The glycophosphatidylinositol (GPI) anchor pathway plays an essential role in posttranslational modification of proteins to facilitate proper membrane anchoring and trafficking to lipid rafts, which is critical for many cell functions, including embryogenesis and neurogenesis. GPI biosynthesis is a multi-step process requiring the activity of over 25 distinct genes, most of them belonging to the phosphatidylinositol glycan (PIG) family and associated with rare neurodevelopmental disorders. PIGQ encodes the phosphatidylinositol glycan class Q protein and is part of the GPI-N-acetylglucosaminyltransferase complex that initiates GPI biosynthesis from phosphatidylinositol (PI) and N-acetylglucosamine (GlcNAc) on the cytoplasmic side of the endoplasmic reticulum (ER). Pathogenic variants in the PIGQ gene have been previously reported in 10 patients with congenital hypotonia, early-infantile epileptic encephalopathy, and premature death occurring in more than half cases. We detected a novel homozygous variant in PIGQ (NM_004204.5: c.1631dupA; p.Tyr544fs*79) by WES trio-analysis of a male patient with a neurodevelopmental disorder characterized by nonprogressive congenital ataxia, intellectual disability, generalized epilepsy, and cerebellar atrophy. Flow cytometry confirmed deficiency of several GPI-anchored proteins on leukocytes (CD14, FLAER). Clinical features of this case broaden the phenotypic spectrum of PIGQ-related GPI deficiency, outlining the importance of glycophosphatidylinositol (GPI) anchor pathway in the pathogenesis of cerebellar ataxia.

In December 2016 and in June 2017, respectively, the FDA and EMA approved Nusinersen as the first treatment for SMA.Bambino Gesù Hospital started to treat patients with the SMA type 1, from november 2016, as part of the expanded access programm (EAP), and from november 2017, after the commercial approval , the later onset forms. We recruited patients followed in the Neuromuscular Unit. We activated a multidisciplinary team composed of neurologists, pneumologists, anaesthesiologists, radiologists, physiotherapists and pharmacists, in order to prepare the drug, assess the motor functional abilities and monitor the effectiveness, assess the respiratory function and the risk of sedation and perform the injection in severe scoliosis. The intratecal delivery was performed by pneumologists or neurologists. In ASA3 the intrathecal administration was performed with local, in ASA2 patients anaesthesia was induced in all patients with Propofol and the procedure was performed in NORA. In patients with complex spine due to severe scoliosis or spinal instrumentation the procedures were performed with fluoroscopic guide. Results: we treated 57 patients (29 SMAI, 15 SMAII and SMAIII). The age range was 2 m-7.9 ys. 20 patients were in NIV (8 type I, 4 type II); 13 type I patients had tracheostomy; 20 patients had scoliosis (10 SMA1, 6 SMAII, 2 SMAIII) of whom 6 were submitted to spine surgery; 8 patients received the intrathecal injection by fluoroscopic guide. In 8 SMA1 patients the treatment was stopped (in 5 for no effectiveness, in 3 for SAE). 24 patients completed 1 year of treatment. In 66 % of patients improvement in muscle strength or in QOL together to stabilization of respiratory and swallowing function was served. Nusinersen is effective, feasible and safe even in patients with complex spinal anatomies and respiratory insufficiency. To guarantee the quality of the procedure, we recommend establishing an experienced interdisciplinary team.

Other Authors: M. Rollo, P. Toma', G.S. Colafati, G. Esposito, A. Cosi, P. Martelli, L. Giordano, F. Causin, E. Lafe, F. Zappoli, S.M. Bova, T. Foiadelli, G. Sanfilippo, L. Grazian, L. De Carlo, A. Spalice. Objective: To characterize moyamoya (MM) phenomenon, including both moyamoya disease (MMD; isolated moyamoya) and moyamoya syndrome (MMS; moyamoya associated with another condition) in a nationwide pediatric cohort. Methods: Retrospective chart and radiological review of children with MM referred to Italian centers belonging to the Italian Society of Pediatric Neurology. Results: 39 patients from 15 centers were included (51% males). Race: white in 33, Asian in 4, African in 1. 17 patients had MMD, 22 MMS. Among MMD patients, 17/17 were symptomatic at diagnosis. Mean age at onset was 4.2 years (range 0.5–10 years; 35% < 2 years). Mean time from onset to diagnosis was 13 months. Symptoms at diagnosis: 15 ischemic events, 3 seizures, 5 headache, 1 movement disorder (10/17 > 1 symptom). 5/17 patients had posterior involvement. At follow-up, 5 had radiological disease progression; 13/17 underwent neurosurgery; 12/17 had neurological impairments (5 cognitive, 4 motor, 3 both). Among MMS patients (etiologies: genetic, infectious, hematologic, endocrine disorders, radiotherapy), 17/22 were symptomatic at diagnosis. Mean age at onset was 4.7 years (range 1.2–14.6; 40% < 2 years), mean time from onset to diagnosis was 2.5 years, symptoms at diagnosis: 15 ischemic events (12 stroke), 6 focal seizures, 1 headache, 1 movement disorder (12/17 more than 1 symptom). Posterior involvement in 7/20. At follow-up (21/22), 6 had radiological disease progression, 15/21 underwent neurosurgery, and 15/21 had neurological impairment (7 severe multifactorial deficits). Conclusion: Compared with other pediatric series, our cohort is characterized by lower age at onset, and minor diagnostic delay. Age and symptoms at onset, acute and chronic morbidity are similar in MMD and MMS. Probably due to the effect of the associated condition, patients with MMS present a greater proportion of severe deficits at follow-up.

The 22q13 deletion syndrome, also known as Phelan-McDermid Syndrome (PMS), is a chromosomal microdeletion syndrome characterized by neonatal hypotonia, normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features.Almost all of the 22q13 deletions published so far have been described as terminal.It is believed that the SHANK3 gene is the major candidate gene for the neurologic features of the syndrome.Neuroradiological findings in PMS include arachnoid cyst, delayed myelination, frontal lobe hypoplasia, hypogenesis of corpus callosum and ventriculomegaly.We describe a 3-year-old girl with severe developmental delay and right opercular polymicrogyria associated with 22q13.2-22q13.33deletion.

Purpose: To evaluate the efficacy and tolerability of Perampanel (PER) in children and adolescents with refractory epilepsies in daily clinical practice conditions.Patients and methods: This Italian multicenter retrospective observational study was performed in 16 paediatric epilepsy centres. Inclusion criteria were: (i) <= 18 years of age, (ii) history of refractory epilepsy, (iii) a follow-up >= 5 months of PER add-on therapy. Exclusion criteria were: (i) a diagnosis of primary idiopathic generalized epilepsy, (ii) variation of concomitant AEDs during the previous 4 weeks. Response was defined as a >= 50% reduction in monthly seizure frequency compared with the baseline.Results: 62 patients suffering from various refractory epilepsies were included in this study: 53% were males, the mean age was 14.2 years (range 6-18 years), 8 patients aged < 12 years. Mean age at epilepsy onset was 3.4 years and the mean duration of epilepsy was 10.8 years (range 1-16), which ranged from 2 seizures per-month up to several seizures per-day (mean number = 96.5). Symptomatic focal epilepsy was reported in 62.9% of cases. Mean number of AEDs used in the past was 7.1; mean number of concomitant AEDs was 2.48, with carbamazepine used in 43.5% of patients. Mean PER daily dose was 7.1 mg (2-12 mg). After an average of 6.6 months of follow-up (5-13 months), the retention rate was 77.4% (48/62). The response rate was 50%; 16% of patients achieved >= 75% seizure frequency reduction and 5% became completely seizure free. Seizure aggravation was observed in 9.7% of patients. Adverse events were reported in 19 patients (30.6%) and led to PER discontinuation in 4 patients (6.5%). The most common adverse events were behaviour disturbance (irritability and aggressiveness), dizziness, sedation and fatigue.Conclusion: PER was found to be a safe and effective treatment when used as adjunctive therapy in paediatric patients with uncontrolled epilepsy. (C) 2016 Elsevier B.V. All rights reserved.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive compulsive disorders (OCD) consistently exacerbate in temporal correlation to a Group A beta-haemolytic streptococcal infection. In children with PANDAS, there is speculation about whether tonsillectomy or adenotonsillectomy might improve the neuropsychiatric course. Our objective was to examine whether such surgery impacted remission or, in patients without remission, modified clinical course of the disease, streptococcal antibody titers, neuronal antibodies or clinical severity of Obsessive-Compulsive Disorder (OCD) and/or tics. Study participants (n = 120) with positive PANDAS criteria were recruited, examined, and divided into surgical or non-surgery groups. The surgical group consisted of children with tonsillectomy or adenotonsillectomy (n=56). The remaining children were categorized as non-surgery (n=64). Clinical follow-up was made every 2 months for more than 2 years. Surgery did not affect symptomatology progression, streptococcal and neuronal antibodies, or the clinical severity of neuropsychiatric symptoms in these children. In conclusion, in our series clinical progression, antibody production, and neuropsychiatric symptom severity did not differ on the basis of surgical status. We cannot uphold surgical management as likely to impact positive remission rates, course of OCD/tics, or antibody concentrations in children with PANDAS.

Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4–74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non‐SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café‐au‐lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14–13.11], which were more frequent in SNF vs MNFSR (p = 0.0271).

Voltage-gated sodium channels (Nav) are neuronal channels responsible for action potential initiation. Any alteration of the kinetics that determine the gating of these channels can have impact on cellular excitability. Abnormal Nav1.1, one of the five isoforms present in the nervous system, and encoded by the sodium channel !1 subunit (SCN1A) gene, has been associated with a wide spectrum of epileptic phenotypes clinically ranging from extremely benign to very severe forms. Most of these forms share febrile seizures as main or presenting seizures type. In this review the authors summarize the SCN1A-related epileptic phenotypes discovered to date together with the main underlying genetic mechanisms.

Background and purposes To determine the prevalence of SLC2A1 mutations in children with early-onset absence epilepsy (EOAE) and to investigate whether there were differences in demographic and electroclinical data between patients who became seizure-free with anti-epileptic drug (AED) monotherapy (group I) and those who needed add-on treatment of a second AED (group II). Methods We reviewed children with EOAE attending different Italian epilepsy centers. All participants had onset of absence seizures within the first 3years of life but otherwise conformed to a strict definition of childhood absence epilepsy. Mutation analysis of SLC2A1 was performed in each patient. Results Eighty-four children (57 in group I, 27 in group II) fulfilled the inclusion criteria. No mutation in SLC2A1 was found. There were no statistical differences between the two groups with regard to F/M ratio, age at onset of EOAE, early history of febrile seizures, first-degree family history for genetic generalized epilepsy, duration of AED therapy at 3years after enrollment, use of AEDs at 3years, failed withdrawals at 3years, terminal remission of EOAE at 3years, and 6-month follow-up EEG data. Mean duration of seizures/active epilepsy was significantly shorter in group I than in group II (P=0.008). Conclusions We demonstrate that in a large series of children with rigorous diagnosis of EOAE, no mutations in SLC2A1 gene are detected. Except for duration of seizures/active epilepsy, no significant differences in demographic and electroclinical aspects are observed between children with EOAE who responded well to AED monotherapy and those who became seizure-free with add-on treatment of a second AED.

Since the outbreak of novel influenza A (H1N1) in 2009, various neurologic complications have been cited.1 A 2-month-old girl died of a rapidly progressive encephalopathy after influenza infection. MRI, performed after 12 hours from the onset of symptoms, showed bilateral and symmetric lesions including the thalamus, the cortical–subcortical regions of the occipital and parietal lobes, and brainstem tegmentum …

Intrauterine exposure to alcohol may result in a distinct pattern of craniofacial abnormalities and CNS dysfunction, designated fetal alcohol syndrome (FAS). The spectrum of brain malformations associated with maternal alcohol abuse during pregnancy is broader than the relatively uniform phenotype of FAS,1 with the most striking …

Rasmussen encephalitis (RE) is a chronic inflammatory disease leading to unilateral hemispheric atrophy, associated with progressive neurological dysfunction and intractable seizures. The best approach to RE is hemispherectomy. However long-term immunotherapy seems to prevent or slow down hemispheric tissue loss and the associated functional decline.

Craniosynostosis (craniostenosis) is premature fusion of the sutures of the cranial vault. Several factors can affect the growth of the cranial vault during embryonic life and after birth, leading to different types of craniosynostosis; these can be classified on the basis of the specific sutures that are fused. Prognosis is improved by early diagnosis, and it is important to establish the correct approach to these patients on the basis of clinical and neuroradiological investigation. The first priority is to identify the type of craniosynostosis and to distinguish between the types that require surgical intervention and those that do not. We report on the different forms of nonsyndromic craniosynostosis, their clinical and neuroradiological diagnoses, and surgical strategies. Conclusion: The aim of this review is to provide to paediatricians a correct diagnostic approach and management of children affected from nonsyndromic craniosynostosis, for which a careful physical, ophthalmological and neurological examination is fundamental, whereas brain Computed tomography and magnetic resonance imaging are necessary for patients in which the diagnosis is uncertain or for cases of syndromic craniosynostosis.