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Nucleic Acids Research Aug 2023Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked...
Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Neural Crest; Microphthalmos; Euchromatin; Chromosomal Proteins, Non-Histone; Muscle, Skeletal; Phenotype; Chromatin
PubMed: 37334829
DOI: 10.1093/nar/gkad523 -
Indian Journal of Ophthalmology Jul 2022To compare the clinical and biometric characteristics of children presenting with nanophthalmos (NO group) with that of age-matched controls (CO group).
PURPOSE
To compare the clinical and biometric characteristics of children presenting with nanophthalmos (NO group) with that of age-matched controls (CO group).
METHODS
Electronic medical records of 40 children (<18 years of age) with diagnosis of nanophthalmos (NO), presented to a tertiary center in Tamil Nadu between January 2010 and December 2019, were reviewed and compared with 30 age-matched controls (CO) presenting for routine eye examination between October 2019 and December 2019. Clinical parameters compared were best-corrected visual acuity (BCVA), axial length (AxL), keratometry (K), anterior chamber depth (ACD), lens thickness (LT), retinochoroidal scleral thickness (RCS), corneal diameter, central corneal thickness (CCT), intraocular pressure (IOP), lens axial length factor (LAF), and lens thickness/anterior chamber depth ratio (LT/ACD).
RESULTS
Mean age of the NO group was 8.95 ± 4.0 years. Mean spherical equivalent (SE) in NO group was 10.87 ± 3.1 D and was inversely correlated to AxL (r = -0.46, P value = 0.003). All biometric parameters (AxL, ACD, LT, RCS, LAF, and LT/ACD), except CCT were significantly different between NO and CO groups. NO group children had 52.5% visual impairment with BCVA ≤ 6/24 and 17.5% had esotropia. Common ocular associations in NO group were amblyopia (64.3%), primary angle-closure glaucoma (PACG) (17.8%), pigmentary retinopathy (14.3%), and retinal detachment (3.6%). Angle-closure disease was seen in 50% of NO group and 30% underwent laser peripheral iridotomy (LPI). There was a significant difference in SE, ACD, and LAF among NO children with AxL <17 mm or >17 mm. Multivariable regression analysis revealed a significant correlation of SE and ACD with AxL.
CONCLUSION
Nanophthalmos in children often present as amblyopia with visual impairment and strabismus. NO group with AxL <17 mm, had angle-closure disease as a common association with significantly lower ACD, higher SE, and LAF. All morphometric characteristics, except CCT, were significantly different between NO and CO groups. Close monitoring with serial biometry in NO group is needed for the timely diagnosis and prompt intervention to avoid visual impairment, due to glaucoma.
Topics: Amblyopia; Biometry; Child; Child, Preschool; Humans; India; Microphthalmos; Sclera; Vision, Low
PubMed: 35791127
DOI: 10.4103/ijo.IJO_2880_21 -
Trends in Immunology Feb 2020Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate... (Review)
Review
Microphthalmia/TFE (MiT) transcription factors (TFs), such as transcription factor EB (TFEB) and transcription factor E3 (TFE3), are emerging as key regulators of innate immunity and inflammation. Rapid progress in the field requires a focused update on the latest advances. Recent studies show that TFEB and TFE3 function in innate immune cells to regulate antibacterial and antiviral responses downstream of phagocytosis, interferon (IFN)-γ, lipopolysaccharide (LPS), and adenosine receptors. Moreover, overexpression of TFEB or TFE3 can drive inflammation in vivo, such as in atherosclerosis, while in other scenarios they can perform anti-inflammatory functions. MiT factors may constitute potential therapeutic targets for a broad range of diseases; however, to harness their therapeutic potential, sophisticated ways to manipulate MiT factor activity safely and effectively must be developed.
Topics: Humans; Immunity, Innate; Inflammation; Microphthalmos; Transcription Factors
PubMed: 31959514
DOI: 10.1016/j.it.2019.12.003 -
Indian Journal of Ophthalmology Dec 2022Congenital hereditary endothelial dystrophy affects the Descemet membrane and endothelium, resulting in corneal decompensation. Penetrating keratoplasty (PKP) has been... (Review)
Review
Congenital hereditary endothelial dystrophy affects the Descemet membrane and endothelium, resulting in corneal decompensation. Penetrating keratoplasty (PKP) has been the gold-standard surgical management until recently; however, at present, endothelial keratoplasty (DSEK/DSAEK/n-DSEK: Descemet-stripping or non-Descemet stripping endothelial keratoplasty and DMEK/n-DMEK: Descemet membrane endothelial keratoplasty) is being preferred due to lesser intraoperative and postoperative complications, early visual recovery, and comparable visual outcomes. Endothelial keratoplasty (EK) can be challenging, especially in pediatric eyes with CHED due to smaller eyeballs, shallow anterior chambers, phakic status, and poor intraoperative visibility due to thick and hazy corneas. A total of 198 articles matched our search strategy. After screening for duplication and going through the titles and abstracts, 12 relevant original articles, one case series, and six case reports were included in this review. Various surgical modifications have to be adopted in comparison to adult eyes to overcome the aforementioned difficulties. Regardless, studies have shown favorable visual outcomes with better graft survival and fewer complications in eyes that underwent EK compared to PKP. Hence, timely surgical intervention and strict amblyopia management can result in better final visual outcomes. The purpose of this review is to summarize various intraoperative difficulties and the surgical modifications required, different surgical techniques, visual and graft-related outcomes, and various complications of EK in CHED eyes.
Topics: Adult; Humans; Child; Corneal Dystrophies, Hereditary; Corneal Transplantation; Keratoplasty, Penetrating; Eye; Microphthalmos
PubMed: 36453297
DOI: 10.4103/ijo.IJO_1313_22 -
Acta Ophthalmologica Jun 2021To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their...
PURPOSE
To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients with MFRP variants, based on a detailed literature review of genotype-phenotype correlations.
METHODS
Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole-exome sequencing and variant calling in core genes including MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A. A minigene assay was performed for functional characterization of a splice site variant.
RESULTS
Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants in MFRP (c.497C>T, c.899-3C>A, c.1180G>A), and PRSS56 (c.1202C>A), and a recurrent de novo variant in FAM111A (c.1706G>A) in a patient with Kenny-Caffey syndrome type 2, were identified. In addition, we report co-inheritance of MFRP-related nanophthalmos and ADAR-related Aicardi-Goutières syndrome.
CONCLUSION
Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; DNA; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Testing; Humans; Male; Membrane Proteins; Microphthalmos; Middle Aged; Mutation; Pedigree; Phenotype; Young Adult
PubMed: 32996714
DOI: 10.1111/aos.14615 -
Ophthalmic Genetics Jun 2021: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive...
: To describe a family with presumed gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the gene was confirmed in the proband by Sanger sequencing.: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.
Topics: Adult; Craniofacial Abnormalities; Developmental Disabilities; Female; Hearing Loss; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Male; Microphthalmos; Mosaicism; Pedigree; SOXB1 Transcription Factors; Sex Chromosome Disorders; Exome Sequencing
PubMed: 33719903
DOI: 10.1080/13816810.2021.1888127 -
Systematic Reviews Feb 2022Microphthalmos and nanophthalmos are uncommon ocular conditions, whereby affected eyes have smaller dimensions compared to the normal population. Microphthalmos and...
INTRODUCTION
Microphthalmos and nanophthalmos are uncommon ocular conditions, whereby affected eyes have smaller dimensions compared to the normal population. Microphthalmos and nanophthalmos present several challenges to ophthalmologists; they have spontaneous and post-operative sequelae such as high hyperopia, angle-closure glaucoma, uveal effusion syndrome, and retinal detachment. This systematic review and meta-analysis intends to assess the prevalence of both the spontaneous complications associated with nanophthalmos and microphthalmos, as well as the post-surgical complications associated with nanophthalmos or microphthalmos.
METHODS AND ANALYSIS
Articles will be searched for, on four online databases: PubMed, EMBASE, Scopus, and Web of Science. Two independent reviewers will identify the studies according to prespecified inclusion and exclusion criteria. All studies included with participants diagnosed with microphthalmos or nanophthalmos in one or both eyes, will be included if they have (i) more than 4 cases and (ii) defined microphthalmos/nanophthalmos as an axial length of < 21 mm or a high lens/eye volume ratio. Nanophthalmos may have an additional diagnostic criterion of posterior wall thickness greater than 1.7 mm. The prevalence of the following complications will be assessed: high hyperopia (spherical equivalent >3D), angle closure glaucoma, uveal effusion syndrome, retinal detachment, and chorioretinal folds. Studies that will be excluded are those that have not adequately defined the criteria for the diagnosis of nanophthalmos or microphthalmos, those studies that have less than five cases, studies with criteria not defined above, and deemed unsuitable, and studies in languages other than English with no published translation. Relevant data will be extracted and assessed for the risk of bias in each article using a modified Joanna Briggs Institute (JBI) assessment tool. The data will then be pooled to determine the prevalence of complications among patients with microphthalmos and nanophthalmos. If the data allows, subgroup analysis will be carried out according to axial length as well as subtype of microphthalmos/nanophthalmos (simple, complex, relative anterior, and posterior).
DISCUSSION
Although nanophthalmos is an uncommon condition that affects the eye, its management and complications can be sight-threatening. Thus, it is important to counsel patients and their families correctly (in the case of children) upon diagnosis and prior to any surgical intervention. This can only be done if the overall prevalence of complications is known.
REGISTRATION
PROSPERO CRD42021227847.
Topics: Child; Humans; Hyperopia; Meta-Analysis as Topic; Microphthalmos; Prevalence; Systematic Reviews as Topic
PubMed: 35139896
DOI: 10.1186/s13643-022-01889-5 -
European Journal of Medical Genetics Feb 2024Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these...
Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The purpose of this investigation was to assess the frequency and the types of associated anomalies among cases with an/microphthalmia in a geographically well defined population of northeastern France of 387,067 consecutive pregnancies from 1979 to 2007. Of the 98 infants with an/microphthalmia born during this period (prevalence at birth of 2.53 per 10,000), 88.8 % had associated anomalies. Cases with associated anomalies were divided into recognizable conditions (25 (25.5%) cases with chromosomal and 17 (17.3%) cases with non chromosomal conditions), and non recognizable conditions (45-45.9%- cases with multiple congenital anomalies -MCA). Trisomy 13 and trisomy 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, oculo-auriculo-vertebral spectrum, CHARGE syndrome and VACTERL association were most often present in recognizable non chromosomal conditions. Anomalies in the musculoskeletal, cardiovascular and central nervous systems were the most common other anomalies in cases with MCA and non recognizable conditions. However, given the limitation of the limited numbers of cases there should be urging caution in interpreting these results. In conclusion the frequency of associated anomalies in infants with anophthalmia and microphthalmia emphasizes the need for a thorough investigation of these cases. Routine screening for other anomalies especially musculoskeletal, cardiac and central nervous systems anomalies may need to be considered in infants with anophthalmia and microphthalmia, and referral of these cases for genetic counselling seems warranty.
Topics: Infant; Infant, Newborn; Pregnancy; Female; Humans; Anophthalmos; Microphthalmos; Heart Defects, Congenital; Limb Deformities, Congenital; CHARGE Syndrome; Prevalence
PubMed: 38110175
DOI: 10.1016/j.ejmg.2023.104892 -
International Ophthalmology Mar 2021To evaluate the fovea in nanophthalmic eyes using spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA), and to investigate the relationship...
PURPOSE
To evaluate the fovea in nanophthalmic eyes using spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA), and to investigate the relationship between the macular microstructure and visual acuity.
METHODS
This is a retrospective case series of five nanophthalmic patients. The foveal avascular zone (FAZ) area was measured in superficial and deep vascular layers with OCTA. The thickness of the inner retinal layer (IRL) was measured with SD-OCT. The ratio of the foveal and parafoveal IRL thickness (fIRL/pIRL ratio) was calculated. The relationship between these parameters and visual acuity was then investigated.
RESULTS
Eight eyes were identified as nanophthalmic with a mean axial length of 17.19 ± 1.44 mm (range: 15.71 to 19.88 mm). The mean best-corrected visual acuity (BCVA) in the logarithm of the minimum angle of resolution (logMAR) was 0.12 ± 0.18 (range: - 0.18 to 0.40). OCTA showed that FAZs were either absent or undeveloped in the superficial and deep capillary plexuses. Two patients did not show any visual impairments despite small FAZ and a shallow foveal depression. Although the BCVA was significantly correlated with the deep FAZ size, it did not correlate with the superficial FAZ size, axial length, or fIRL/pIRL ratio. However, the refractive error, axial length, and deep FAZ size were all significantly correlated with the fIRL/pIRL ratio.
CONCLUSIONS
The FAZs were commonly found to be small in the superficial and deep capillary plexuses. Although the deep FAZ size correlated with visual acuity, it is unclear whether the retinal microstructure and the FAZ size are responsible for the visual impairments observed in the same individuals.
Topics: Fluorescein Angiography; Fovea Centralis; Humans; Microphthalmos; Retinal Vessels; Retrospective Studies; Tomography, Optical Coherence; Visual Acuity
PubMed: 33188472
DOI: 10.1007/s10792-020-01633-9