Diagnosis and Treatment of Lacrimal Gland Prolapse: A Narrative Review.

BACKGROUND: Lacrimal gland prolapse (LGP) is considered to be one of the causes for upper eyelid contour abnormality that should be recognized and treated properly to yield satisfactory outcomes in blepharoplasty. To describe current findings about the prevalence, pre- and intraoperative diagnosis of LGP and its treatment options. METHODS: PubMed and Google Scholar were thoroughly searched for articles published describing the diagnosis and treatment of LGP. RESULTS: The reported prevalence of LGP by various authors varies between 10 and 60% based on their preoperative or intraoperative reports. Techniques such as dacryoadenopexy, modified dacryoadenopexy, and dacryoplasty have been described to secure the prolapsed lacrimal gland back into its original position. Additionally, creating a Whitnall's barrier has also been suggested as a method to reposition the gland. While all these surgical procedures have shown promising immediate results, there is a lack of published data on their long-term outcomes. CONCLUSION: Diagnosis and proper treatment of LGP could enhance the cosmetic results of upper eyelid blepharoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Inactivation of DRG1, encoding a translation factor GTPase, causes a recessive neurodevelopmental disorder.

PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.

Dietary Antioxidant Capacity Indices are Negatively Correlated to LDL-Oxidation in Adults.

Introduction: Former research studies have demonstrated controversial associations between dietary indices and oxidative stress biomarkers including oxidized low-density lipoprotein (ox-LDL) and malondialdehyde (MDA). So, in this cross-sectional study, we aimed to assess the association of dietary total antioxidant capacity (DTAC), oxidative balance score, and phytochemical index (PI) with ox-LDL/MDA in a healthy adult population of Shiraz, Iran. Methods: 236 individuals participated in this cross-sectional study. DTAC, OBS, and PI were calculated using a 168-item food frequency questionnaire (FFQ), which was previously validated in Iran. We measured ox-LDL and MDA in blood samples of the participants using commercially existing kits. Crude and adjusted models of linear regression were used to evaluate the relation of dietary indices with ox-LDL and MDA. Results: There was a significant association between ox-LDL and DTAC in both crude (ß = -1.55; 95% CI: -2.53, -0.58; P-trend = 0.002) and adjusted (ß = -1.65 95% CI: -2.66, -0.64; P-trend = 0.001) models. Also, a negative association was observed between ox-LDL and PI in the crude (ß = -1.26 95% CI: -2.33, -0.29; P-trend = 0.01) and adjusted (ß = -1.36 95% CI: -2.38, -0.34; P-trend = 0.01) models. Conclusion: Results of this study showed that DTAC and PI were inversely associated with ox-LDL as markers of lipid peroxidation. But no correlations were seen between MDA and dietary antioxidant indices.

Tissue Extract from Brittle Star Undergoing Arm Regeneration Promotes Wound Healing in Rat.

This study set out to evaluate the wound healing properties of brittle star extracts in vitro and in vivo. Due to the great arm regeneration potential of the brittle star, Ophiocoma cynthiae, the present study aimed to evaluate the wound healing effect of hydroalcoholic extracts of brittle star undergoing arm regeneration in wound healing models. The brittle star samples were collected from Nayband Bay, Bushehr, Iran. After wound induction in the arm of brittle stars, hydroalcoholic extracts relating to different times of arm regeneration were prepared. The GC-MS analysis, in vitro MTT cell viability and cell migration, Western blot, and computational analysis tests were performed. Based on the in vitro findings, two BSEs were chosen for in vivo testing. Macroscopic, histopathological and biochemical evaluations were performed after treatments. The results showed positive proliferative effects of BSEs. Specifically, forty-two compounds were detected in all groups of BSEs using GC-MS analysis, and their biological activities were assessed. The MTT assay showed that the 14 d BSE had a higher proliferative effect on HFF cells than 7 d BSE. The cell migration assay showed that the wound area in 7 d and 14 d BSEs was significantly lower than in the control group. Western blot analysis demonstrated an increase in the expression of proliferation-related proteins. Upon the computational analysis, a strong affinity of some compounds with proteins was observed. The in vivo analysis showed that the evaluation of wound changes and the percentage of wound healing in cell migration assay in the 7 d BSE group was better than in the other groups. Histopathological scores of the 7 d BSE and 14 d BSE groups were significantly higher than in the other groups. In conclusion, the hydroalcoholic extract of O. cynthiae undergoing arm regeneration after 7 and 14 days promoted the wound healing process in the cell and rat skin wound healing model due to their proliferative and migratory biological activity.

Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder.

NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development.

Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Association between plant and animal proteins intake with lipid profile and anthropometric indices: A cross-sectional study.

BACKGROUND: Results of studies on the effects of plant and animal proteins on lipid profile are controversial. So we aimed to assess the relationship between plant and animal protein intake with lipid profile and novel anthropometric indices in healthy individuals. METHOD: In this cross-sectional study, 236 participants have selected from Shiraz medical centers (Iran) through random cluster sampling. Food intakes were assessed using a 168-items food frequency questionnaire (FFQ). Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were measured. Anthropometric indices including a body shape index (ABSI), abdominal volume index (AVI), buddy roundness index (BRI), and conicity index (CI) were calculated. RESULTS: In the crude and fully adjusted models, more consumption of plant proteins was associated with TG levels (OR = 2.31; 95% CI: 1.08, 4.95; P = 0.03 and OR = 2.39; 95% CI: 1.03, 5.15; P = 0.04). Also, there was a significant direct association between plant proteins and BRI in the curd model (OR = 3.55; 95% CI: 1.32, 9.54; P = 0.01), and after adjusting for age and energy intake (OR = 3.32; 95% CI: 1.21, 9.14; P = 0.01). More consumption of plant proteins was related to higher CI in the crude model (OR = 3.06; 95% CI: 1.12, 8.31; P = 0.03), but not in the fully adjusted model. CONCLUSION: We found that a higher intake of plant proteins was associated with a higher TG level, BRI, and CI index. However, more research is needed to confirm these relations and provide the evidence needed to exert these findings into clinical practice.

Facial and Abducens Nerve Palsies Following COVID-19 Vaccination: Report of Two Cases.

A broad spectrum of neurological side effects has been reported after immunisation for COVID-19, including functional neurological disorders, cerebral vascular events, cerebral venous thrombosis, intracerebral haemorrhage, neuroleptic malignant syndrome, cranial nerve palsies, and otologic manifestations. Multiple cranial neuropathies have also been reported following vaccination in which involvement of VII nerve is the most prevalent, followed by the VI, III, and IV nerves. We describe two male patients, one with with facial nerve palsy and the other with abducens nerve palsy following COVID-19 vaccination. The patient with facial nerve palsy received the AstraZeneca vaccine 2 days before the symptoms began. In contrast, the patient with the abducens palsy had received his first dose of the Sinopharm vaccine 7 days previously. Both patients demonstrated a gradual recovery within the next 2 months. Further studies are required to investigate the proper relationship between cranial nerve palsies and vaccinations.

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome).

BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. OBJECTIVE: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. RESULTS: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. CONCLUSION: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.

An analysis of factors associated with graft topographic outcomes after deep anterior lamellar keratoplasty.

PURPOSE: To investigate the correlations between preoperative, operative, and postoperative factors and corneal graft topographic parameters after deep anterior lamellar keratoplasty (DALK) performed in keratoconus-affected eyes. METHODS: This prospective, interventional study enrolled 44 eyes. Graft topographic parameters, including keratometric astigmatism and the surface regularity index (SRI), were assessed after complete suture removal. Univariate analyses were used to evaluate the effects of preoperative factors (donor quality, donor and recipient age, keratoconus severity), operative factors (graft size, donor button roundness, roundness and centration of the donor-recipient junction), and postoperative factors (time point of suture removal) on postoperative topographic parameters. RESULTS: The roundness of the donor-recipient junction after complete suture removal had a significant association with the roundness of the donor button after trephination (P = 0.04) and the amount of graft decentration relative to the limbus (P = 0.03). A significant correlation was found between the value of graft decentration relative to the limbus and postoperative keratometric astigmatism (P = 0.001) and between the roundness of the donor-recipient junction and the postoperative SRI (P = 0.02). The flat axis of the keratometric astigmatism and the longer axis of the graft lay in the direction of graft displacement. Other investigated factors had no significant association with postoperative topographic indices. CONCLUSION: Graft displacement relative to the limbus and roundness of the donor-recipient junction were the main predictors of graft astigmatism and regularity, respectively, after DALK. Noncircularity of the donor button after trephination could increase the graft surface irregularity indirectly by influencing the roundness of the surgical wound.

Outcomes of big-bubble deep anterior lamellar keratoplasty for pediatric keratoconus.

PURPOSE: To evaluate the outcomes and complications of deep anterior lamellar keratoplasty (DALK) performed for pediatric keratoconus. METHODS: This retrospective study enrolled 44 consecutive eyes of 39 keratoconus-affected children (≤ 18 years of age). All patients underwent big-bubble DALK from March 2004 to June 2016. The outcome measures included postoperative best spectacle-corrected visual acuity (BSCVA), manifest refraction, keratometry readings, and complications. RESULTS: The mean participant age was 16.8 ± 1.4 years, and the mean follow-up period was 68.5 ± 39.9 months. Successful big bubble was achieved in 33 eyes (75.0%), while the surgical technique was predescemetic DALK in 11 (25.0%). The mean BSCVA changed from 1.34 ± 0.49 LogMAR preoperatively to 0.24 ± 0.10 LogMAR postoperatively (P < 0.001). The mean keratometry decreased from 59.54 ± 5.17 D preoperatively to 46.23 ± 2.17 D postoperatively (P < 0.001). The complications encountered during the study period were intraoperative Descemet's membrane perforation (n = 5, 11.4%), the Urrets Zavalia syndrome (n = 1, 2.3%), graft epithelial problems (n = 3, 6.8%), subepithelial graft rejection (n = 5, 11.4%), high intraocular pressure (n = 8, 18.2%), and traumatic wound dehiscence (n = 2, 4.6%). Suture-related complications included premature loosening (n = 13, 29.6%), broken sutures (n = 12, 27.3%), suture-tract vascularization (n = 6, 13.6%), suture-associated abscesses (n = 5, 11.4%), and suture cheese wiring (n = 2, 4.6%). A clear graft was found in 40 eyes (90.9%) at the last follow-up examination. CONCLUSION: This study showed promising results with big-bubble DALK in keratoconus-affected children. A frequent and close follow-up with dedicated parental involvement is essential for the early recognition and management of postoperative complications.

Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function.

Next-generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway.

Configuration of recipient corneal cut after mechanical trephination in keratoconus.

PURPOSE: To determine the roundness of recipient corneal cuts after mechanical trephination and to investigate possible factors that could affect the corneal bed configuration in deep anterior lamellar keratoplasty (DALK). METHODS: This study enrolled 85 eyes with keratoconus that underwent DALK. Recipient corneas were partially trephined using a new, unused, disposable Hessburg-Barron suction trephine. Photographs that best represented the recipient corneal cut were selected, and ImageJ software was used to evaluate the roundness of recipient bed. The effect of potential variables on the roundness of cuts was investigated using the univariate analyses. RESULTS: The mean patient age was 31.0 ± 9.0 years. The mean recipient trephine size was 8.04 ± 0.29 mm (range 7.5-8.50 mm). The recipient cut roundness was 0.922 ± 0.070, varying from 0.78 to 1.0. The roundness of the corneoscleral limbus (0.874 ± 0.074) which represented the shape of recipient cornea was the main predictor of the configuration of recipient cut (r = 0.84, P < 0.001). Other preoperative characteristics investigated were mean keratometry (P = 0.63), keratometric astigmatism (P = 0.18), central corneal thickness (P = 0.64), keratoconus severity (P = 0.37), and trephine size (P = 0.50) that demonstrated no significant associations with the roundness of cut. CONCLUSIONS: The recipient corneal cut after mechanical trephination may not be circular. The roundness of recipient bed was primarily affected by the roundness of corneoscleral limbus, indicating that the shape of recipient cut tends to follow the original shape of the cornea.

Expression of Pluripotency Markers, SOX2 and OCT4, in Pterygium Development.

Pterygium is a common ocular surface disease characterized by the abnormal epithelial proliferation, matrix remodeling, vascularization and the migration of the lesion. Although the etiology of pterygium is elusive, recent studies have focused on the role of limbal stem cells (LSCs) damage and effects of UVB. This study aimed to determine the expression levels of pluripotent markers of SOX2 and OCT4 in primary pterygium and normal conjunctiva. Using real time polymerase chain reaction (PCR), the SOX2 and OCT4 expressions were compared in primary pterygium and normal conjunctiva. This study assessed the correlation between SOX2 mRNA expression and OCT4 mRNA expression, as well as the association between the clinicopathological indices and both gene expression levels. The relative mRNA expression levels of OCT4 genes in primary pterygium were significantly reduced compared to the normal conjunctiva tissues. The association between OCT4 gene expression and the clinicopathological indices reported significant laterality (P = .004) and marginal growth activity indices (P = .063). The univariate correlation between the SOX2 and OCT4 expressions was statistically significant (P = .001). The present study emphasized the downregulation of pluripotent marker OCT4 genes in the pterygium. It is speculated that these results may predict a new avenue for exploring the role of stem cell deficiency in the development of pterygium.

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.

Greater adherence to the dietary approaches to stop hypertension (DASH) dietary pattern is associated with lower blood pressure in healthy Iranian primary school children.

PURPOSE: The dietary determinants of children blood pressure (BP) are poorly understood. We examined the association between adherence to the dietary approaches to stop hypertension (DASH) dietary pattern and BP in healthy Iranian primary school children. METHODS: This cross-sectional study was conducted among a representative sample (n = 407) of healthy Shirazi students aged 6-12 years. Subjects' systolic and diastolic BP were measured by a validated oscillometric BP monitor. Usual dietary intakes over the past 12 months were assessed using a valid and reproducible 168-item semi-quantitative food frequency questionnaire via face-to-face interviews. A DASH score was calculated for each subject based on his/her energy-adjusted intakes of 8 major dietary components emphasized or minimized in the DASH dietary pattern. The higher the DASH score of a subject, the more his/her adherence to the DASH dietary pattern. RESULTS: After controlling for several potential confounders in the analysis of covariance models, multivariable-adjusted means of systolic and mean BP of subjects in the highest tertile of DASH score were significantly lower than those in the lowest tertile (for systolic BP: mean difference -6.2 mmHg, P = 0.010; and for mean BP: mean difference -5.4 mmHg, P = 0.013). Furthermore, a similar but statistically insignificant difference was found in terms of multivariable-adjusted means of diastolic BP (mean difference -3.9 mmHg, P = 0.146). CONCLUSIONS: The findings suggest that greater adherence to the DASH dietary pattern is associated with lower BP in healthy Iranian primary school children. However, future prospective studies of adequate methodological quality are warranted to confirm these findings.

A Western dietary pattern is associated with higher blood pressure in Iranian adolescents.

PURPOSE: The dietary determinants of adolescent blood pressure (BP) are not well understood. We determined the association between major dietary patterns and BP in a sample of Iranian adolescents. METHODS: This cross-sectional study was conducted among a representative sample (n = 557) of Shirazi adolescents aged 12-19 years. Participants' systolic and diastolic BP was measured using a validated oscillometric BP monitor. Usual dietary intakes during the past 12 months were assessed using a valid and reproducible 168-item semiquantitative food frequency questionnaire through face-to-face interviews. Principal component factor analysis was used to identify major dietary patterns based on a set of 25 predefined food groups. RESULTS: Overall, three major dietary patterns were identified, among which only the Western pattern (abundant in soft drinks, sweets and desserts, salt, mayonnaise, tea and coffee, salty snacks, high-fat dairy products, French fries, and red or processed meats) had a significant association with BP. After adjusting for potential confounders in the analysis of covariance models, multivariable adjusted means of the systolic and mean BP of subjects in the highest tertile of the Western pattern score were significantly higher than those in the lowest tertile (for systolic BP: mean difference 6.9 mmHg, P = 0.001; and for mean BP: mean difference 4.2 mmHg, P = 0.003). A similar but statistically insignificant difference was observed in terms of diastolic BP. CONCLUSIONS: The findings suggest that a Western dietary pattern is associated with higher BP in Iranian adolescents. However, additional large-scale prospective studies with adequate methodological quality are required to confirm these findings.