Mehmet Akif Ozdemir

Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

BACKGROUND Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature

Abstract: Thiamine‐responsive megaloblastic anemia syndrome (TRMA) is an autosomal recessive disorder with features that include megaloblastic anemia, mild thrombocytopenia and leukopenia, sensorineural deafness and diabetes mellitus. In this disease, the active thiamine uptake into cells is disturbed. Treatment with pharmacological doses of thiamine ameliorates the megaloblastic anemia and diabetes mellitus. Previous studies have demonstrated that the disease is caused by mutations in the SLC19A2 gene encoding a high‐affinity thiamine transporter. We present a 5‐yr‐old‐boy with TRMA and, because of its rarity, we review the literature.

Inherited biallelic CSF3R mutations in severe congenital neutropenia

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis.

Lithium-induced hematologic changes in patients with bipolar affective disorder

We planned this study to examine the effects of short-term (10-day) and long-term (6 months) administration of lithium in patients with bipolar affective disorder, those who may be given lithium in nontoxic prophylactic doses

Childhood Stroke: Results of 130 Children From a Reference Center in Central Anatolia, Turkey

BACKGROUND Although stroke among children is rare, it can cause significant morbidity and mortality. We aim to share our experience of children with arterial ischemic stroke. METHODS The initial symptoms, demographical features, risk factors, neurological examination, neuroradiological findings, and clinical follow-up data of 130 Turkish children seen between 2002 and 2013 were retrospectively analyzed. RESULTS Sixty-eight patients were male. Thirty of the children were aged from 1 to 12 months (seven of them died in this period). Focal neurological signs were the most common presentation, and hemiplegia or hemiparesis were the most common focal signs. Underlying risk factors were detected in 103 patients. Infections and congenital heart disease were the most common risk factors. Seven of the nine children with recurrent arterial ischemic strokes had one or more underlying diseases (moyamoya disease in two children along with factor V Leiden mutation, tuberculous meningitis, congenital heart disease, homocystinuria, and hemiconvulsion-hemiplegia-epilepsy syndrome). The arterial ischemic stroke was located in the middle cerebral circulation in 68 (36 left and 32 right) and in the posterior cerebral artery in 41. Eighteen children died. The neurological outcome was assessed in 98 children. Of these children, 66 children have neurological deficits and 52 children have seizures. Stroke in the first year of life is more often fatal. Recurrent stroke is associated with poor prognosis. CONCLUSION Tuberculous meningitis is still a risk factor for arterial ischemic stroke in Turkey. Arterial ischemic stroke in the first year of life and recurrent arterial ischemic stroke represent poor prognostic features.

Management of Hyperleukocytosis and Prevention of Tumor Lysis Syndrome with Low-Dose Prednisone Continuous Infusion in Children with Acute Lymphoblastic Leukemia

Introduction: The standard management of childhood acute lymphoblastic leukemia with hyperleukocytosis is unclear and its treatment has focused on prompt leukocytoreduction. Cytoreductive therapies have been used for the prevention of tumor lysis syndrome, but the outcomes have been variable and their benefits have not been proven in controlled clinical trials. This condition needs further investigation to develop effective therapeutic strategies. Methods: In the present prospective trial, 15 children with acute lymphoblastic leukemia and hyperleukocytosis (range 101–838 × 109/l) were treated with intravenous low-dose prednisone continuous infusion (6 mg/m2/24 h). Doses were increased daily and on approximately the fifth day, the full dose of prednisone (60 mg/m2/day) was applied. Results: The mean reduction in white blood cell count achieved by this treatment was 34.4% on first day, 56.9% on second day and 76.6% on third day. The treatment was well tolerated. None of the 15 patients developed life-threatening metabolic disorders or required dialysis. Conclusions: Intravenous low-dose prednisone continuous infusion treatment can prevent the progression to tumor lysis syndrome and it may be used for the patients presenting with white blood cell counts between 100 and 400 × 109/l in centers where leukoapheresis is not readily available.

Determination of thermal conductivities of solid and liquid phases for rich-Sn compositions of Sn-Mg alloy

The variations of thermal conductivities of solid phases versus temperature for pure Sn and Sn-1 wt% Mg, Sn-2 wt% Mg, and Sn-6 wt% Mg binary alloys were measured with a radial heat flow apparatus. Thermal conductivity variations versus temperature for pure Sn and Sn-1 wt% Mg, Sn-2 wt% Mg, and Sn-6 wt% Mg binary alloys were found to be 60.60 ± 3.63, 61.99 ± 3.71, 68.29 ± 4.09, and 82.04 ± 4.92 W/Km, respectively. The thermal conductivity ratios of liquid phase to solid phase for pure Sn and eutectic Sn-2 wt% Mg alloy at their melting temperature were found to be 1.11 and 1.08, respectively, with a Bridgman type directional solidification apparatus. Thus the thermal conductivities of liquid phases for pure Sn and eutectic Sn-2 wt% Mg binary alloy at their melting temperature were evaluated to be 67.26 ± 4.03 and 73.75 ± 4.42 W/Km, respectively, by using the values of solid phase thermal conductivities and the thermal conductivity ratios of the liquid phase to the solid phase.

Congenital Acute Lymphoblastic Leukemia: Report of a Case with Leukemia Cutis

Congenital leukemia is an extremely rare disease, diagnosed at birth or within the first month of life. Most of the neonatal cases reported have acute nonlymphoblastic (acute monoblastic or myelomonoblastic) leukemia, in contrast to the predominance of acute lymphoblastic leukemia found in later childhood. Acute lymphoblastic leukemia (ALL) may occur but is exceedingly rare, most often of B cell lineage, and with a worse prognosis than childhood ALL.1 Generally, cases present with marked leukocytosis, petechia, ecchymoses, and extramedullary involvement, with massive hepatosplenomegaly, cutaneous nodules, and central nervous system leukemia. The clinical findings of neonatal leukemia are variable. Often the disease is characterized by a rapid downhill course, but it may be unpredictable. Some neonates show signs of leukemia at birth and die shortly thereafter, while others appear normal following delivery but clinical and hematologic problems develop later. In a third group, leukemia is not discovered until the third to sixth week of life, with a history suggestive of hematologic abnormalities dating back a few weeks earlier.2 We describe a case of congenital pre–B-cell ALL in a newborn female baby with striking features of leukemia cutis.

The efficacy of vitamin K2 and calcitriol combination on thalassemic osteopathy.

Thalassemic osteopathy (TOSP) has emerged as a topic of interest, as the optimized transfusion regimens and iron chelations has markedly improved the survival of the patients suffering from thalassemia major (TM) and increased the life expectancy. The aim of this prospective monocentric pilot study was to investigate the effects of a dietary supplement with vitamin K2 (50 mcg menaquinone-7) and vitamin D (5 mcg calcitriol) on the patients with TOSP. Twenty children (12 girls, 8 boys; age varied from 3 to 18 y) with &bgr; TM, who underwent regular blood transfusion and iron chelation therapy, were enrolled in this study and investigated at the initial, sixth, and 12th month of the treatment. We detected a significant improvement in the bone mineral density and Z-score at the lumbar spine area of the patients at the sixth and 12th month of the treatment, especially in the prepubertal group. We also found a decrease in the ratio of undercarboxylated osteocalcin to carboxylated osteocalcin, however, this was not found to be significant. Although the natural course of TOSP is worsening or at least stabilizing, our pilot study demonstrated that vitamin K2 and calcitriol combination clearly has a positive effect on the bone mineral density of the children with TM during a 1-year period. Supplementation of menaquinone-7 instead of drugs is an augmented physiological intake and seems a beneficial alternative for the treatment of TOSP. Further studies on a large number of participants are necessary to highlight the effect of vitamin K2 on TOSP.

Experimental determination of interfacial energy for solid Zn solution in the Sn-Zn eutectic system

The grain boundary groove shapes for Zn solid solution in equilibrium with Sn-Zn eutectic liquid were observed with a radial heat flow apparatus. From the observed grain boundary groove shapes, the Gibbs-Thomson coefficient, the solid-liquid and the grain boundary energy for the Zn solid solution in equilibrium with Sn-Zn eutectic liquid were determined to be (2.32 ± 0.13)×10−8 Km, (120.87 ± 13.29)×10−3 J.m−2 and (194.76 ± 23.37)×10−3 J.m−2, respectively. The termal conductivity of the eutectic Sn-9 wt% Zn solid solution, κS, was obtained as 74.74 W/Km by using a radial heat flow apparatus. The thermal conductivity ratio of the eutectic liquid to the eutectic solid, R = κL/κS was found to be 0.58 with a Bridgman-type directional growth apparatus. Thus, the value of the thermal conductivity of eutectic Sn-9 wt% Zn liquid solution, κL, was obtained as 43.82 W/Km.