%) reported minor side effects.
Treatment with CAIs decreased FZT in more than half of the children with XLRS. This effect was observed within 1 month in the majority of patients. Carbonic anhydrase inhibitor treatment restores retinal anatomy and may contribute to creating optimal circumstances for gene therapy.
Background
Early‐onset photoreceptor dystrophies are a major cause of irreversible visual impairment in children and young adults. This clinically heterogeneous group of disorders can be caused by ...mutations in many genes. Nevertheless, to date, 30%–40% of cases remain genetically unexplained. In view of expanding therapeutic options, it is essential to obtain a molecular diagnosis in these patients as well. In this study, we aimed to identify the genetic cause in two siblings with genetically unexplained retinal disease.
Methods
Whole exome sequencing was performed to identify the causative variants in two siblings in whom a single pathogenic variant in TULP1 was found previously. Patients were clinically evaluated, including assessment of the medical history, slit‐lamp biomicroscopy, and ophthalmoscopy. In addition, a functional analysis of the putative splice variant in TULP1 was performed using a midigene assay.
Results
Clinical assessment showed a typical early‐onset photoreceptor dystrophy in both the patients. Whole exome sequencing identified two pathogenic variants in TULP1, a c.1445G>A (p.(Arg482Gln)) missense mutation and an intronic c.718+23G>A variant. Segregation analysis confirmed that both siblings were compound heterozygous for the TULP1 c.718+23G>A and c.1445G>A variants, while the unaffected parents were heterozygous. The midigene assay for the c.718+23G>A variant confirmed an elongation of exon 7 leading to a frameshift.
Conclusion
Here, we report the first near‐exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two patients with an early‐onset photoreceptor dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.
In this study, we report the first near‐exon RNA splice variant that is not present in a consensus splice site sequence in TULP1, which was found in a compound heterozygous manner with a previously described pathogenic TULP1 variant in two siblings with an early‐onset retinal dystrophy. We provide proof of pathogenicity for this splice variant by performing an in vitro midigene splice assay, and highlight the importance of analysis of noncoding regions beyond the noncanonical splice sites in patients with inherited retinal diseases.
PDF
