Maria Grazia Calevo

Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or Rolandic spikes

Nine children (five males, four females; age range 6 years 1 month to 11 years 1 month) affected by benign epilepsy of childhood with centrotemporal or Rolandic spikes (BECRS) with EEG evidence of marked activation of interictal epileptic discharges (IEDs) during sleep, and nine unaffected control children matched for age, sex, and socioeconomic status, were enrolled in a prospective study. At the time of detection of IED activation during sleep, patients showed a mean Full-Scale IQ score within the normal range, but significantly below that of control participants; neuropsychological assessment revealed disorders in visuospatial short-term memory (Corsis Block Tapping Test), attention, and cognitive flexibility (Trail Making Test and Stroop Color-Word Test), picture naming, and fluency (Bentons Naming Test and Word Fluency), visuoperceptual skill (Ghent-Poppelreuter and Street Gestalt Completion Tests) and visuomotor coordination (Bender Test). After detection of IED activation during sleep, children were followed up for 2 years. At the time of IED remission (T1), neuropsychological re-evaluation showed a notable increase in IQ score and a significant improvement (t-test: p<0.007) in visuomotor coordination, non-verbal short-term memory, sustained attention and mental flexibility, picture naming, and visual-perceptual performance. At T1, patients performance did not differ from the controls (Mann-Whitney U test).

Reduced folate carrier polymorphism (80A-->G) and neural tube defects.

Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A→G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case–control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR=2.35; 95% CI 1.21–4.58) and mothers (OR=2.74; 95% CI 0.92–8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A→C and RFC-1 80A→G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A→G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruple-mutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases=11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.

Severe neurologic complications after hematopoietic stem cell transplantation in children

Objective: To describe and evaluate the incidence and risk factors of severe neurologic events (SNE) in pediatric recipients of allogeneic or autologous hematopoietic stem cell transplantation (HSCT) for hematologic or nonhematologic diseases. Methods: Retrospective analysis of 272 consecutive children admitted to the G. Gaslini Children’s Research Institute and given HSCT (70 from unrelated donors, 115 from related donors, and 87 autologous) between June 1985 and January 2001. Results: Thirty-seven children (13.6%) developed SNE after a median of 90 days (range, 5 days to 8.8 years) after HSCT. Cyclosporine A (CSA) neurotoxicity was the most frequent SNE (n = 21), followed by irradiation or chemotherapy injury (n = 7), CNS infections (n = 7), cerebrovascular events (n = 3), and immune-mediated etiology SNE (n = 2). Eleven patients (30%) died because of the neurologic complications. Type of HSCT, treatment with total body irradiation (TBI), acute graft-vs-host disease (GvHD), GvHD >grade 2, and treatment with CSA were associated with a significant increased risk of SNE. Conclusions: Severe neurologic complications are frequent (14%) among children receiving HSCT, causing 8.5% of deaths after transplant. Transplant from allogeneic donor, especially if unrelated, the development of severe acute GvHD grade >2, and the use of TBI in the preparative regimen are the main risk factors for such complications.

Evaluation of a methylenetetrahydrofolate-dehydrogenase 1958G>A polymorphism for neural tube defect risk

AbstractGenetic variants of enzymes involved in the folate pathway might be expected to have an impact on neural tube defect (NTD) risk. Given its key role in folate metabolism, the methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) gene could represent an attractive candidate in NTD aetiology. In this study, the impact of the MTHFD1 1958G>A polymorphism on NTD risk in the Italian population was examined both by hospital-based case-control and family-based studies. The MTHFD1 1958G>A polymorphism was genotyped in 142 NTD cases, 125 mothers, 108 fathers and 523 controls. An increased risk was found for the heterozygous 1958G/A (OR=1.69; P=0.04) and homozygous 1958A/A (OR=1.91; P=0.02) genotypes in the children. Significant association was also found when combined 1958G/A and 1958A/A genotypes of cases were compared with the 1958G/G genotype (OR=1.76; P=0.02). The risk of an NTD-affected pregnancy of the mothers was increased 1.67-fold (P=0.04) only when a dominant effect (1958G/A or 1958A/A vs 1958G/G) of the 1958A allele was analysed. The combined TDT/1-TDT (Z=2.11; P=0.03) and FBAT (Z=2.4; P=0.01) demonstrated a significant excess of transmission of the 1958A allele to affected individuals. In summary, our results indicate that heterozygosity and homozygosity for the MTHFD1 1958G>A polymorphism are genetic determinants of NTD risk in the cases examined.

A multicenter experience on patient and technique survival in children on chronic dialysis

In this study we compared patient and technique survival of 163 new hemodialysis (HD) patients (age 11.4±3.1xa0years) and 295 peritoneal dialysis patients (7.7±4.8xa0years. P< 0.001), treated in 23 dialysis centers participating in the Italian Registry of Pediatric Chronic Peritoneal Dialysis (CPD) during the years 1989–2000. Three HD (1.8%) and 17 CPD (5.8%) patients died; the overall average death rate was 9.8/1,000 patient-years in HD and 29.8/1,000 patient-years in CPD patients. No statistically significant difference in patient survival between CPD and HD was found, while the survival of 102 CPD children younger than 5xa0years at the start of dialysis was lower (P=0.0001) than that of 193 CPD and 160 HD patients aged 5–15xa0years. We registered 12 modality failures among HD (7.4%) patients and 44 among CPD (14.9%) patients. The main causes were vascular access failure and patient choice in HD, and infection in CPD patients. Technique survival was lower (P=0.007) in CPD than in HD patients; a statistically significant difference (P=0.01) was also observed between both the 0- to 5- and the 5- to 15-year-old CPD patients and the HD patients aged 5–15xa0years. Logistic regression analysis confirmed age at initiation of dialysis to be a predictor of patient death (P=0.0001) in the whole patient population, and of technique failure in HD (P=0.006) but not in CPD patients (P=0.16).

Epilepsy in Rett syndrome: clinical and genetic features.

Epilepsy often occurs in Rett syndrome and is considered a major problem. The aim of this study was to define the clinical features of epilepsy and the correlation between seizures and both genotype and clinical phenotype in the Rett population. One hundred sixty-five patients with Rett syndrome referred to four Italian centers were recruited. All patients underwent video/EEG monitoring and molecular analysis of the MECP2 gene or, in negative cases, of the CDKL5 and FOXG1 genes. The frequency of epilepsy was 79%. Drug-resistant epilepsy occurred in 30% of all our patients with Rett syndrome and in 38% of those with epilepsy. Our findings demonstrate that epilepsy differs among the various phenotypes and genotypes with respect to age at onset, drug responsiveness, and seizure semiology. The Hanefeld and preserved speech variants represent the extremes of the range of severity of epilepsy: the preserved speech variant is characterized by the mildest epileptic phenotype as epilepsy is much less frequent, starts later, and is less drug resistant than what is observed in the other phenotypes. Another important finding is that seizure onset before 1 year of age and daily frequency are risk factors for drug resistance. Thus, this study should help clinicians provide better clinical counseling to the families of patients with Rett syndrome.

Poland syndrome with bilateral features: Case description with review of the literature†

Poland syndrome (PS) has been described as unilateral pectoral muscle deficiency variably associated with ipsilateral thoracic and upper limb anomalies. Bilateral hypoplasia/aplasia of the pectoralis muscle and upper limb defects in association with variable thoracic muscles, chest wall deformities and lower limb defects have been infrequently reported in the literature. We report on a 3½‐year‐old girl with clinical features consisting in bilateral asymmetric pectoral muscle defects (complete agenesis on the left side and agenesis of the sternocostal head on the right side), nipple hypoplasia, left rib defect, and right hand symbrachydactyly. In this study, we reviewed the bilateral features present in our patient and those described in the literature. Hypotheses explaining bilateral features in PS are reviewed.

Exercise capacity in apparently healthy survivors of cancer

Aims: To evaluate cardiopulmonary exercise tolerance in a large cohort of apparently healthy paediatric cancer survivors in order to determine their participation in sporting activities. Methods: A total of 84 young (<21 years) asymptomatic childhood cancer survivors, who had been exposed to anthracyclines (mean dose 212 mg/m2) and/or chest irradiation (median dose 2000 cGy), with normal left ventricular systolic function at rest (fractional shortening >29%), and 79 healthy controls were studied. Exercise testing was performed on a treadmill ergometer. Gas exchange analysis and derived variables were measured on a breath-by-breath basis. Pulmonary functional evaluation was performed before exercise. Echocardiographic evaluation at rest was performed within one month before the exercise test. Results: There were no differences in exercise responses between patients and controls. In boys <13 years, mean VO2 max was slightly but significantly lower than in controls. This finding was thought to be a result of decreased physical fitness as all the other exercise parameters were similar to those in the controls. Conclusions: Results show that apparently healthy survivors of paediatric cancer can take part in dynamic sporting activities if they exhibit a normal response to cardiopulmonary exercise testing, while those that exhibit a reduced VO2 max should be re-evaluated after an aerobic training programme, and should undergo tailored dynamic physical activity if the VO2 max does not normalise.

Cystosonography and voiding cystourethrography in the diagnosis of vesicoureteral reflux

Abstract. The availability of US (ultrasonography) contrast media in the last few years has prompted investigation into their use in the diagnosis of vesicoureteral reflux (VUR) in children, a common cause of urinary tract infections (UTI) or pyelonephritis. We performed voiding cystourethrography (VCUG) and cystosonography (CSG) in the same session in 158 children (M/F 97/61, mean age 3.9xa0years, age range 0.1–12.7xa0years) with clinical suspicion of VUR, studied over a year with an ATL plus 3000 real-time scanner (ATL Ultrasound, Bothell, USA), equipped with 2- to 4- and 4- to 7-MHz convex transducers. US contrast medium Levovist (Schering, Berlin, Germany) was used. VCUG and CSG diagnosed 74 (24.2%) and 77 (25.2%) cases of VUR, respectively. There was no agreement in 67 cases (22%). The percentage of false negatives was similar and high with both techniques. CSG seems to be more sensitive in detecting intermediate (second- and third-degree) VUR. In spite of the moderate relative diagnostic adequacy of both methods, we believe that CSG is an alternative to VCUG, avoiding the risk of ionizing radiation, in the following conditions: (1) first diagnosis in females (not in males, due to the poor vesical and urethral anatomical detail it provides), (2) VUR follow-up, (3) VUR diagnosis in megaureters and/or in ureteroceles, and (4) VUR diagnosis in transplanted kidneys. Further improvements of CSG, both in US contrast media and in US technique, could possibly increase its sensitivity.

Etiology of non-immune hydrops fetalis: An update

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non‐immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF‐Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi‐center series of NIHF cases collected and classified using the same schemes in diagnostic work‐ups to allow for comparisons of larger numbers of cases.