Hedef Gen Yeni Nesil Dizileme Yöntemi ile Subakut Sklerozan Panensefalit (SSPE) Hastalığı İlişkili Gen Mutasyonlarının Tespiti

Subacute sclerosing panencephalitis (SSPE) is a chronic progressive neurodegenerative disease of the central nervous system effecting children and young adults. First symptoms are mental deterioration, myoclonia and behavioral changes progresing to gait disturbances. Later on patients become beddridden and comatose. The disease eventually cause death of the patient in several years. In this study, new generation sequencing designed for primary immunodeficiencies was used to reveal the immunological mechanisms in the development of SSPE. Fifty three patients who were diagnosed with SSPE in Section of Pediatric Neurology, Hacettepe University, İhsan Doğramacı Children’s Hospital were included in this study. Diagnosis was based on clinical findings, CSF measles index and EEG findings. Illumina 5 system was used for sequencing. Forty two patient were male and 11 patient were female. The mean age of the patients was 16±3,2 years. The mean age for measles was 24 ± 18 months. Interpretation of the results revealed that polimorphisms that are likely disease causing were detected in 15 patients. Five patients had MCM4 variant, 3 patients had TNFRSF13B variant, 2 patient had IRF3 variant and SERPING1, TTC7A, DOCK8, LRBA, C1q, TYK2, LRRC8A vatiants were detected only at one patient. The variants found in the study will assist on new studies in determining the immune mechanisms that may be related to measles virus pathogenesis.Hacettepe Üniversitesi Bilimsel Araştırmalar Birimi tarafından desteklenmiştir.İÇİNDEKİLER ONAY SAYFASI iii YAYIMLAMA VE FİKRİ MÜLKİYET HAKLARI BEYANI iv ETİK BEYAN v TEŞEKKÜR vi ÖZET vii ABSTRACT viii İÇİNDEKİLER ix SİMGELER VE KISALTMALAR xi ŞEKİLLER xiii TABLOLAR xiv 1. GİRİŞ 1 2. GENEL BİLGİLER 3 2.1. Kızamık Virüsü 3 2.1.1. Proteinler 3 2.1.2. Hücre Reseptörleri 5 2.1.3. Viral Yayılım 5 2.1.4. Kızamık 5 2.1.5. Kızamık Virüsünün Neden Olduğu Santral Sinir Sistemi Tabloları 7 2.2. Subakut Sklerozan Panensefalit 8 2.2.1. Klinik Bulgular 8 2.2.2. Pataloji 14 2.2.3. Tanı 14 2.2.4. Tedavi 15 2.3. Antiviral İmmünite 16 2.3.1. Patern Tanıma Reseptörleri Aktivasyonu ve İnterferon Üretimi 18 2.3.2. Tip I İnterferonlar ve Etkileri 19 2.3.3. NK Hücreleri 20 2.3.4. Makrofaj 21 2.3.5. Kompleman 22 2.3.6. CD8+ Sitotoksik T Hücreler 22 2.3.7. CD4+ Th1 Hücreleri 24 2.3.8. İnterferon Gama ve Etkileri 24 2.3.9. Humarol İmmünite 25 2.3.10. Virüslerin İmmun Sistemden Kaçış Yolları 25 2.4. Santral Sinir Sistemi Viral Enfeksiyon 27 2.4.1. Beyin Lenfatikleri 27 2.4.2. Santral Sinir Sistemine Viral Giriş 28 2.4.3. SSS Viral Enfeksiyonu 30 2.4.4. SSS’de Uzun Süreli Viral Enfeksiyon 32 2.4.5. SSPE de Genetik Çalışmalar 33 2.5. Genetik Yaklaşımlar 36 3. BİREYLER VE YÖNTEM 38 3.1. Bireyler 38 3.2. Yöntem 38 3.2.1. DNA İzolasyonu 38 3.2.2. Hedeflenmiş Gen Analizi 39 3.3. İstatistiksel Analizler 40 4. BULGULAR 41 4.1. Klinik Değerlendirme 41 4.2. Hastalığa Neden Olabilecek Genetik Bulgular 42 5. TARTIŞMA 46 6. SONUÇLAR VE ÖNERİLER 50 7. KAYNAKLAR 51 8. EKLER Ek 1. Tez Çalışmasıyla İlgili Etik Kurul İzni Ek 2. Orjinallik Ekran Çıktısı Ek 3. Dijital Makbuz 9. ÖZGEÇMİŞSubakut sklerozan panensefalit (SSPE) çocuk ve genç erişkinlerde kızamık infeksiyonu sonrası görülen ilerleyici nörodejeneratif hastalıktır. İlk bulgular bilişsel fonksiyonlarda kayıp, miyokloni ve davranış değişiklikleri şeklinde başlar. Daha sonra denge bozukluğu eklenerek hastalar yatağa bağımlı hale gelerek kaybedilir. Primer immün yetmezlik hastalıklarının her geçen gün farklı tabloları tanımlanmaktadır. Bu çalışmada SSPE’nin gelişiminden sorumlu immünolojik mekanizmaların ortaya konulabilmesi için primer immün yetmezliklere yönelik olarak düzenlenen yeni nesil dizileme yapılması amaçlandı. Hacettepe Çocuk Nöroloji Bölümü’nde takip edilen 53 SSPE hastası çalışmaya dahil edildi. Tanıları klinik bulgulara, BOS kızamık indeksine ve EEG bulgularına göre konuldu. Dizileme işleminde Illumina 5 sistemi kullanıldı. Hastaların 42’si erkek, 11’i kız olup ortalama yaş 16±3,2 yıldır. Hastalarda ortalama kızamık geçirme yaşı 24±18 aydır. Yapılan değerlendirmede 15 hastada hastalık yapıcı olduğu düşünülen varyant tespit edildi. MCM4 varyantı 5 hastada, TNFRSF13B varyantı 3 hastada, IRF3 varyantı 2 hastada görüldü. Sadece bir hastada görülen varyantlar; SERPING1, TTC7A, DOCK8, LRBA, C1q, TYK2, LRRC8A mutasyonlarıdır. Çalışma sonucu bulunan varyantlar kızamık virüsü ile ilişkili olabilecek immün mekanizmaların belirlenmesinde yeni çalışmalara ışık tutacaktır

Case Series of Mercury Toxicity Among Children in a Hot, Closed Environment

Mercury poisoning is much more prevalent in the general population than possibly many physicians realize. We present data on 26 pediatric cases with mercury intoxication from exposure to mercury by inhalation or skin contact as a result of a broken thermometer in a school laboratory. This is the largest pediatric series in Turkey. During a 3-month period, the study team observed the children for clinical symptoms, physical findings, and blood and mercury levels. Of all patients, 21 inhaled, 3 inhaled and touched the element, and 2 took the mercury home. Sixteen children were symptomatic at admission, although blood mercury levels in the symptomatic children were higher than those in asymptomatic children (P = 0.003). The urine mercury levels were not statistically different between the groups at the admission (P > 0.05). The exposure times were 3.5 and 2 hours for symptomatic and asymptomatic children, respectively (P = 0.003). The 2 children who took the mercury home had the highest blood mercury levels and the most prolonged exposure time. N-acetylcysteine and chelation treatments were started in 21 children who had symptoms of mercury intoxication and high mercury levels in their blood or urine. No adverse effects were observed during chelation therapy. Prompt removal of children from contaminated environments and proper decontamination or elimination of devices containing large amounts of mercury from schools are necessary to prevent serious complications caused by exposure to mercury

Long-term effects of vagus nerve stimulation in refractory pediatric epilepsy: A single-center experience

Introduction: Vagus nerve stimulation (VNS) has been used as an adjunctive therapy for both children and adults with refractory epilepsy, over the last two decades. In this study, we aimed to evaluate the long-term effects and tolerability of VNS in the pediatric drug-resistant epilepsy (DRE) and to identify the predictive factors for responsiveness to VNS.Methods: We retrospectively reviewed the medical records of pediatric patients who underwent VNS implantation between 1997 and 2018. Patients with >= 50% reduction of seizure frequency compared with the baseline were defined as "responders". The clinical characteristics of responders and nonresponders were compared.Results: A total of 58 children (male/female: 40/18) with a mean follow-up duration of 5.7 years (3 months to 20 years) were included. The mean age at implantation was 12.4 years (4.5 to 18.5 years). Approximately half (45%) of our patients were responders, including 3 patients (5.8%) who achieved seizure freedom during follow-up. The age of seizure-onset, duration of epilepsy, age at implantation, and etiologies of epilepsy showed no significant difference between responders and nonresponders. Responders were more likely to have focal or multifocal epileptiform discharges (63%) on interictal electroencephalogram (EEG), when compared to nonresponders (36%) (p = .07). Vocal disturbances and paresthesias were the most common side effects, and in two patients, VNS was removed because of local reaction.Conclusion: Our series had a diverse etiological profile and patients with transition to adult care. Long-term follow-up showed that VNS is an effective and well-tolerated treatment modality for refractory childhood onset epilepsy. Age at implantation, duration of epilepsy and underlying etiology are not found to be predictors of responsiveness to VNS. Higher response rates were observed for a subset of patients with focal epileptiform discharges

Role of serostatus in pediatric neuromyelitis optica spectrum disorders: A nationwide multicentric study

Background: Neuromyelitis optica spectrum disorders (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS) mostly presenting as optic neuritis and acute myelitis. NMOSD can be associated with seropositivity for aquaporin 4 antibody (AQP4 IgG), myelin oligodendrocyte glycoprotein antibody (MOG IgG), or can be seronegative for both. In this study, we retrospectively examined our seropositive and seronegative pediatric NMOSD patients. Method: Data were collected from all participating centres nationwide. Patients diagnosed with NMOSD were divided into three subgroups according to serology: AQP4 IgG NMOSD, MOG IgG NMOSD, and double seronegative (DN) NMOSD. Patients with at least six months of follow-up were compared statistically. Results: The study included 45 patients, 29 female and 16 male (ratio:1.8), mean age 15.16 ± 4.93 (range 5.5–27) years. Age at onset, clinical manifestations, and cerebrospinal fluid findings were similar between AQP4 IgG NMOSD (n = 17), MOG IgG NMOSD (n = 10), and DN NMOSD (n = 18) groups. A polyphasic course was more frequent in the AQP4 IgG and MOG IgG NMOSD groups than DN NMOSD (p = 0.007). The annualized relapse rate and rate of disability were similar between groups. Most common types of disability were related to optic pathway and spinal cord involvement. Rituximab in AQP4 IgG NMOSD, intravenous immunoglobulin in MOG IgG NMOSD, and azathioprine in DN NMOSD were usually preferred for maintenance treatment. Conclusion: In our series with a considerable number of double seronegatives, the three major serological groups of NMOSD were indistinguishable based on clinical and laboratory findings at initial presentation. Their outcome is similar in terms of disability, but seropositive patients should be more closely followed-up for relapses

Characteristics of pediatric multiple sclerosis: The Turkish pediatric multiple sclerosis database

Objective To document the clinical and paraclinical features of pediatric multiple sclerosis (MS) in Turkey. Methods Data of MS patients with onset before age 18 years (n = 193) were collected from 27 pediatric neurology centers throughout Turkey. Earlier-onset (<12 years) and later-onset (?12 years) groups were compared. Results There were 123 (63.7%) girls and 70 (36.3%) boys aged 4–17 years, median 14 years at disease onset. Family history of MS was 6.5%. The first presentation was polysymptomatic in 55.4% of patients, with brainstem syndromes (50.3%), sensory disturbances (44%), motor symptoms (33.2%), and optic neuritis (26.4%) as common initial manifestations. Nineteen children had facial paralysis and 10 had epileptic seizures at first attack; 21 (11%) were initially diagnosed with acute disseminated encephalomyelitis (ADEM). Oligoclonal bands were identified in 68% of patients. Magnetic resonance imaging revealed periventricular (96%), cortical/juxtacortical (64.2%), brainstem (63%), cerebellum (51.4%), and spinal cord (67%) involvement. Visual evoked potentials (VEP) were abnormal in 52%; serum 25-hydroxyvitamin D levels were low in 68.5% of patients. The earlier-onset group had a higher rate of infection/vaccination preceding initial attack, initial diagnosis of ADEM, longer interval between first 2 attacks, and more disability accumulating in the first 3 years of the disease. Conclusion Brainstem and cerebellum are common sites of clinical and radiological involvement in pediatric-onset MS. VEP abnormalities are frequent even in patients without history of optic neuropathy. Vitamin D status does not appear to affect the course in early disease. MS beginning before 12 years of age has certain characteristics in history and course

Re-examining the characteristics of pediatric multiple sclerosis in the era of antibody-associated demyelinating syndromes.

Background: The discovery of anti-myelin oligodendrocyte glycoprotein (MOG)-IgG and anti-aquaporin 4 (AQP4)-IgG and the observation on certain patients previously diagnosed with multiple sclerosis (MS) actually have an antibody-mediated disease mandated re-evaluation of pediatric MS series. Aim: To describe the characteristics of recent pediatric MS cases by age groups and compare with the cohort established before 2015. Method: Data of pediatric MS patients diagnosed between 2015 and 2021 were collected from 44 pediatric neurology centers across Turkiye. Clinical and paraclinical features were compared between patients with dis-ease onset before 12 years (earlier onset) and >= 12 years (later onset) as well as between our current (2015-2021) and previous (< 2015) cohorts. Results: A total of 634 children (456 girls) were enrolled, 89 (14%) were of earlier onset. The earlier-onset group had lower female/male ratio, more frequent initial diagnosis of acute disseminated encephalomyelitis (ADEM), more frequent brainstem symptoms, longer interval between the first two attacks, less frequent spinal cord involvement on magnetic resonance imaging (MRI), and lower prevalence of cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCBs). The earlier-onset group was less likely to respond to initial disease-modifying treatments. Compared to our previous cohort, the current series had fewer patients with onset < 12 years, initial presentation with ADEM-like features, brainstem or cerebellar symptoms, seizures, and spinal lesions on MRI. The female/male ratio, the frequency of sensorial symptoms, and CSF-restricted OCBs were higher than reported in our previous cohort. Conclusion: Pediatric MS starting before 12 years was less common than reported previously, likely due to exclusion of patients with antibody-mediated diseases. The results underline the importance of antibody testing and indicate pediatric MS may be a more homogeneous disorder and more similar to adult-onset MS than previously thought