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Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior of some PNSTs compared to others are not precisely known. Considering that lipid homeostasis plays a crucial role in fibrotic/inflammatory processes and in several cancers, we hypothesized that the lipid asset was also unbalanced in this group of nerve tumors. Through untargeted lipidomics, NFs presented a significant increase in ceramide, phosphatidylcholine, and Vitamin A ester. PNFs displayed a marked decrease in 34 out of 50 lipid class analyzed. An increased level of ether- and oxidized-triacylglycerols was observed; phosphatidylcholines were reduced. After sphingolipidomic analysis, we observed six sphingolipid classes. Ceramide and dihydroceramides were statistically increased in NFs. All the glycosylated species appeared reduced in NFs, but increased in PNFs. Our findings suggested that different subtypes of PNSTs presented a specific modulation in the lipidic profile. The untargeted and targeted lipidomic approaches, which were not applied until now, contribute to better clarifying bioactive lipid roles in PNS natural history to highlight disease molecular features and pathogenesis.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.

In anticipation of the "Chiari and Syringomyelia Consensus Conference" held in Milan in 2019, we performed a systematic literature review on the management of Chiari malformation type 1 (CM1) and syringomyelia (Syr) in children.We aimed to summarize the available evidence and identify areas where consensus has not been reached and further research is needed.In accordance with PRISMA guidelines, we formulated seven questions in Patients-Interventions-Comparators-Outcomes (PICO) format. Six PICOs concerned CM1 children with/without additional structural anomalies (Syr, craniosynostosis, hydrocephalus, tethered cord, and cranio-vertebral junction anomalies), and one PICO Syr without CM1. We searched Medline, Embase, Cochrane, and NICE databases from January 1, 1999, to May 29, 2019. Cohort studies, controlled and randomized clinical trials (CCTs, RCTs), and systematic reviews were included, all pertinent only to patients ≤ 18 years of age.For CM1, 3787 records were found, 460 full texts were assessed and 49 studies (46 cohort studies, one RCT, and two systematic reviews) were finally included. For Syr, 376 records were found, 59 full texts were assessed, and five studies (one RCT and four cohort studies) were included. Data on each PICO were synthetized narratively due to heterogeneity in the inclusion criteria, outcome measures, and length of follow-up of the included studies.Despite decades of experience on CM1 and Syr management in children, the available evidence remains limited. Specifically, there is an urgent need for collaborative initiatives focusing on the adoption of shared inclusion criteria and outcome measures, as well as rigorous prospective designs, particularly RCTs., (© 2021. Fondazione Società Italiana di Neurologia.)

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency., Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy"., Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms., Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: Large interhemispheric cysts (IHC) with partial or complete agenesis of corpus callosum (ACC) constitute a heterogeneous group of rare disorders. Neurosurgical treatment, in the terms of if, when and how to operate, remains unclear METHODS: We performed a surgical literature review of series or reports of IHCs with callosal anomalies; we evaluated whether revision surgeries were necessary and considered the dimensional change in the cyst postoperatively and the developmental outcome. We also reported our experience with sfour patients treated by programmable cysto-peritoneal (CP) shunting. Patients' clinical history, neuroradiological and neuropsychological performances were evaluated pre and post operatively., Results: The review included 133 patients with surgically-treated IHCs. Although most authors are in agreement to perform surgery if the patients present signs of raised ICP and to not intervene in those completely asymptomatic, for other signs and symptoms the debate is still open; only few authors performed cognitive tests pre and post-operatively. Shunting procedures were successful in 60% of our reviewed cases and often lead to a major cyst collapse. Craniotomy achieves good results but is extremely invasive. Endoscopy is minimally invasive and our review demonstrated a success rate of 66%. However, endoscopy does not ensue a complete cyst collapse. Our series and review seem to suggest a possible link between parenchymal re-expansion and cognitive outcome., Conclusions: Early and effective surgery seems to obtain a greater cerebral parenchyma re-expansion and long-term cognitive evolution. Endoscopy is safe and reliable, but more data is needed on the impact of uncomplete cyst collapse on neurocognitive outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4-20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, -to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort., Results: TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist., Conclusion: The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45 dim CD34 + CD133 + mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM ( p < 0.01) and in Hyper/NormoPP than in HypoPP2 ( p = 0.02). Cold-induced myotonia was more frequently observed in PMC ( n = 34) than in SCM ( n = 23) ( p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP ( n = 4), SCM ( n = 5), and PMC ( n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC ( p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum., (Copyright © 2020 Maggi, Brugnoni, Canioni, Tonin, Saletti, Sola, Piccinelli, Colleoni, Ferrigno, Pini, Masson, Manganelli, Lietti, Vercelli, Ricci, Bruno, Tasca, Pizzuti, Padovani, Fusco, Pegoraro, Ruggiero, Ravaglia, Siciliano, Morandi, Dubbioso, Mongini, Filosto, Tramacere, Mantegazza and Bernasconi.)

Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1 , NF2 , SPRED1 , SMARCB1 , and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate., (© 2020 The Authors. Human Mutation published by Wiley Periodicals, Inc.)

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Objective of the Study: To give a full overview of the clinical presentation of PTEN mutations in pediatric patients and to propose a pediatric follow-up protocol., Methods: Recruitment of 16 PTEN mutated children (age 6 months-11 years) from two pediatric centers in Milan (Italy) between 2006 and 2017. All the patients underwent clinical and neurologic evaluations, cognitive and behavioral tests, and brain MRI; they are currently following an oncologic follow-up., Results: Extreme macrocephaly is present in all the patients (69% HC above +4 SD). Neuropsychiatric issues have high prevalence, with 56% of patients showing developmental delay and 25% showing autism spectrum disorder. Brain MRI reveals in 75% of the patients at least one of the following: enlarged perivascular spaces, white matter anomalies, and/or downward displacement of the cerebellar tonsils through the foramen magnum, resulting in Chiari I malformation in two patients. Vascular malformations have a prevalence of 19%, with further evidence that complex cardiovascular malformations may be related to PTEN mutations; 31% of patients present hamartomas. None of our patients have so far experienced any oncologic complication., Conclusions: We suggest to screen for PTEN mutations all children presenting macrocephaly and one of the following: neurodevelopmental issues, one of the three major brain MRI anomalies, cutaneous lesions, vascular malformations, family history positive for PTEN related malignancies; or also with macrocephaly alone when exceeding +3 SD. Basing on our cohort results and further recent studies on the condition, we recommend a follow-up protocol that includes annual clinical and dermatological examination, thyroid and abdominal US, and Fecal Occult Blood test plus neurodevelopmental evaluation, heart US (to exclude congenital heart malformations), and brain MRI (to exclude Chiari I malformation) at diagnosis., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5' tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher's exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni's correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype-phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions., Competing Interests: The authors declare that they have no conflict of interest.

Neurofibromatosis type-1 (NF1) is a monogenic tumor-predisposition syndrome creating a wide variety of cognitive and behavioral abnormalities, such as decrease in cognitive functioning, deficits in visuospatial processing, attention, and social functioning. NF1 patients are at risk to develop neurofibromas and other tumors, such as optic pathway gliomas and other tumors of the central nervous system. Few studies have investigated the impact of an additional diagnosis of brain tumor on the cognitive outcome of children with NF1, showing unclear results and without controlling by the effect of surgery, radio- or chemotherapy. In the present mono-institutional study, we compared the behavioral and cognitive outcomes of 26 children with neurofibromatosis alone (NF1) with two age-matched groups of 26 children diagnosed with NF1 and untreated optic pathway glioma (NF1 + OPG) and 19 children with NF1 and untreated other central nervous system tumors (NF1 + CT). NF1 + CT and NF1 + OPG showed significantly impaired cognitive abilities compared to NF1 group, with weaknesses in visuo-spatial abilities, visual scanning and verbal working memory, while general verbal abilities are preserved. Moreover, NF1 + OPG patients present more frequent internalizing problems and increased oppositional-deviant behaviors. These results suggest that the co-diagnosis of a brain tumor in NF1 children may partially worsen the cognitive and emotional outcome.

Non-coding RNAs (ncRNAs) are known to regulate gene expression at the transcriptional and post-transcriptional levels, chromatin remodeling, and signal transduction. The identification of different species of ncRNAs, microRNAs (miRNAs), circular RNAs (circRNAs), and long ncRNAs (lncRNAs)-and in some cases, their combined regulatory function on specific target genes-may help to elucidate their role in biological processes. NcRNAs' deregulation has an impact on the impairment of physiological programs, driving cells in cancer development. We here carried out a review of literature concerning the implication of ncRNAs on tumor development in neurofibromatosis type 1 (NF1), an inherited tumor predisposition syndrome. A number of miRNAs and a lncRNA has been implicated in NF1-associated tumors, such as malignant peripheral nerve sheath tumors (MPNSTs) and astrocytoma, as well as in the pathognomonic neurofibromas. Some authors reported that the lncRNA ANRIL was deregulated in the blood of NF1 patients with plexiform neurofibromas (PNFs), even if its role should be further elucidated. We here provided original data concerning the association of a specific genotype about ANRIL rs2151280 with the presence of optic gliomas and a mild expression of the NF1 phenotype. We also detected the LOH of ANRIL in different tumors from NF1 patients, supporting the involvement of ANRIL in some NF1-associated tumors. Our results suggest that ANRIL rs2151280 may be a potential diagnostic and prognostic marker, addressing early diagnosis of optic glioma and predicting the phenotype severity in NF1 patients.

Purpose of Review: The current review summarizes recent advances on three important issues in neurofibromatosis type 1 (NF1) management: the identification of specific NF1 gene mutations predicting the risk for developing neurological malignancies; the molecular features of NF1-associated tumors and their differences from sporadic neoplasms; genetic, epigenetic, or microenviromental factors leading benign tumors to a malignant transformation in NF1., Recent Findings: The association between the risk of developing optic pathway glioma and specific germiline NF1 mutations is still debated and further studies are needed with large, new cohorts of patients. The available evidences suggest that gliomas and malignant peripheral nerve sheath tumors (MPNSTs) in NF1 have a distinct genetic signatures, different from those observed in sporadic neoplasms. Some neoplasms, very rare in general population, such as subependymal giant cell astrocytoma, can be observed in NF1. A subgroup of low-grade NF1-gliomas, some MPNSTs and plexiform neurofibromas contain abundant T lymphocyte infiltrates suggesting that immunotherapy could be a potential therapeutic approach., Summary: These data support the notion that next-generation sequencing efforts are helpful in the genetic characterization of NF1-associated malignancies A better knowledge of those tumors at the genomic level, is essential for addressing new treatments and may contribute to a deeper comprehension of NF1/RAS signaling also in sporadic cancers.

Purpose: Chiari malformation type I (CMI) is a common pediatric neurologic anomaly that can be associated with a variety of genetic disorders; however, it is not always clear whether the observed associations are real or random. The knowledge of the real associations could provide useful guidance to clinicians. Furthermore, it could be of help to better understand the still unknown genetic etiology of CMI., Methods: With the aim of implementing such insights, we retrospectively reviewed clinical, neuroradiological, and genetic data of patients harboring CMI evaluated at the Child Neurology Unit of our institution between January 2008 and December 2018., Results: The cohort consists of 205 patients (111 males and 94 females), with a mean age at diagnosis of 6.3 years (range 0-18 years). 188 patients completed an average follow-up period of 5.2 years (range one month-18 years). Mean age at last assessment was 11.4 years (range nine months-23 years). 127 (62%) children have been classified as syndromic due to the presence of neurodevelopmental disorders, phenotypic anomalies, or malformations. Among syndromic CMI children, a molecular diagnosis was identified in 35/127 (27.6%) (20 males and 15 females). The most common diagnoses were syndromic craniosynostosis in 8/35 children (22.9%), among which sevenare FGFR-related and one ERF-related craniosynostosis; disorders of the RAS/MAPK pathway, termed RASopathies or RAS/MAPK syndromes in 9/35 (25.7%); disorders of the PTEN-PI3K/AKT signal transduction cascade, termed PTENopathies in 3/35 children (8.6%); and chromosomal rearrangements in 6/35 patients (17.1%), two of whom with del16p11.2., Conclusions: We polarized our attention on the defined genetic diagnoses focusing not only on the phenotypic hallmarks but also on the phenotypic overlapping features. In addition, we discussed the pathophysiological mechanisms leading to progressive cerebellar ectopia and the involved molecular pathways. Along with the recent literature evidence, we suppose that interactions between FGFR and RAS/MAPK pathway and between RAS/MAPK and PTEN-PI3K/AKT pathways could explain some phenotypic overlapping features and could have a significant role in the pathogenesis of CMI.

Purpose: Chiari 1 malformation (CM1) is a well-known association with complex craniosynostosis (CC), while it has been rarely reported in association with monosynostosis. The aim of the present study is to investigate on the association between CM1 and untreated sagittal synostosis (USS)., Method: The study included 48 cases of sagittal synostosis (SS), untreated for misdiagnosis and associated with CM1. The children were firstly diagnosed for CM1 by MRI (mean age 9) than for SS (mean age 10.5) by three-dimensional computerized tomography (3D-CT), which documented the absence of the sagittal suture, in the presence of residual indentation of all the other sutures. Syndromic cases were diagnosed by clinical evaluation and molecular studies., Results: Of the 48 children harboring CM1 plus USS, 21 were asymptomatic for CM1 and are still on follow-up, while 27 children were operated for syringomyelia and scoliosis and/or occurrence of symptoms, three of them had an acute presentation (two papilledema and one sleep apneas) and 11 children had a documented increase of preoperative ICP. Craniovertebral decompression (CVD) was the first-line surgery in 24 children, 16 with duroplasty and five without and eight had also cerebellar (CBL) tonsil coagulation. A cranial vault remodelling was firstly performed in three children. Fifteen percent of children submitted to CVD needed a revision for cerebrospinal fluid (CSF) collection, while two needed both the supra- and infratentorial decompressive procedure and another two needed a treatment for the associated hydrocephalus., Conclusions: The present study identified an USS in 27 (15.5%) of 174 CM1 children operated for a symptomatic CM1. We suggest to define this association CM1 plus USS, a new subtype of complex CM1. For the high percentage of complications and multiple procedures needed to solve the CM1, we advise to identify by 3D-CT scan these children before performing CVD. Our finding suggests also that, if left untreated, SS may lead to the delayed occurrence of a challenging subset of CM1.

Background: Plexiform neurofibromas (PN) can determine pain, nerve function impairment, and, when extremely large, also deformity. Surgical is often partial, with possible recurrence, and the risk of malignant transformation., Method: We describe the surgical strategy in a case of huge multiple plexiform neurofibromas of the left arm. We attempted to achieve a safe resection under the intraoperative guidance of fluorescein, with a dedicated microscope filter (YELLOW560). This technique can be also applied to other locations., Conclusion: Fluorescein-guided surgery, coupled with intraoperative neurophysiological monitoring, increases the safe resection rate, considering the risks of neurological deficits and the possible malignant transformation.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes ( TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1 ) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B , SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970&#95;2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors., Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study., Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970&#95;2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970&#95;2972del., Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

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Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results., Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies., Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed., Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.

Visual-spatial impairment has long been considered a hallmark feature of neurofibromatosis type 1 (NF1). No study investigating the cognitive and neuropsychological profile of NF1 used the Rey Complex Figure Test (RCFT) task as the primary measure of visual-perceptual abilities taking into consideration all functions involved including the strategic processing style. We compared 18 children with NF1, 17 siblings (S), and 18 typically developing children (TD) at intelligence scale and RCFT copy, recall, and recognition trials; we also evaluated the copy strategy as a measure of a visual-processing style. Children with NF1 had normal total IQ, with cognitive weaknesses in the perceptual organization and working memory in line with the existing literature. At the RCFT copy, immediate and delay recall scores are significantly lower in NF1 than S and TD, while recognition is in the normal range in all groups. Copy style was poor and less efficient in children with NF1 and correlated to copy and recall ability, but the effect of the group in the RCFT copy and recall remained significantly controlling for strategic approach. The present study confirms visuospatial impairment in children with NF1, due to a deficit in perceptual analysis of shape and their spatial features, in visuomotor integration efficiency and strategies, in recall memory, while recognition memory is preserved. A more configural/holistic style may facilitate both the visual-perceptual and visuomotor ability and the recall process. Visuoperceptual impairment in NF1 seems to be a unified process from early visual processing to higher order functions (planning, strategy, and executive functioning).

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1 gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53 and CDKN2A, frequent mutations of ATRX associated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1 wild-type subgroup enriched with ATRX mutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78.

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

PTEN hamartoma tumor syndrome (PHTS) refers to a group of clinical conditions caused by germline mutations in the PTEN tumor suppressor gene. Increasing evidence has documented that PHTS may be associated with a broader spectrum of structural brain abnormalities, including dysplastic gangliocytoma of the cerebellum, brain tumors, vascular malformations, white matter abnormalities, dilated perivascular spaces and cortical dysplasia. We report a PTEN-mutated child showing macrocephaly, mild intellectual disability and epilepsy symptomatic of right occipital polymicrogyria, who also developed Chiari I Malformation (CIM) that repeatedly required surgical correction. We suppose that the association between PHTS and CIM could be not coincidental, thus extending the spectrum of neurological manifestations of PHTS and highlighting the role of brain MRI in the management of PHTS patients. We suggest that genes within the RAS-MAPK and PI3-AKT pathways might have a significant role in the pathogenesis of CIM in such patients., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Studies of executive function and its relationship with brain T2-weighted hyperintensities in children with neurofibromatosis type 1 (NF1) have yielded inconsistent results. We examined 16 children with NF1 aged 8 to 15 years, of normal intelligence, and compared their findings to those of 16 siblings and 16 typically developing children using the Behavioural Assessment of the Dysexecutive Syndrome in Children (BADS-C). NF1 patients had an adequate overall score at BADS-C, but showed significantly lower performance than typical peers in the Key Search subtest. This is a task that must be solved without any given rules, in which subjects must devise a strategy and an efficient search pattern transferable to other similar real situations. The Key Search scores were not correlated with number and signal characteristics of T2-weighted hyperintensities. Planning without external indications is impaired in children with NF1 because they have to rely entirely on self-organization and monitoring; this study provides information for remediation programs designed to improve functioning in daily life.

The SPRED1 gene encodes a protein involved in the Ras/MAPK (mitogen-activated protein kinase) signaling pathway. Mutations in SPRED1 have been reported to cause Legius Syndrome, a rare developmental disorder that shares some clinical features with Neurofibromatosis-1. Direct sequencing was used to define SPRED1 mutations. We present two previously undescribed mutations: a frameshift mutation causing a stop codon, which was identified in an Italian family (p.Ile60Tyrfs*18) and a missense variation, which was identified in one sporadic Italian case (p.Pro422Arg). Our results led us to hypothesize that these modifications may contribute to the Legius Syndrome phenotype. Further studies will be needed to determine the roles of these mutations in the mechanisms of Legius Syndrome.

Electroencephalographic (EEG) photoparoxysmal response has been little investigated in very young patients. We studied 5055 patients aged less than 5 years with no acquired brain damage, who underwent EEG recording. We determined the prevalence and significance of photoparoxysmal response induced by 1 to 20 Hz photic stimulation. Fifty-three showed photoparoxysmal response and were diagnosed as having Dravet syndrome (11), epileptic encephalopathy with myoclonic seizures (8), neurodegenerative disorders (8), benign idiopathic epilepsies (9), and static disorders with a known or suspected genetic origin (17). Photoparoxysmal response occurred in response to 1 to 5 Hz trains in 41.5% subjects. In most patients with epileptic encephalopathies, photoparoxysmal response was a transient finding: in 53.2%, it failed to be replicated in the recordings performed more than 6 months after initial evaluation. Photoparoxysmal response is rare in patients aged less than 5 years and has some peculiarities such as occurrence with low-frequency stimuli. Its distribution in specific conditions indicates that photoparoxysmal response may be useful in diagnostic workup., (© The Author(s) 2015.)

Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970&#95;2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA-based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

Objective: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms., Methods: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable., Results: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts., Interpretation: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction., (Copyright © 2012 American Neurological Association.)

Children may present a peculiar picture of CIM, as syncopes and acute paraparesis. In a series of 99 children operated for CIM at FINCB there were no major surgical morbidity nor mortality. The preoperative symptoms improved more in this pediatric series than in the adult cases treated at the same institution in the same period; a reason could be the shorter duration of symptoms and another the children plasticity. An untreated nonsyndromic craniosynostosis was present in 10 cases. In our hands, the results of the limited extradural decompression were poor. In some CIM associated with psychiatric symptoms an unexpected improvement was observed after tonsilar resection. The associated Syringomyelia reduced in more than 80% of children and disappeared in a significant number. The rare associated tethered cord (5%) needed a double treatment, detethering by itself being insufficient to treat also tonsillar descent. The clinical symptoms are often more serious in children than in the adults, but the results of surgery, especially on the syrinx, are better.

Numerous studies on adults have confirmed that the cerebellum has a role in processing higher brain functions, and evidence of this role has emerged more recently in developmental age as well. Various types of congenital lesion are associated with neuropsychological impairments and behavioral changes that can sometimes even give rise to a picture of autism. Acquired cerebellar lesions (especially tumors and stroke) in children of normal intelligence have enabled different neuropsychological profiles to be identified, depending on the cerebellar site involved. In Chiari malformation, the cerebellar structures are squeezed and crowded inside the posterior fossa and along the time this could generate various kinds of cognitive and behavioral disorders. Currently available data remain inconclusive, however, and prospective longitudinal studies on sizable series will be needed to ascertain whether and to what degree Chiari malformations may negatively affect mental functioning in developmental age.

The clinical features of Chiari I Malformation (CIM) may be related to the compression of dural and/or neural structures at the craniocervical junction or to the associated syringomyelia. Additionally, patients may exhibit symptoms and signs of associated disorders. CIM is a heterogeneous and multifactorial disorder including congenital and acquired forms; it can also be found as an isolated malformation or in association with many clinical conditions. We analyse the clinical features in a series of 65 children with CIM, focusing on the high frequency of associated clinical disorders. We emphasise the importance of a careful clinical and neurological assessment for a proper diagnosis and a correct management of these patients.

Chiari malformations 1, 2, 3 represent different degrees of herniation of posterior fossa content into the cervical canal (Chiari 1 and 2), or through an upper-cervical meningocele (Chiari 3), whereas Chiari 4 anomaly consists of hypoplasia of the cerebellum. Chiari 1 malformation (CM1) is the commonest anomaly; it is probably related to a mesodermal defect that create a congenitally small posterior fossa, subsequent overcrowding of its contents and herniation through the foramen magnum. The diagnosis of CM1 is based on the demonstration of the downward displacement and particular shape of the cerebellar tonsils into the upper cervical spinal canal associated with obliteration of the subarachnoid spaces at the level of the foramen magnum. MRI has a fundamental role in the correct identification of the anatomical aspects of this malformation and associated anomalies and represents the imaging modality of choice.

Stroke is among the top 10 causes of death in childhood. More than half of the surviving children have long-term neurological sequelae. Ischemic stroke (IS) includes arterial ischemic stroke and cerebral venous thrombosis with venous infarction. Haemorrhagic stroke (HS) includes intracerebral haematoma or subarachnoid haemorrhage. Risk factors for stroke are different in children and in adults. 10-30% of IS have no identified risk factors. However, multiple risk factors are recognizable in the majority of stroke in children; thus, a comprehensive diagnostic evaluation is crucial. Vascular abnormalities, such as arteriovenous malformations, aneurysms, vessel dissection, stenosis, and moyamoya disease, are frequently associated with both IS and HS and lead to high recurrence rates. Endovascular and surgical treatment options are sometimes indicated, performed on the basis of expert opinion, and extrapolated from the adult procedures. In the present paper, we review the recent literature and we discuss the treatment in five cases managed at our institutions.

We present the neuropsychological and linguistic follow-up of a girl with bilateral perisylvian polymicrogyria during 4 years of gestural and verbal speech therapy. Some researchers have suggested that children with bilateral perisylvian polymicrogyria mentally fail to reach the syntactic phase and do not acquire a productive morphology. This patient achieved a mean length of utterance in signs/gestures of 3.4, a syntactic phase of completion of the nuclear sentence and the use of morphological modifications. We discuss the link between gesture and language and formulate hypotheses on the role of gestural input on the reorganization of compensatory synaptic circuits.

The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180&#95;182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death., ((c) 2009 Wiley-Liss, Inc.)

To date, 43 patients have been described with mutations in or involving the CDKL5 gene. The typical phenotype includes early-onset, often intractable epileptic seizures and severe mental retardation with very limited progress in psychomotor development. Most patients also show impaired social interaction with avoidance of eye-to-eye contact, and some clinical features reminiscent of Rett syndrome (RTT), including stereotypic hand movements, lack of purposeful hand use, acquired microcephaly, and generalized hypotonia. We report on the case of a 5-year-old girl with a de novo CDKL5 gene mutation who developed early puberty, which has not been described before.

We assessed intelligence and receptive and expressive language skills in 6 children, ages 7 years 9 months to 12 years 4 months, with bilateral perisylvian polymicrogyria of variable extent and with dysarthria of different severity. In view of the recent findings of a close relationship between word and gesture, we also examined the communicative use of gesture. We found that mental retardation was related to the extent of cortical malformation; lexical comprehension, but not morphosyntactic comprehension, and verbal production were more compromised than expected from nonverbal intellectual abilities; lack of verbal language was not compensated by the use of referential gestures. Results are discussed suggesting that compromised verbal and gestural communication in bilateral perisylvian polymicrogyria are not due simply to mental retardation and/or dysarthria but also to dysfunction of Sylvian fissure areas concerned with the totality of language processing.

Most published neuropsychologic studies on frontal lobe epilepsy have been performed on mixed groups of adults and adolescents with epilepsies of varying etiology. The cognitive profile of frontal lobe epilepsy in children has not been defined. The purpose of this study was to assess neuropsychologic performance in children with frontal lobe epilepsy. Intelligence and executive functions were examined in eight children (age 6 7/12 years to 13 11/12 years) with frontal lobe epilepsy. Performance was related to the focus side, seizure frequency, and age of epilepsy onset. Frontal lobe epilepsy was associated with a range of frontal dysfunctions, but IQ was generally spared. Left focus was associated with deficits in categorization, verbal long-term memory, and detailed visuospatial analysis. Frequent seizures correlated with attention difficulties and inability to inhibit impulsive responses. Children whose epilepsy appeared before age 6 years had reduced ability to change behavioral strategies. Frontal epileptic activity alone can cause selective frontal deficits, the severity and nature of which are related to side, seizure frequency, and age of epilepsy onset. These findings require confirmation on larger series of selected children.

Late outcome in 12 children treated by radical surgery for craniopharyngioma is presented. None of the patients presented underwent fractionated traditional or stereotactic radiotherapy. The results show no neurological (except visual dysfunction in 6 subjects), cognitive or short-term memory deficits. Three children were found to have a minor attention deficit. In 5 cases "frontal lobe" malfunctioning was disclosed, and in 5 there were bursts of unpredictable anger. Three children showed worsening of functioning at school: a combination of various causes is suggested to explain the worsening of academic performances. The size of the sample calls for a careful evaluation of results, with due consideration for the influence of various factors on outcome. Multicentre studies are required to increase the sample size and achieve more general conclusions.