Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease

How to Cite This Article: Rashnonejad A, Onay H, Atik T, Atan Sahin O, Gokben S, Tekgul H, Ozkinay F. Molecular Genetic Analysis of Survival Motor Neuron Gene in 460 Turkish Cases with Suspicious Spinal Muscular Atrophy Disease. Iran J Child Neurol. Autumn 2016; 10(4):30-35.AbstractObjectiveTo describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. Materials & MethodsA retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University’s Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014.The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation–dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers. ResultsUsing PCR-RFLP test, 159 of 324 postnatal and 18 of 77 prenatal cases were detected to have SMN1 deletions. From positive samples, 88.13% had a homozygous deletion in both exon 7 and exon 8 of SMN1. Using MLPA, 54.5% of families revealed heterozygous deletions of SMN1, and 2 or 3 copies of SMN2, suggesting a healthy SMA carrier. Among patients referred for SMA testing, the annual percentage of patients diagnosed as SMA has decreased gradually from 90.62% (2003) down to 20.83% (2014). ConclusionAlthough PCR-RFLP method is a reliable test for SMA screening, MLPA is a necessary additional test and provide relevant data for genetic counseling of families having previously affected child. The gradual decrease in the percentage of patients molecularly diagnosed as SMA shows that clinicians have begun to use genetic tests in the differential diagnosis of muscular atrophies. Cost and availability of these genetic tests has greatly attributed to their use.   References1. Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valprotae. Ann Neurol 2006;59:970-5.2. Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet 2009;85:408-13.3. Striano P, Boccella P, Sarappa C, Striano S. Spinal muscular atrophy and progressive myoclonic epilepsy: one case report and characteristics of the epileptic syndrome. Seizure 2004;13:582-6.4. Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228-37.5. Van der Steege G, Grootscholten PM, Van der Vlies P, Draaijers TG, Osinga J, Cobben JM, et al. PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 1995;345:985-6.6. Rekik I, Boukhris A, Ketata S, Amri M, Essid N, Feki I, et al. Deletion analysis of SMN and NAIP genes in Tunisian patients with spinal muscular atrophy. Ann Indian Acad Neurol 2013;16:57-61.7. de Souza Godinho FM, Bock H, Gheno TC, Saraiva-Pereira ML. Molecular Analysis of Spinal Muscular Atrophy: A genotyping protocol based on TaqMan realtime PCR. Genet Mol Biol 2012;35:955-9.8. Burghes AH. When deletion is not a deletion? When it is converted? Am J Hum Genet 1997;61:9-15.9. Kubo Y, Nishio H, Saito K. A new method for SMN1 and hybrid SMN gene analysis 1. in spinal muscular atrophy using long-range PCR followed by sequencing. J Hum 2. Genet 2015;60:233-9.10. Ogino S, Leonard DG, Rennert H, Wilson RB. Spinal Muscular Atrophy Genetic Testing Experience at an Academic Medical Center. J Mol Diagn 2002;4:53-8.11. Baumbach-Reardon L, Sacharow S, Ahearn ME. Spinal Muscular Atrophy, X-Linked Infantile. Gene Review 1993.12. Khaniani MS, Derakhshan SM, Abasalizadeh S. Prenatal diagnosis of spinal muscular atrophy: clinical experience and molecular genetics of SMN gene analysis in 36 cases. J Prenat Med 2013;7:32-4.13. Lin SP, Chang JG, Jong YJ, Yang TY, Tsai CH, Wang NM, et al. Prenatal prediction of spinal muscular atrophy in Chinese. Prenat Diagn 1999;19:657-61.14. Cobben JM, Scheffer H, De visser M, Van der Steege G, Verhey JB, Osigna J, et al. Prenatal prediction of spinal muscular atrophy. Experience with linkage studies and consequences of present SMN deletion analysis. Eur J Hum Genet 1996;4:231-6.15. Miskovic M, Lalic T, Radivojevic D, Cirkovic S, Ostojic S, Guc-Scekic M. Ten years of experience in molecular prenatal diagnosis and carrier testing for spinal muscular atrophy among families from Serbia. Int J Gynaecol Obstet 2014;124:55-8.16. Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Burghes AHM, Wirth B, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med 2002;4:20–26.17. Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet 2002;110:301-7.18. Wirth B. An update on the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228–37

Practical recommendations of the EAU-ESPU guidelines committee for monosymptomatic enuresis-Bedwetting

Background and Aims The objective of this update of the EAU-ESPU guidelines recommendations for nocturnal enuresis was to review the recent published literature of studies, reviews, guidelines regarding the etiology, diagnosis and treatment options of nocturnal enuresis and transform the information into a practical recommendation strategy for the general practitioner, pediatrician, pediatric urologist and urologist. Material and Methods Since 2012 a monthly literature search using Scopus (R) was performed and the relevant literature was reviewed and prospectively registered on the European Urology bedwetting enuresis resource center (). In addition, guideline papers and statements of the European Society for Paediatric Urology (ESPU), the European Association of Urology (EAU), the National Institute for Health and Care Excellence (NICE) and the International Children Continence Society (ICCS) were used to update the knowledge and evidence resulting in this practical recommendation strategy. Recommendations have been discussed and agreed within the working group of the EAU-ESPU guidelines committee members. Results The recommendations focus to place the child and his family in a control position. Pragmatic analysis is made of the bedwetting problem by collecting voiding and drinking habits during the day, measuring nighttime urine production and identification of possible risk factors such as high-volume evening drinking, nighttime overactive bladder, behavioral or psychological problems or sleep disordered breathing. A questionnaire will help to identify those risk factors. Conclusion Motivation of the child is important for success. Continuous involvement of the child and the family in the treatment will improve treatment compliance, success and patient satisfaction

Are there any benefits of using an inlay graft in the treatment of primary hypospadias in children?:A systematic review and metanalysis

INTRODUCTION: Dorsal inlay graft urethroplasty (DIGU) has been described as an effective method for hypospadias repair with the proposed advantage of reducing the risk of complications. We aimed to systematically assess whether DIGU has any additional advantages over standard tubularized incised plate urethroplasty (TIPU) repair in children with primary hypospadias. MATERIALS AND METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. The a priori protocol is available at the PROSPERO database (CRD42020168305). A literature search was conducted for relevant publications from 1946 until January 10, 2020 in seven different databases. Randomized controlled trials (RCTs), comparative studies (TIPU vs DIGU) and single arm case series (>20 cases) of DIGU were eligible for inclusion. Secondary hypospadias, two-stage repairs, disorders of sex development, significant curvature of >30°, and a mean or median follow-up of less than 12 months were excluded. DISCUSSION: A total of 499 articles were screened and 14 studies (3 RCTs, 5 non-randomized studies (NRSs), and 6 case series) with a total of 1753 children (distal: 1334 (76%) and proximal: 419 (24%)) were found eligible. Mean follow-up of the studies was between 16 and 77 months. DIGU was found superior to TIPU in decreasing meatal/neourethral stenosis (p = 0.02, 95% CI 0.02-0.78). All other parameters were found comparable including overall complications, fistula and glans dehiscence rates. Success rates were similar among the groups ranging between 48% and 96% for DIGU and 43-96% in the TIPU group. The lack of standardization in the definition of complications and success was the major limitation of this study. CONCLUSIONS: Using an inlay graft during primary hypospadias repair decreases the risk of meatal/neourethral stenosis. However, current evidence does not demonstrate superiority of DIGU over TIPU in terms of treatment success and overall complication rates

The prognostic value of testicular microlithiasis as an incidental finding for the risk of testicular malignancy in children and the adult population:A systematic review. On behalf of the EAU pediatric urology guidelines panel

Introduction: The exact correlation of testicular microlithiasis (TM) with benign and malignant conditions remains unknown, especially in the paediatric population. The potential association of TM with testicular malignancy in adulthood has led to controversy regarding management and follow-up. Objective: To determine the prognostic importance of TM in children in correlation to the risk of testicular malignancy or infertility and compare the differences between the paediatric and adult population. Study design: We performed a literature review of the Medline, Embase and Cochrane controlled trials databases until November 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) Statement. Twenty-six publications were included in the analysis. Results: During the follow-up of 595 children with TM only one patient with TM developed a testicular malignancy during puberty. In the other 594 no testicular malignancy was found, even in the presence of risk factors. In the adult population, an increased risk for testicular malignancy in the presence of TM was found in patients with history of cryptorchidism (6% vs 0%), testicular malignancy (22% vs 2%) or sub/infertility (11–23% vs 1.7%) compared to TM-free. The difference between paediatric and adult population might be explained by the short duration of follow-up, varying between six months and three years. With an average age at inclusion of 10 years and testicular malignancies are expected to develop from puberty on, testicular malignancies might not yet have developed. Conclusion: TM is a common incidental finding that does not seem to be associated with testicular malignancy during childhood, but in the presence of risk factors is associated with testicular malignancy in the adult population. Routine monthly self-examination of the testes is recommended in children with contributing risk factors from puberty onwards. When TM is still present during transition to adulthood a more intensive follow-up could be considered

EAU-ESPU pediatric urology guidelines on testicular tumors in prepubertal boys

Background: Testicular tumors in prepubertal boys account for 1–2% of all solid pediatric tumors. They have a lower incidence, a different histologic distribution and are more often benign compared to testicular tumors in the adolescent and adult group. This fundamental difference should also lead to a different approach and treatment. Objective: To provide a guideline for diagnosis and treatment options in prepubertal boys with a testicular mass. Method: A structured literature search and review for testicular tumors in prepubertal boys was performed. All English abstracts up to the end of 2019 were screened, and relevant papers were obtained to create the guideline. Results: A painless scrotal mass is the most common clinical presentation. For evaluation, high resolution ultrasound has a detection rate of almost 100%, alpha-fetoprotein is a tumor marker, however, is age dependent. Human chorionic gonadotropin (HCG) was not a tumor marker for testis tumors in prepubertal boys. Conclusion: Based on a summary of the literature on prepubertal testis tumors, the 2021 EAU guidelines on Pediatric Urology recommend a partial orchiectomy as the primary approach in tumors with a favorable preoperative ultrasound diagnosis

EAU/ESPU guidelines on the management of neurogenic bladder in children and adolescent part I diagnostics and conservative treatment

BACKGROUND: In childhood, the most common reason for a neurogenic bladder is related to spinal dysraphism, mostly myelodysplasia.AIMS: Herein, we present the EAU/ESPU guidelines in respect to the diagnostics, timetable for investigations and conservative management including clean intermittent catheterization (CIC).MATERIAL AND METHODS: After a systematic literature review covering the period 2000 to 2017, the ESPU/EUAU guideline for neurogenic bladder underwent an update.RESULTS: The EAU/ESPU guideline panel advocates a proactive approach. In newborns with spina bifida, CIC should be started as soon as possible after birth. In those with intrauterine closure of the defect, urodynamic studies are recommended be performed before the patient leaves the hospital. In those with closure after birth urodynamics should be done within the next 3 months. Anticholinergic medication (oxybutynin is the only well-investigated drug in this age group-dosage 0.2-0.4 mg/kg weight per day) should be applied, if the urodynamic study confirmed detrusor overactivity. Close follow-up including ultrasound, bladder diary, urinalysis, and urodynamics are necessary within the first 6 years and after that the time intervals can be prolonged, depending on the individual risk and clinical course. In all other children with the suspicion of a neurogenic bladder due to various reasons as tethered cord, inflammation, tumors, trauma, or other reasons as well as those with anorectal malformations, urodynamics-preferable video-urodynamics, should be carried out as soon as there is a suspicion of a neurogenic bladder and conservative treatment should be started soon after confirmation of the diagnosis of neurogenic bladder. With conservative treatment the upper urinary tract is preserved in up to 90%, urinary tract infections are common, but not severe, complications of CIC are quite rare and continence can be achieved at adolescence in up to 80% without further treatment.DISCUSSION AND CONCLUSIONS: The transition into adulthood is a complicated time for both patients, their caregivers and doctors, as the patient wants to become independent from caregivers and treatment compliance is reduced. Also, transition to adult clinics for patients with neurogenic bladders is often not well-established.</p

Normative Values of Transcranial Magnetic Stimulation-Evoked Parameters for Healthy Developing Children and Adolescents

Context: Normative data-containing transcranial magnetic stimulation (TMS) evoked parameters are essential for correctly interpreting healthy development and assessing neuroplastic changes in certain neurologic disorders. Aims: The aim is to investigate corticospinal pathways by applying TMS to healthy developing children and adolescents. Settings and Design: In this cross-sectional study, we measured TMS evoked parameters associated with cortical and spinal stimulation obtained from the four extremities of 46 healthy children and adolescents (21 boys and 25 girls; mean +/- standard deviation age: 6.4 +/- 1.2 years; range: 3.0-20.5 years). Statistical Analysis: Spearman's correlation coefficients were calculated for each variable (weight and height) as a function of motor evoked potential (MEP) response latency and central motor conduction time (CMCT). Pearson's Chi-square test was used to determine the inter-variable correlations. Results: Latencies of MEPs were correlated with age (P < 0.001, r = 0.6948) and height (P < 0.006, r = 0.7994). Amplitudes of active-state MEPs were significantly higher than those of resting-state MEPs associated with the upper and lower extremities. The mean values for active-state MEP latencies were lower than those for resting-state MEPs. The CMCT and magnitudes of latency jumps were calculated using reliable MEP data for children and adolescents. Additionally, the unresponsiveness rates were significantly higher for children aged below 7 years. Conclusion: The TMS evoked parameters investigated in this study are necessary to accurately assess corticospinal pathway development in healthy children and adolescents

Serum lipid profile in children receiving anti-epileptic drug monotherapy: Is it atherogenic?

WOS: 000242002500008PubMed ID: 17128563The effect of anti-epileptic drugs (AEDs) on serum lipid profile is controversial in children as well as in adults. We longitudinally studied serum lipid profile in 34 newly diagnosed epileptic children receiving AED monotherapy with valproic acid (VPA), carbamazepine (CBZ) or phenobarbital (PB). Serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A1 (Apo A1) and apolipoprotein B (Apo B) were measured at baseline and after 2 years of AED monotherapy. Atherosclerotic indices of TC/ HDL-C and Apo A1/Apo B ratios were calculated. Although there were some alterations in serum lipid profile with AED without statistical significance, the atherosclerotic indices of TC/HDL-C and Apo A1/Apo B ratios did not change significantly after 2 years of monotherapy. Only serum TGs levels significantly decreased with VPA monotherapy. These data suggest that 2 years AED monotherapy with VPA, CBZ or PB did not cause a significant level of concern for an atherogenic effect in children with epilepsy