Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the
gene. It causes bilateral pediatric cataract and ...hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in
, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in
was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in
(c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both
and
genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.
Introduction
Inherited retinal dystrophies (IRDs) represent a genetically diverse group of progressive, visually debilitating diseases. Adult and paediatric patients with vision loss due to IRD ...caused by biallelic mutations in the 65-kDa retinal pigment epithelium (
RPE65
) gene are often clinically diagnosed as retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA). This study aimed to understand the epidemiological landscape of
RPE65
gene-mediated IRD through a systematic review of the literature, as the current evidence base for its epidemiology is very limited.
Methods
Medline, Embase, and other databases were searched for articles on the epidemiology of
RPE65
gene-mediated IRDs from inception until June 2021. Studies were included if they were original research articles reporting the epidemiology of RP and LCA and/or proportion of
RPE65
gene mutations in these clinically diagnosed or molecularly confirmed IRDs patients.
Results
A total of 100 studies with relevant data were included in this systematic review. The range for prevalence of LCA and RP in the literature was 1.20–2.37 and 11.09–26.43 per 100,000, respectively. The proportion of
RPE65
mutations in clinically diagnosed patients with LCA was found to be between ~ 2–16% within the US and major European countries (France, Germany, Italy, Spain, and the UK). This range was also comparable to our findings in the Asian region for
RPE65
-LCA (1.26–16.67%). Similarly, for these European countries,
RPE65
-RP was estimated between 0.23 and 1.94%, and
RPE65
-IRD range was 1.2–14%. Further, in the Americas region, mutations in
RPE65
were reported to cause 1–3% of RP and 0.8–3.7% of IRD cases. Lastly, the
RPE65
-IRD range was 4.81–8% in the Middle East region.
Conclusions
There are significant variations in reporting of
RPE65
proportions within countries as well as regions. Generating robust epidemiological evidence on
RPE65
gene-mediated IRDs would be fundamental to support rare disease awareness, timely therapeutic intervention, and public health decision-making.
Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. ...Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil.
Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders ...affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype–phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.
Primary congenital glaucoma (PCG), occurs due to the developmental defects in the trabecular meshwork and anterior chamber angle in children. PCG exhibits genetic heterogeneity and the CYP1B1 gene ...has been widely implicated worldwide. Despite the diverse mutation spectra, the clinical implications of these mutations are yet unclear. The present study attempted to delineate the clinical profile of PCG in the background of CYP1B1 mutations from a large cohort of 901 subjects from India (n=601) and Brazil (n=300).
Genotype-phenotype correlations was undertaken on clinically well characterized PCG cases from India (n=301) and Brazil (n=150) to assess the contributions of CYP1B1 mutation on a set of demographic and clinical parameters. The demographic (gender, and history of consanguinity) and quantitative clinical (presenting intraocular pressure IOP and corneal diameter CD) parameters were considered as binary and continuous variables, respectively, for PCG patients in the background of the overall mutation spectra and also with respect to the prevalent mutations in India (R368H) and Brazil (4340delG). All these variables were fitted in a multivariate logistic regression model using the Akaike Information Criterion (AIC) to estimate the adjusted odds ratio (OR) using the R software (version 2.14.1).
The overall mutation spectrum were similar across the Indian and Brazilian PCG cases, despite significantly higher number of homozygous mutations in the former (p=0.024) and compound heterozygous mutations in the later (p=0.012). A wide allelic heterogeneity was observed and only 6 mutations were infrequently shared between these two populations. The adjusted ORs for the binary (demographic) and continuous (clinical) variables did not indicate any susceptibility to the observed mutations (p>0.05).
The present study demonstrated a lack of genotype-phenotype correlation of the demographic and clinical traits to CYP1B1 mutations in PCG at presentation. However, the susceptibility of these mutations to the long-term progression of these traits are yet to be deciphered.
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. Pathogenic variants in six genes ...encoding proteins composing the cone phototransduction cascade (
,
,
,
,
) and of the unfolded protein response (
) have been related to ACHM cases, while
and
alone are responsible for most cases. Herein, we provide a clinical and molecular overview of 42 Brazilian patients from 38 families affected with ACHM related to biallelic pathogenic variants in the
and
genes. Patients' genotype and phenotype were retrospectively evaluated. The majority of
variants were missense, and the most prevalent
variant was c.1148delC (p.Thr383Ilefs*13), resulting in a frameshift and premature stop codon, which is compatible with previous publications in the literature. A novel variant c.1893T>A (p.Tyr631*) in the
gene is reported for the first time in this study. A great variability in morphologic findings was observed in our patients, although no consistent correlation with age and disease stage in OCT foveal morphology was found. The better understanding of the genetic variants landscape in the Brazilian population will help in the diagnosis of this disease.
To analyze the outer retinal layers using spectral domain optical coherence tomography (SD-OCT) in patients with cone-rod dystrophy.
The diagnosis of cone-rod dystrophy was determined by primary cone ...involvement or concomitant loss of both cones and rods. Electroretinography showed implicit time shift at 30-Hz flicker response and prevalent decrease of photopic over scotopic responses. Using SD-OCT, the outer retina was retrospectively evaluated in 24 eyes of 12 patients with cone-rod dystrophy. From the innermost to the outermost, the four studied hyperreflective outer retinal bands were labeled Band 1, the external limiting membrane; Band 2, the ellipsoid zone; Band 3, the interdigitation zone between the cone outer segments and the apical processes of the retinal pigment epithelium; and Band 4, the retinal pigment epithelium complex.
The mean age of study patients was 30 years, and the median visual acuity was 20/30. A ring maculopathy appearance involving the fovea area was observed in all study eyes. There was an absence of interdigitation zone in the entire length of SD-OCT scan, including the foveal area, in all 24 study eyes. Outside the foveal area, the external limiting membrane and ellipsoid zone were intact in all study eyes. The intensity of the ellipsoid zone was decreased in the entire length of SD-OCT scan in all study eyes. Within the foveal area, there was loss of the external limiting membrane and ellipsoid zone in 20 (83%) and 22 eyes (92%), respectively. The retinal pigment epithelium complex was identified in all study eyes. None of the study eyes revealed cystoid macular edema.
SD-OCT scans demonstrated complete absence of the interdigitation zone in patients with cone-rod dystrophy. Consistent with the known histology of animal models of cone dystrophy, this finding may represent abnormal outer retinal morphology, including an absence of the outer segments themselves or a defective or absent interdigitation between the apical processes of the retinal pigment epithelium with the cone outer segments.
Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (
) has the smallest number of reported ...variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in
in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of
is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.
Ophthalmological abnormalities may occur in specific subtypes of hereditary spastic paraplegia (HSP) and in genetic diseases that present with spastic paraplegia mimicking HSP. These ophthalmological ...changes may precede the motor symptoms and include pigmentary retinal degeneration, ophthalmoplegia, optic atrophy, cataracts and nystagmus. Some ophthalmological abnormalities are more prevalent in specific forms of HSP. Considering that the diagnosis of HSP is usually difficult and complex, specific ophthalmological changes may guide the genetic testing. There are other genetic diseases such as autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), X-linked adrenoleukodystrophy and spastic paraplegia, optic atrophy and neuropathy (SPOAN) that may mimic HSP and also may present with specific ophthalmological changes. In this article, we review the main ophthalmological changes observed in patients with HSP and HSP-like disorders.
•Hereditary spastic paraplegia may present with ophthalmological manifestations.•Important ophthalmological change associated with SPG15 is retinal degeneration.•Ptosis and progressive external ophthalmoplegia are clues for the diagnosis of SPG7.
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