Ayse Balat

Disruption of PTPRO Causes Childhood-Onset Nephrotic Syndrome

Idiopathic nephrotic syndrome (INS) is a genetically heterogeneous group of disorders characterized by proteinuria, hypoalbuminemia, and edema. Because it typically results in end-stage kidney disease, the steroid-resistant subtype (SRNS) of INS is especially important when it occurs in children. The present study included 29 affected and 22 normal individuals from 17 SRNS families; genome-wide analysis was performed with Affymetrix 250K SNP arrays followed by homozygosity mapping. A large homozygous stretch on chromosomal region 12p12 was identified in one consanguineous family with two affected siblings. Direct sequencing of protein tyrosine phosphatase receptor type O (PTPRO; also known as glomerular epithelial protein-1 [GLEPP1]) showed homozygous c.2627+1G>T donor splice-site mutation. This mutation causes skipping of the evolutionarily conserved exon 16 (p.Glu854_Trp876del) at the RNA level. Immunohistochemistry with GLEPP1 antibody showed a similar staining pattern in the podocytes of the diseased and control kidney tissues. We used a highly polymorphic intragenic DNA marker-D12S1303-to search for homozygosity in 120 Turkish and 13 non-Turkish individuals in the PodoNet registry. This analysis yielded 17 candidate families, and a distinct homozygous c.2745+1G>A donor splice-site mutation in PTPRO was further identified via DNA sequencing in a second Turkish family. This mutation causes skipping of exon 19, and this introduces a premature stop codon at the very beginning of exon 20 (p.Asn888Lysfs*3) and causes degradation of mRNA via nonsense-mediated decay. Immunohistochemical analysis showed complete absence of immunoreactive PTPRO. Ultrastructural alterations, such as diffuse foot process fusion and extensive microvillus transformation of podocytes, were observed via electron microscopy in both families. The present study introduces mutations in PTPRO as another cause of autosomal-recessive nephrotic syndrome.

Plasma lipid and lipoprotein concentrations in pregnancy induced hypertension.

OBJECTIVES Aim of this study was to evaluate implication of pregnancy induced hypertension on maternal plasma lipid, lipoprotein, apolipoprotein concentrations and lipid peroxidation products by a comparison of normal pregnancy vs. preeclampsia. DESIGN AND METHODS Thirty-four women with preeclampsia and 32 healthy pregnant women (controls) in the third trimester were recruited for this study. RESULTS In the preeclamptic group plasma total triglyceride, low density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA) and apolipoprotein B (apo-B) were significantly increased, while plasma high density lipoprotein cholesterol (HDL-C) was significantly decreased compared to that of control group. There was no significant difference in total cholesterol and apolipoprotein A1 (apo-A1) concentrations. CONCLUSION Our findings suggest that preeclampsia share some metabolic characteristics with coronary artery disease such as dislipidemia and increased lipid peroxidation. However lipoprotein concentrations may be better biochemical markers of dislipidemia in the preeclamptic state than the corresponding apolipoproteins.

Central corneal thickness is lower in osteogenesis imperfecta and negatively correlates with the presence of blue sclera

Background:  Osteogenesis imperfecta (OI) is a rare, autosomal‐inherited, connective tissue disorder characterised by bone fractures, deafness and blue sclera. Additional ocular findings are decreased ocular rigidity, myopia, glaucoma, keratoconus, corneal opacity, small corneal diameter and congenital Bowmans layer agenesis.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Craniofacial Anthropometry in a Turkish Population

OBJECTIVE To present norms and demonstrate the anthropometric variations in fronto-occipital circumference, inner and outer canthal distances, near and distant [far] anatomical interpupillary distance, canthal index, and circumference-interorbital index across age and sex in urban Turkish subjects. PARTICIPANTS Three thousand four hundred forty-eight subjects (1852 male, 1596 female) aged 7 to 40 years were included in this study. METHODS Three age groups were studied: children aged 7 to 15 years, young adults aged 16 to 25 years, and adults aged 26 to 40 years. Mean values for each measured parameter were determined at each age between 7 and 25 years. Subjects were also divided into nine age subgroups to observe the change of each parameter with advancing age. RESULTS The fronto-occipital circumference and outer canthal distance of males was significantly (p <.001) wider than females in all age groups. The near and distant interpupillary distances of male subjects were, on average, wider than the female subjects with greater differences with advancing age. Across all subjects aged 7 to 40 years, the mean of all measured parameters and calculated indexes of men and boys was significantly different from girls and women (p <.001). The mean for interpupillary distances in our study in both sexes were found to be similar to Arabian, Hong Kong, and British children; larger than those of Chinese, Black, Indian, and Caucasians; and smaller than those of Mexican children and a mixed European population. CONCLUSION This study clearly shows the anthropometric variation for fronto-occipital circumference, inner canthal distance, outer canthal distance, near and distant interpupillary distance, canthal index, and circumference-interorbital index with age. These developmental data and the normal values of these measurements in healthy subjects are useful for dysmorphologists in the early identification of some craniofacial syndromes, hyper- and hypotelorism, and congenital or posttraumatic telecanthus and of planning surgical intervention. We suggest that the comparison of craniofacial dimensions of a patient must be performed with normal standards specific for age as well as sex and race.

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS

Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.

Plasma nitrite levels, total antioxidant status, total oxidant status, and oxidative stress index in patients with tension-type headache and fibromyalgia

OBJECTIVES Tension-type headache (TTH) and fibromyalgia syndrome (FM) are worldwide seen chronic pain syndromes of unknown etiology. Despite the growing body of data on pathophysiology and generation mechanisms of pain; our knowledge on pain mechanisms in both FM and TTH is yet to be limited. PATIENTS AND METHODS We investigated the plasma nitrite levels, total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) in 35 TTH, 33 FM patients and 31 healthy controls. RESULTS The mean plasma nitrite levels and TAS levels were significantly low and OSI was found to be significantly high in TTH and FM groups compared to the control group (p=0.001, p=0.001, p=0.001 and p=0.001, respectively). The mean serum TOS levels were also significantly higher in FM group according to the control group (p=0.034), but there was not a significant difference between TTH and control groups (p=0.066). CONCLUSION These results indicated that; FM and TTH patients revealed higher oxidative stress index and lower total nitrite levels than healthy controls. We conclude that oxidative stress may have a role in the pathophysiological mechanisms of TTH and FM, although, whether it is the cause or the consequence, is not clear.

Urotensin-II Immunoreactivity in Children with Chronic Glomerulonephritis

Background. Human urotensin-II (hU-II) is one of the most potent vasoconstrictors in mammals. To our knowledge, there is no study about the role of U-II in childhood glomerulonephritis.We first determined the expression of h U‐II in kidneys of children with chronic glomerular diseases. Methods. Normal human kidneys were obtained from postmortem biopsies and compared with the kidney biopsy specimens of 24 children with membranoproliferative glomerulonephritis (MPGN) and 6 children with membranous GN. Kidney needle biopsies in 10% neutral buffered-formalin prior to routine processing through to embedded blocking sections were cut, and immunohistochemical reactions were performed on parafin-embedded tissue by an avidin-biotin peroxidase complex method. The antibodies used in the present study were hU-II. The positivities were revealed as weak (+), moderate (++), and severe (+++), according to the color intensity. Results. In kidneys of children with MPGN, differently fom the normal kidneys, more dense U-II immunoreactivity was seen in the glomerular basement membrane (GBM), glomerular mesangium, Bowman capsule, and tubules. Interestingly, we also observed U-II immunoreactivity in crescents. In children with MGN, U-II was mostly seen in GBM and Bowman capsule. Conclusion. Our findings suggest that U-II may have a possible autocrine/paracrine function in the kidneys, and may be an important target molecule in studying renal pathophsiology.

The Changes of Plasma Malondialdehyde, Nitric Oxide, and Adrenomedullin Levels in Patients with Preeclampsia

Objective. The aim of the study was to investigate the role of malondialdehyde, nitric oxide and adrenomedullin in the etiopathogenesis of preeclampsia. Material and Methods. Forty-two pregnant women with preeclampsia and 30 healthy pregnant women were involved. The plasma concentrations of malondialdehyde, nitric oxide, and adrenomedullin were compared between the study group and the control group. Results. In women with preeclampsia the plasma concentrations of malondialdehyde was higher while nitric oxide and adrenomedullin concentrations were lower compared to control subjects. Conclusion. We concluded that the plasma levels of ADM and NO are decreased while MDA levels are increased in subjects with preeclampsia and that might contribute to the pathophysiology of preeclampsia through the lack of a paracrine vasodilatory effect on uteroplacental blood flow.

Malondialdehyde, nitric oxide and adrenomedullin levels in patients with primary dysmenorrhea

Aim:  The aim of the study was to examine whether there was a relationship between primary dysmenorrhea and serum levels of malondialdehyde (MDA), nitric oxide (NO) and adrenomedullin (AM) in young women.