No abstract

The family of Tre2‐Bub2‐Cdc16 (TBC)‐domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP‐independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss‐of‐function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B‐deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival.

Sturge-Weber syndrome is a heterogeneous neurocutaneous syndrome with facial and leptomeningeal angiomas, glaucoma, seizures, stroke-like episodes, and mental retardation. The authors critically evaluated the clinical manifestations, outcome, and natural history in 30 patients with Sturge-Weber syndrome followed up from January 1985 to May 2010. Of the patients, 15 were males, age at diagnosis ranged from 1 month to 43 years. Typical port-wine stain nevus occurred in 26 (86%), it was bilateral in 2 (8%), and it was absent in 4 (4%). Nine patients had glaucoma (30%), 3 required surgery. Four had transient hemiparesis. All patients had seizures; they were well controlled in 22 (73.3%); in 8 they remained drug resistant. Three patients underwent surgery and became seizure-free. Of the 17 who had mental subnormality, 14 (82.4%) had seizure onset before 2 years. An early age at seizure onset and those with drug-resistant seizures had more severe degree of mental subnormality. Uncontrolled seizures, mental subnormality, visual handicap, and cosmetic disfiguration were the major impediments in life.

Varicose veins of lower extremities are a heritable common disorder. Mechanisms underlying its pathogenesis are still vague. Structural failures such as valve weakness and wall dilatation in saphenous vein result in venous retrograde flow in lower extremities of body. Reflux of blood leads to distal high venous pressure resulting in distended veins. In an earlier study, we observed a positive association between c.-512C4T FoxC2 gene polymorphism and upregulated FoxC2 expression in varicose vein specimens. FoxC2 overexpression in vitro in venous endothelial cells resulted in the elevated mRNA expression of arterial endothelial markers such as Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2). We hypothesized that an altered FoxC2-Dll4 signaling underlies saphenous vein wall remodeling in patients with varicose veins. Saphenous veins specimens were collected from 22 patients with varicose veins and 20 control subjects who underwent coronary artery bypass grafting. Tissues were processed for paraffin embedding and sections were immunostained for Dll4, Hey2, EphrinB2, a-SMA, Vimentin, and CD31 antigens and examined under microscope. These observations were confirmed by quantitative real-time PCR and western blot analysis. An examination of varicose vein tissue specimens by immunohistochemistry indicated an elevated expression of Notch pathway components, such as Dll4, Hey2, and EphrinB2, and smooth muscle markers, which was further confirmed by gene and protein expression analyses. We conclude that the molecular alterations in Dll4-Hey2 signaling are associated with smooth muscle cell hypertrophy and hyperplasia in varicose veins. Our observations substantiate a significant role for altered FoxC2-Dll4 signaling in structural alterations of saphenous veins in patients with varicose veins. In conjunction with the presence of genes conferring disease susceptibility, various risk factors, such as prolonged standing, an increased body mass index, and preganancy, increases the mean venous pressure, in the lower extremities. 3,4 Pfisterer et al in 2014 found in an experimental mouse model that an escalated venous filling pressure induces varicose-like venous remodeling. This process to a greater extent mimics detrimental remodeling processes observed in human varicose veins. 5 The precise molecular mechanisms underlying the pathogenesis and progression of varicose veins are unclear. We have earlier observed a significant association of FoxC2 c.-512C4T polymorphism with the presence of varicose veins in patients. FoxC2 was also upregulated at both transcript and protein levels in varicose vein tissues of patients with varicose veins. 6 In venous endothelial cells transfected with FoxC2-overexpressing mammalian vectors, the presence of putative arterial endothelial markers Delta-like ligand 4 (Dll4) and Hairy/enhancer-of-split related with YRPW motif protein 2 (Hey2) were found.

Mucolipidosis-IIIγ (ML-IIIγ) is a recessively inherited slowly progressive skeletal dysplasia caused by mutations in GNPTG. We report the genetic and clinical findings in the largest cohort with ML-IIIγ so far: 18 affected individuals from 12 families including 12 patients from India, five from Turkey, and one from the USA. With consanguinity confirmed in eight of 12 families, molecular characterization showed that all affected patients had homozygous pathogenic GNPTG genotypes, underscoring the rarity of the disorder. Unlike ML-IIIαβ, which present with a broader spectrum of severity, the ML-III γ phenotype is milder, with onset in early school age, but nonetheless thus far considered phenotypically not differentiable from ML-IIIαβ. Evaluation of this cohort has yielded phenotypic findings including hypertrophy of the forearms and restricted supination as clues for ML-IIIγ, facilitating an earlier correct choice of genotype screening. Early identification of this disorder may help in offering a timely intervention for the relief of carpal tunnel syndrome, monitoring and surgery for cardiac valve involvement, and evaluation of the need for joint replacement. As this condition may be confused with rheumatoid arthritis, confirmation of diagnosis will prevent inappropriate use of immunosuppressants and diseasemodifying agents.

No abstract

No abstract

Abstract. Intraocular gnathostomiasis is a rare parasitic infection caused by the third-stage larvae of spiruroid nematode Gnanthostoma spp. seen mostly in tropical and subtropical regions. It is a food-borne zoonosis caused by ingestion of raw or undercooked freshwater fish, amphibians, reptiles, birds, and mammals, all of which are known to harbor advanced third-stage larvae of Gnanthostoma spp. To date, 74 cases of intraocular gnathostomiasis have been reported from 12 different countries. Only four countries have reported more than 10 cases each, and India shares the rare distinction of being one of them, with 14 cases. Surprisingly, not a single case of cutaneous gnanthostomiasis has ever been reported from India. We present one such case of intraocular gnathostomiasis in a 41-year-old male who presented with an actively motile worm attached to the iris, and we review the pertinent literature of all such cases reported from India.