Ali Duzova

Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population

Familial Mediterranean Fever (FMF) is a recessive disorder characterised by episodes of fever and neutrophil-mediated serozal inflammation. The FMF gene (MEFV) was recently identified and four common mutations characterised. The aim of this study was to determine the carrier rate in the Turkish population and the mutation frequency in the clinically diagnosed FMF patients. We found a high frequency of carriers in the healthy Turkish population (20%). The distribution of the five most common MEFV mutations among healthy individuals (M694V 3%, M680I 5%, V726A 2%, M694I 0% and E148Q 12%) was significantly different (P<0.005) from that found in patients (M694V 51.55%, M680I 9.22%, V726A 2.88%, M694I 0.44% and E148Q 3.55%).

The Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study: Objectives, Design, and Methodology

BACKGROUND AND OBJECTIVES Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. A systemic arteriopathy and cardiomyopathy has been characterized in pediatric dialysis patients by the presence of morphologic and functional abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Comorbidity in Children with CKD (4C) Study is a multicenter, prospective, observational study aiming to recruit more than 600 children, aged 6 to 17 years, with initial GFR of 10 to 45 ml/min per 1.73 m(2). The prevalence, degree, and progression of cardiovascular comorbidity as well as its association with CKD progression will be explored through longitudinal follow-up. The morphology and function of the heart and large arteries will be monitored by sensitive noninvasive methods and compared with aged-matched healthy controls. Multiple clinical, anthropometric, biochemical, and pharmacologic risk factors will be monitored prospectively and related to the cardiovascular status. A whole-genome association study will be performed to identify common genetic variants associated with progression of cardiovascular alterations and/or renal failure. Monitoring will be continued as patients reach end-stage renal disease and undergo different renal replacement therapies. RESULTS While cardiovascular morbidity in adults is related to older age and additional risk factor load (e.g., diabetes), the role of CKD-specific factors in the initiation and progression of cardiac and vascular disease are likely to be characterized with greater sensitivity in the pediatric age group. CONCLUSIONS The 4C study is expected to provide innovative insight into cardiovascular and renal disease progression in CKD.

Carotid Artery Intima-Media Thickness and Distensibility in Children and Adolescents Reference Values and Role of Body Dimensions

Carotid intima-media thickness (cIMT) and carotid artery distensibility are reliable screening methods for vascular alterations and the assessment of cardiovascular risk in adult and pediatric cohorts. We sought to establish an international reference data set for the childhood and adolescence period and explore the impact of developmental changes in body dimensions and blood pressure (BP) on carotid wall thickness and elasticity. cIMT, the distensibility coefficient, the incremental modulus of elasticity, and the stiffness index &bgr; were assessed in 1155 children aged 6 to 18 years and sex-specific reference charts normalized to age or height were constructed from 1051 nonobese and nonhypertensive children. The role of body dimensions, BP, and family history, as well as the association between cIMT and distensibility, was investigated. cIMT increased and distensibility decreased with age, height, body mass index, and BP. A significant sex difference was apparent from the age of 15 years. Age- and height-normalized cIMT and distensibility values differed in children who are short or tall for their age. By stepwise multivariate analysis, standardized systolic BP and body mass index were independently positively associated with cIMT SD scores (SDS). Systolic BP SDS independently predicted all distensibility measures. Distensibility coefficient SDS was negatively and &bgr; SDS positively associated with cIMT SDS, whereas incremental modulus of elasticity was independent of cIMT. Morphological and functional aspects of the common carotid artery are particularly influenced by age, body dimensions, and BP. The reference charts established in this study allow to accurately compare vascular phenotypes of children with chronic conditions with those of healthy children.

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGKε, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgkε colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGKε variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

Disease severity in children and adolescents with Familial Mediterranean Fever: A comparative study to explore environmental effects on a monogenic disease

Background: Worldwide, familial Mediterranean fever (FMF) is the most common autoinflammatory disease. It has been suggested that environmental factors affect the phenotype as some patients do not develop the complication of secondary amyloidosis. Objective: To analyse whether disease severity in Turkish children with FMF, living in Turkey and Germany is different. Patients and methods: A total of 55 Turkish children living in Turkey were compared with 45 Turkish children born and raised in Germany. Mean age among the group from Turkey and Germany was 42.2 and 44.29 months, respectively. M694V was the leading mutation in both groups. The severity scores were compared with two scoring systems, modified according to published paediatric data for dosage. Results: There was no significant difference between the mean C-reactive protein and erythrocyte sedimentation rate levels of the two groups. According to the modified Sheba Center score, 78.2% of patients from the group living in Turkey had a severe course compared with 34.1% from the group living in Germany. The modified score of Pras et al also showed more severe disease in the patients from Turkey. The difference between the two groups for both scoring systems were significant (both p<0.05). Conclusions: We believe the modified scores that we introduce can be widely used for children. Our results suggest that the environment affects the phenotype of a monogenic disease of the innate inflammatory pathway.

Carbamazepine poisoning: treatment with plasma exchange

Lethal cases due to carbamazepine overdose have been reported. There are contradicting reports about the efficiency of hemodialysis, hemoperfusion and plasmapheresis for the treatment of carbamazepine poisoning. We present a case of carbamazepine intoxication successfully managed with plasma exchange. The patient was a 15-year-old girl. On admission there was no evidence of trauma, Glascow Coma Scale scored 6. Further questioning of the parents revealed the patient had taken at least 23 tablets of Tegretol® (4.6 g) 6 h before the admission. The carbamazepine level was 190μmol/l. Orogastric lavagewasfollowedby activated charcoal. Within 20 h after admission there was no improvement in her neurological status. It was thus decided to perform plasmapheresis. At the end of the procedure she started to respond to verbal stimuli. Carbamazepine level immediately after the procedure was 101 μmol/l, and at the 36th, 60th and 84th hours were 72, 33 and 20 μmol/l, respectively. The patient was discharged on the fourth day. We have not observed any rebound in our patient. Thus we suggest that simple plasma exchange by plasma replacement is a cheaper and effective method for the treatment of intoxication with carbamazepine orsimilar drugs.

Ataxia and peripheral neuropathy: rare manifestations in Henoch-Schönlein purpura.

Abstract. Henoch-Schönlein purpura (HSP) is a multisystemic vasculitis. Nervous system involvement is usually underestimated. Headaches, mental status changes and seizures are the most frequent neurologic symptoms. Ataxia and mononeuropathy are both very rare. We present an 11-year-old boy with HSP who suffered from ataxia during the initial presentation and peripheral neuropathy at the time of a relapse. Brainstem vasculitic involvement was shown by magnetic resonance imaging, while cranial tomography was normal. All the neurologic symptoms and signs resolved following bolus methylprednisolone administration. Ten months later he had a second course of HSP with skin and renal involvement. A percutaneous renal biopsy, which was performed due to persistent hematuria, revealed mesangial proliferation with IgA deposition. During that period the patient experienced pain and numbness in the right foot and leg; electromyography showed signs of mononeuritis multiplex involving the right posterior tibial nerve. The patient responded to steroid therapy.

Carotid intima–media thickness in children and young adults with renal transplant: Internal carotid artery vs. common carotid artery

Abstract:  Cardiovascular diseases are the main causes of morbidity and mortality following renal transplantation. Atherosclerotic structural changes, which can be detected by high‐resolution B‐mode ultrasonography, begin before clinical findings. However, little is known about the extent of these abnormalities in children after renal transplantation. We aimed to determine early structural changes of large arteries in renal transplant recipients without cardiovascular disease and to evaluate the role of clinical and laboratory features on IMT of carotid arteries. IMT and hemoglobin, serum levels of creatinine, acute phase proteins, lipid profile, and homocysteine were examined in 24 asymptomatic renal transplant recipients (median age 16.5 yr; range 8–25), and 20 healthy controls (median age 16 yr; range 9–24). CCA and ICA were evaluated in patients and controls with a high‐resolution B‐mode ultrasonography in multiple projections to optimize detection of carotid IMT. Measurement of IMT of both CCA [0.36 mm (range 0.16–0.48) vs. 0.28 mm (range 0.21–0.35), p < 0.001] and ICA [0.27 mm (range 0.16–0.48) vs. 0.22 mm (range 0.1–0.26), p < 0.001] were significantly higher in renal recipients than in healthy controls. Among several parameters assessed, only significant correlations were found between duration of CRF, duration of dialysis prior to transplantation and ICA‐IMT (p = 0.06 and p = 0.02, respectively) and between mean past serum calcium–phosphorus ion product and CCA‐IMT (p = 0.002). In conclusion, our observations indicate that vascular changes begin early in the course of CRF and are directly related to time on CRF and dialysis. These changes can be detected by measuring CCA/ICA‐IMT ultrasonographically. We suggest that early renal transplantation can potentially avoid long‐term cardiovascular events in children with end stage kidney disease.

FMF50: a score for assessing outcome in familial Mediterranean fever

Background Colchicine is the main treatment for familial Mediterranean fever (FMF). However, biological agents and other treatments are available for patients who are unable to receive optimal treatment. Objective To develop outcome criteria that define response to treatment. Methods Two rounds of Delphi exercise were followed by a consensus conference enabling the definition of the criteria to be employed. Data for patients with FMF responding and resistant to their treatment were obtained from the FMF Arthritis Vasculitis and Orphan disease Research in paediatric rheumatology (FAVOR) website. The suggested criteria were analysed and validated in this patient cohort. Sensitivity/specificity measures and the ability of the score to discriminate between patients with active and inactive disease via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Compliance with the maximum dose of the drug was considered essential for evaluation of the patients. Seven criteria were suggested in the consensus conference. The performance of each criterion, in differentiating between resistant and responsive patients, was tested. The final set of criteria was defined as at least 50% improvement in five of six criteria, without worsening in any one defined response to treatment with a very high sensitivity and specificity. The items of this FMF50 included: 1. Percentage change in the frequency of attacks with the treatment. 2. Percentage change in the duration of attacks with the treatment. 3. Patients/parents’ global assessment of disease severity (10 cm visual analogue scale (VAS)). 4. Physicians’ global assessment of disease severity (10 cm VAS). 5. Percentage change in arthritis attacks with the treatment. 6. Percentage change in C-reactive protein, erythrocyte sedimentation rate or serum amyloid A level with the treatment. Conclusions The FMF50 produced is a user-friendly measurement tool to guide physicians and can be used in clinical trials.

Acute tumour lysis syndrome following a single‐dose corticosteroid in children with acute lymphoblastic leukaemia

Abstract: Acute tumour lysis syndrome (ATLS) is a well recognised complication of treatment of a variety of malignant disorders. It commonly occurs in patients with non‐Hodgkins lymphoma (NHL) and acute lymphoblastic leukaemia (ALL) with the administration of combined cytotoxic chemotherapy. It is rarely reported after single‐agent corticosteroid therapy. We present two children with acute lymphoblastic leukaemia of T‐cell lineage who developed acute tumour lysis syndrome after a single dose of prednisolone, and methylprednisolone at the beginning of the induction chemotherapy. In the first case (an 11‐yr‐old) ATLS had occurred after an oral dose of prednisolone as small as 12 mg and within 18 h. The second case was a 14‐yr‐old boy with ALL who developed ATLS following a single dose of methylprednisolone. A few similar cases in the English literature are summarised in the report. These cases indicate that acute tumour lysis syndrome may occur after a single dose of corticosteroids. One should be aware of this potentially life‐threatening complication especially while prescribing corticosteroids to patients with NHL and leukaemia.