Snyder-Robinson syndrome (SRS) is a rare X-linked recessive disorder characterized by a collection of clinical features including mild to severe intellectual disability, hypertonia, marfanoid habitus, facial asymmetry, osteoporosis, developmental delay and seizures. Whole genome sequencing (WGS) identified a mutation in the spermine synthase () gene (c.746 A>G, p.
View Article and Find Full Text PDFFGF12 related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the FGF12 gene who presented similar to other published cases having normal early development and responded to phenytoin.
View Article and Find Full Text PDFThe robust detection of disease-associated splice events from RNAseq data is challenging due to the potential confounding effect of gene expression levels and the often limited number of patients with relevant RNAseq data. Here we present a novel statistical approach to splicing outlier detection and differential splicing analysis. Our approach tests for differences in the percentages of sequence reads representing local splice events.
View Article and Find Full Text PDFObjective: Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 () gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families.
Methods: Muscle biopsies, EMG, and whole-exome sequencing were performed.
Results: All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal dysfunction.
Selective pericyte loss, the histological hallmark of early diabetic retinopathy (DR), enhances the breakdown of the blood-retinal barrier (BRB) in diabetes. However, the role of pericytes on BRB alteration in diabetes and the signaling pathways involved in their effects are currently unknown. To understand the role of diabetes-induced molecular alteration of pericytes, we performed transcriptomic analysis of sorted retinal pericytes from mice model of diabetes.
View Article and Find Full Text PDFAlthough there is strong clinical evidence that the control of blood glucose, blood pressure, and lipid level can prevent and slow down the progression of diabetic retinopathy (DR) as shown by landmark clinical trials, it has been shown that these factors only account for 10% of the risk for developing this disease. This suggests that other factors, such as genetics, may play a role in the development and progression of DR. Clinical evidence shows that some diabetics, despite the long duration of their diabetes (25 years or more) do not show any sign of DR or show minimal non-proliferative diabetic retinopathy (NPDR).
View Article and Find Full Text PDFAminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy.
View Article and Find Full Text PDFChromosome 1q41-q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41-q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28.
View Article and Find Full Text PDFEpileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly.
View Article and Find Full Text PDFAim: To explore differential DNA methylation (DNAm) in Aicardi syndrome (AIC), a severe neurodevelopmental disorder with largely unknown etiology.
Patients & Methods: We characterized DNAm in AIC female patients and parents using the Illumina 450 K array. Differential DNAm was assessed using the local outlier factor algorithm, and results were validated via qPCR in a larger set of AIC female patients, parents and unrelated young female controls.
Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the gene segregating within this family (c.
View Article and Find Full Text PDFAim: Young onset type 2 diabetes patients (T2DM-Y) have been shown to possess an increased risk of developing microvascular complications particularly diabetic retinopathy. However, the molecular mechanisms are not clearly understood. In this study, we investigated the serum levels of monocyte chemotactic protein 1 (MCP-1) and cathepsin-D in patients with T2DM-Y without and with diabetic retinopathy.
View Article and Find Full Text PDFRett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked gene, encoding methyl-CpG-binding protein 2. We have created a mouse model ( A140V "knock-in" mutant) expressing the recurrent human A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant ( ) and wild type ( ) male mice.
View Article and Find Full Text PDFIncontinentia pigmenti (IP; Bloch-Sulzberger syndrome; OMIM #308300) is an X-linked dominant neurocutaneous disorder with presumed male lethality. It is usually diagnosed in female newborns based on skin features (erythematous, vesicular, or bullous eruption in linear streaks). The skin lesions evolve into a verrucous stage, followed by atrophy and scarring, leaving linear areas of hypopigmentation and hyperpigmented macules in bizarre patterns following Blaschko's lines.
View Article and Find Full Text PDFPurpose: Aicardi syndrome (AIC) is a congenital neurodevelopmental disorder characterized by infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. Variation in phenotype and disease severity is well documented, but chorioretinal lacunae represent the most constant pathological feature. Aicardi syndrome is believed to be an X-linked-dominant disorder occurring almost exclusively in females, although 46, XY males with AIC have been described.
View Article and Find Full Text PDFDiabetic macular edema (DME) is the major cause of vision loss in diabetic persons. Alteration of the blood-retinal barrier is the hallmark of this disease, characterized by pericyte loss and endothelial cell-cell junction breakdown. Recent animal and clinical studies strongly indicate that DME is an inflammatory disease.
View Article and Find Full Text PDFInflammation in the diabetic retina is mediated by leukocyte adhesion to the retinal vasculature and alteration of the blood-retinal barrier (BRB). We investigated the role of chemokines in the alteration of the BRB in diabetes. Animals were made diabetic by streptozotocin injection and analyzed for gene expression and monocyte/macrophage infiltration.
View Article and Find Full Text PDFEpigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development.
View Article and Find Full Text PDFBackground: The controlled recruitment of monocytes from the circulation to the site of injury and their differentiation into tissue macrophages are critical events in the reconstitution of tissue integrity. Subsets of monocytes/macrophages have been implicated in the pathogenesis of atherosclerosis and tumor vascularity; however, the significance of monocyte heterogeneity in physiologic neovascularization is just emerging.
Materials And Methods: A cranial-based, peninsular-shaped myocutaneous flap was surgically created on the dorsum of wild-type mice (C57BL6) and populations of mice with genetic deletion of subset-specific chemokine ligand-receptor axes important in monocyte trafficking and function (CCL2(-/-) and CX3CR1(-/-)) (n=36 total; 12 mice per group, nine with flap and three unoperated controls).
Middle East Afr J Ophthalmol
January 2012
Most anti-vascular endothelial growth factor (VEGF) therapies in diabetic macular edema are not as robust as in proliferative diabetic retinopathy. Although the VEGF appears to be a good target in diabetic macular edema, the anti-VEGF therapies appear to be of transient benefit as the edema recurs within a few weeks, and repeated injections are necessary. There is new evidence that indicates 'retinal inflammation' as an important player in the pathogenesis of diabetic retinopathy.
View Article and Find Full Text PDF