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Background: Gillespie syndrome is a rare disorder caused by pathogenic variants in ITPR1 gene and characterized by the typical association of cerebellar ataxia, bilateral aniridia and intellectual disability. Since its first description in 1965, less than 100 patients have been reported and only 30 with a molecular confirmation., Methods: We present two additional cases, both carrying a loss-of-function variant in the Gly2539 amino acid residue. We describe the clinical evolution of the patients, one of whom is now 17 years old, and discuss the updated phenotypic spectrum of the disorder., Results: The study gives an overview on the condition, allowing to confirm important data, such as an overall positive evolution of development (with some patient not presenting intellectual disability), a clinical stability of the neurological signs (regardless of a possible progression of cerebellar atrophy) and ocular aspects, and a low prevalence of general health comorbidities., Discussion: Data about development and the observation of middle-aged patients lend support to the view that Gillespie is to be considered a non-progressive cerebellar ataxia, making this concept a key point for both clinicians and therapists, and for the families., (© 2024. The Author(s).)

Introduction: Within Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of compensatory strategies of the intact areas in NonP brain network., Methods: Eleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate whether eventual spared connectivity between basal ganglia and cerebellum explains the different postural motor behavior of NonP and SlowP patients., Results: Cerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum., Discussion: This work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the possible compensatory role of basal ganglia in patients with stable cerebellar malformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Marchese, Palesi, Nigri, Bruzzone, Pantaleoni, Gandini Wheeler-Kingshott, D’Arrigo, D’Angelo and Cavallari.)

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to identify developmental profiles associated with autism spectrum disorder (ASD) and global developmental delay (DD) in pre-school aged Italian children. Developmental profiles were evaluated by means of a standardized tool widely used for the assessment of psychomotor development in early childhood, the Griffiths III scales, recently adapted and standardized for the Italian population. Specifically, we compared the Griffiths III profiles of children with ASD and DD (ASD + DD) with those of children with DD alone. Moreover, we inspected the psychometric function of single items by comparing children with ASD + DD and children with DD with typically developing (TD) children from the Griffiths III normative sample. In this way, we aimed to isolate the effects of each diagnostic class on psychomotor abilities and on the psychometric function of single items. The ASD + DD and DD groups were found to share the presence of lower age equivalent scores relative to their chronological age in all the developmental domains considered: Foundations of Learning, Language and Communication, Eye and Hand Coordination, Personal-Social-Emotional and Gross Motor Skills. However, the DD group displayed a homogeneous profile with similar levels of delay in all developmental domains, while children with ASD + DD exhibited relative weaknesses in the Language and Communication and Personal-Social-Emotional scales. The analysis of the psychometric function drawn for each item has confirmed different profiles in social-communicative and non-verbal items between the two diagnostic groups and in relation to TD normative sample. The Griffiths III is a valid psychometric tool for identifying atypical developmental profiles and its use may be recommended during the diagnostic process of ASD and DD, to detect specific strengths and weaknesses and guide person-centered treatment., (© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Background: The present mono-institutional report aimed to describe the cognitive and behavioral outcomes of low-grade central nervous system (CNS) tumors in a cohort of children treated exclusively with surgical intervention., Methods: Medical records from 2000-2020 were retrospectively analyzed. We included 38 children (mean age at first evaluation 8 years and 3 months, 16 females) who had undergone presurgical cognitive-behavioral evaluation and/or at least 6 months follow-up. Exclusion criteria were a history of traumatic brain injury, stroke, cerebral palsy or cancer-predisposing syndromes., Results: The sample presented cognitive abilities and behavioral functioning in the normal range, with weaknesses in verbal working memory and processing speed. The obtained results suggest that cognitive and behavioral functioning is related to pre-treatment variables (younger age at symptoms' onset, glioneuronal histological type, cortical location with preoperative seizures), timing of surgery and seizure control after surgery, and is stable when controlling for a preoperative cognitive and behavioral baseline. Younger age at onset is confirmed as a particular vulnerability in determining cognitive sequelae, and children at older ages or at longer postsurgical follow-up are at higher risk for developing behavioral disturbances., Conclusions: Timely treatment is an important factor influencing the global outcome and daily functioning of the patients. Preoperative and regular postsurgical cognitive and behavioral assessment, also several years after surgery, should be included in standard clinical practices.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background and Objectives: Heterozygous mutations or deletions of the EBF3 gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of EBF3 -related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking., Methods: We report on 6 patients (2 females and 4 males, age range 2-12 years), of whom 4 carrying a heterozygous point mutation of the EBF3 gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereas EBF3 variants were detected by whole exome sequencing., Results: Phenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable., Discussion: EBF3 -related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose that EBF3 -related syndrome should be classified and treated as a congenital, nonprogressive ataxia., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. The photosensitive form of TTD (PS-TTD) is most commonly caused by mutations in the ERCC2/XPD gene encoding a subunit of the transcription/DNA repair complex TFIIH. Here we report novel ERCC2/XPD mutations affecting proper protein folding, which generate thermo-labile forms of XPD associated with thermo-sensitive phenotypes characterized by reversible aggravation of TTD clinical signs during episodes of fever. In patient cells, the newly identified XPD variants result in thermo-instability of the whole TFIIH complex and consequent temperature-dependent defects in DNA repair and transcription. Improving the protein folding process by exposing patient cells to low temperature or to the chemical chaperone glycerol allowed rescue of TFIIH thermo-instability and a concomitant recovery of the complex activities. Besides providing a rationale for the peculiar thermo-sensitive clinical features of these new cases, the present findings demonstrate how variations in the cellular concentration of mutated TFIIH impact the cellular functions of the complex and underlie how both quantitative and qualitative TFIIH alterations contribute to TTD clinical features., (© 2022 Wiley Periodicals LLC.)

RAI1 is a dosage-sensitive gene whose decreased or increased expression by recurrent and non-recurrent 17p11.2 deletions or duplications causes Smith-Magenis (SMS) or Potocki-Lupski syndromes (PTLS), respectively. Here we report on a 21-year-old female patient showing SMS phenotype who was found to carry a 3.4 kb de novo intragenic RAI1 deletion. Interestingly, a significant increase in RAI1 transcript levels was identified in the patient's, brother's and mother's peripheral blood cells. Allele-specific dosage analysis revealed that the patient's maternally inherited overexpressed RAI1 allele harbors the intragenic deletion, confirming the SMS diagnosis due to the presence of a single wild-type RAI1 functional allele. The mother and brother do not present any PTLS neurologic/behavioral clinical features. Extensive sequencing of RAI1 promoter and predicted regulatory regions showed no potential causative variants accounting for gene overexpression. However, the mother and both children share a novel private missense variant in RAI1 exon 3, currently classified as a VUS (uncertain significance), though predicted by two bioinformatic tools to disrupt the binding site of one specific transcription factor. The reported familial case, the second showing RAI1 overexpression in the absence of RAI1 duplication, may help to understand the regulation of RAI1 dosage sensitivity although its phenotypic effect remains to be determined., (© 2022. The Author(s).)

TRPM3 encodes a transient receptor potential cation channel of the melastatin family, expressed in the central nervous system and in peripheral sensory neurons of the dorsal root ganglia. The recurrent substitution in TRPM3: c.2509G>A, p.(Val837Met) has been associated with syndromic intellectual disability and seizures. In this report, we present the clinical and molecular features of seven previously unreported individuals, identified by exome sequencing, with the recurrent p.(Val837Met) variant and global developmental delay. Other shared clinical features included congenital hypotonia, dysmorphic facial features (broad forehead, deep-set eyes, and down turned mouth), exotropia, and musculoskeletal issues (hip dysplasia, hip dislocation, scoliosis). Seizures were observed in two of seven individuals (febrile seizure in one and generalized tonic-clonic seizures with atonic drops in another), and epileptiform activity was observed in an additional two individuals. This report extends the number of affected individuals to 16 who are heterozygous for the de novo recurrent substitution p.(Val837Met). In contrast with the initial report, epilepsy was not a mandatory feature observed in this series. TRPM3 pathogenic variation should be considered in individuals with global developmental delays, moderate-severe intellectual disability with, or without, childhood-onset epilepsy., (© 2022 Wiley Periodicals LLC.)

KBG syndrome (KBGS) is a neurodevelopmental disorder caused by the Ankyrin Repeat Domain 11 ( ANKRD11 ) haploinsufficiency. Here, we report the molecular investigations performed on a cohort of 33 individuals with KBGS clinical suspicion. By using a multi-testing genomic approach, including gene sequencing, Chromosome Microarray Analysis (CMA), and RT-qPCR gene expression assay, we searched for pathogenic alterations in ANKRD11 . A molecular diagnosis was obtained in 22 out of 33 patients (67%). ANKRD11 sequencing disclosed pathogenic or likely pathogenic variants in 18 out of 33 patients. CMA identified one full and one terminal ANKRD11 pathogenic deletions, and one partial duplication and one intronic microdeletion, with both possibly being pathogenic. The pathogenic effect was established by RT-qPCR, which confirmed ANKRD11 haploinsufficiency only for the three deletions. Moreover, RT-qPCR applied to six molecularly unsolved KBGS patients identified gene downregulation in a clinically typical patient with previous negative tests, and further molecular investigations revealed a cryptic deletion involving the gene promoter. In conclusion, ANKRD11 pathogenic variants could also involve the regulatory regions of the gene. Moreover, the application of a multi-test approach along with the innovative use of RT-qPCR improved the diagnostic yield in KBGS suspected patients.

KIRREL3 is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with CASK gene. Alterations of KIRREL3 have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of KIRREL3 partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo KIRREL3 mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant KIRREL3 variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between KIRREL3 and CASK , we discuss as posterior fossa anomalies may also be part of the phenotype of KIRREL3 -related syndrome., Competing Interests: None declared., (Thieme. All rights reserved.)

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by dominant variants in the Glial Fibrillary Acidic Protein gene. Three main classifications are currently used, the traditional one defined by the age of onset, and two more recent ones based on both clinical features at onset and brain MRI findings. In this study, we retrospectively included patients with genetically confirmed pediatric-onset AxD. Twenty-one Italian patients were enrolled, and we revised all their clinical and radiological data. Participants were divided according to the current classification systems. We qualitatively analyzed data on neurodevelopment and neurologic decline in order to identify the possible trajectories of the evolution of the disease over time. One patient suffered from a Neonatal presentation and showed a rapidly evolving course which led to death within the second year of life (Type Ia). 16 patients suffered from the Infantile presentation: 5 of them (here defined Type Ib) presented developmental delay and began to deteriorate by the age of 5. A second group (Type Ic) included patients who presented a delay in neuromotor development and started deteriorating after 6 years of age. A third group (Type Id) included patients who presented developmental delay and remained clinically stable beyond adolescence. In 4 patients, the age at last evaluation made it not possible to ascertain whether they belonged to Type Ic or Id, as they were too young to evaluate their neurologic decline. 4 patients suffered from the Juvenile presentation: they had normal neuromotor development with no or only mild cognitive impairment; the subsequent clinical evolution was similar to Type Ic AxD in 2 patients, to Id group in the other 2. In conclusion, our results confirm previously described findings about clinical features at onset; based on follow-up data we might classify patients with Type I AxD into four subgroups (Ia, Ib, Ic, Id). Further studies will be needed to confirm our results and to better highlight the existence of clinical and neuroradiological prognostic factors able to predict disease progression., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population., Methods: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed., Results: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam., Conclusions: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced., Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children., Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high., Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.

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.)

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein ( SCAMP5) associated with epilepsy and neurodevelopmental delay. Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp). Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected., Competing Interests: Author XW was employed by the company Cipher Gene Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Jiao, Morleo, Nigro, Torella, D'Arrigo, Ciaccio, Pantaleoni, Gong, Grand, Sanchez-Lara, Krier, Fieg, Stergachis, Wang and Yang.)

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients., (© 2020 Wiley Periodicals LLC.)

Potocki-Lupski syndrome is a condition mainly characterized by infantile hypotonia, developmental delay/intellectual disability (DD/ID), and congenital anomalies, caused by duplications of the 17p11.2 region, encompassing RAI1 gene. Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype. Such aspects, as well as the dysmorphic/malformative ones, have been covered by previous studies; otherwise neurological features have never been systematically described. In order to delineate the neurological phenotype of Potocki-Lupski Syndrome, we collect an 8-patients cohort. Developmental milestones are delayed and a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb. Hypotonia appears a less frequent finding than what previously reported, while motor clumsiness/coordination impairment is frequent. EGG registration demonstrated a common pattern with excess of diffuse rhythmic activity in sleep phases or while the patient is falling asleep. Brain MRI did not reveal common anomalies, although unspecific white matter changes may be present. We discuss such findings and compare them to literature data, offering an overview on the neurological and cognitive-behavioral presentation of the syndrome., (© 2020 Wiley Periodicals LLC.)

Chromosomal microarray analysis is commonly used as screening test for children with neurodevelopmental issues, also in case of complex neurological phenotypes. Developmental delay/intellectual disability is a common presentation sign in pediatric ataxias, diseases with high clinical and genetic heterogeneity. In order to determine the diagnostic yield of Array-CGH in such conditions, all the tests performed in the last 10-year activity of a single referral center in children who present, besides the neurodevelopmental impairment, cerebellar abnormalities have been systematically gathered. The study demonstrates that, except for Dandy-Walker malformation or poly-malformative phenotypes, chromosomal microarray analysis should be discouraged as first-line diagnostic test in pediatric ataxias with neurodevelopmental disability.

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: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children., Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build., Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Heterozygous deletions of the gene PMP22 are associated to hereditary neuropathy with liability to pressure palsies (HNPP), a demyelinating neuromuscular disease causing variable transitory focal muscles weakness. Deletions involving both copies of PMP22 cause more severe phenotypes, with early-onset neuropathy and impairment in motor development. We report a patient with a severe early-onset demyelinating neuropathy, caused by two different inherited deletions of PMP22 , whose parents had an HNPP. The patient showed neurological signs and delay in motor development but normal intellective abilities. A motor and sensitive conduction study showed severe signs of demyelination, suggestive for Dejerine Sottas Syndrome (DSS). The patient's father had a typical HNPP caused by a heterozygous 17p11.2 deletion, encompassing PMP22 . The patient's mother reported no neuropathic symptoms, but in a nerve conduction studies, parents and several relatives showed signs of sensory-motor deficit with focal slowing of conduction at common sites of entrapment. Quantitative analysis of PMP22 , performed in our patient by multiplex ligation-dependent probe amplification, revealed a compound heterozygous status with the same deletion of the father and a deletion of PMP22 exon 5, after proved to be inherited from the mother. Therefore, when we face an early-onset, severe form of neuropathy, we have to consider rare forms of hereditary neuropathy caused by homozygous or compound heterozygous mutations in PMP22 , even if parents are asymptomatic; an exhaustive family history and an electrodiagnostic study are essential to guide genetic tests and to make a diagnosis., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Homozygous and compound heterozygous mutations in GNB5 gene have been associated with a wide spectrum of clinical presentations, ranging from neurodevelopmental issues with or without cardiac arrhythmia (LADCI) to severe developmental delay with epileptic encephalopathy, retinal dystrophy, and heart rhythm abnormalities (IDDCA). While missense or missense/non-sense mutations usually lead to milder form, the biallelic loss of function of GNB 5 gene causes the severe multisystemic IDDCA phenotype. So far, only 27 patients have been described with GNB5 -associated disease. We report the first case of a patient carrying a homozygous 15q21.2 microdeletion, encompassing GNB5 and the two contiguous genes BCL2L10 and MYO5C . The clinical features of the child are consistent with the severe IDDCA phenotype, thus confirming the GNB5 loss-of-function mechanism in determining such presentation of the disease., (Copyright © 2020 Sciacca, Ciaccio, Fontana, Strano, Gilardoni, Pantaleoni and D’Arrigo.)

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661&#95;1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders., Competing Interests: The authors declare no conflicts of interest.

Background: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features., Methods: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder., Results: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function., Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza ® ) enhances SMN2 gene expression. SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases. They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers. Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been investigated yet. Here, we analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the Hammersmith Functional Motor Scale Expanded (HFMSE). Our results demonstrate that myomiR serological levels decrease over disease course upon nusinersen treatment. Notably, miR-133a reduction predicted patients' response to therapy. Our findings identify myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients., Competing Interests: S.B. and L.M. received funds for travel and congress participation from Biogen. R.M. (Riccardo Masson) received founds for meeting attendance from Biogen; he is PI in Hoffmann-La Roche, Avexis and Novartis SMA trials. G.B. has received speaker and consultancy honoraria from AveXis, Inc., Roche, PTC, and Sarepta Therapeutics.

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.)

Objective: The clinical and neurophysiological characteristics of myoclonus in Angelman syndrome (AS) have been evaluated in single case or small cohorts, with contrasting results. We evaluated the features of myoclonus in a wide cohort of AS patients., Methods: We performed polygraphic EEG-EMG recording in 24 patients with genetically confirmed AS and myoclonus. Neurophysiological investigations included jerk-locked back-averaging (JLBA), cortico-muscular coherence (CMC) and generalised partial directed coherence (GPDC). CMC and GPDC analyses were compared to those obtained from 10 healthy controls (HC)., Results: Twenty-four patients (aged 3-35 years, median 20) were evaluated. Sequences of quasi-continuous rhythmic jerks mostly occurred at alpha frequency or just below (mean 8.4 ± 1.4 Hz), without EEG correlate. JLBA did not show any clear transient preceding the jerks. CMC showed bilateral over-threshold CMC in alpha band that was prominent on the contralateral hemisphere in the patient group as compared to HC group. GPDC showed a significantly higher alpha outflow from both hemispheres toward activated muscles in the patient group, and a significantly higher beta outflow from contralateral hemisphere in the HC group., Conclusions: These neurophysiological findings suggest a subcortical generator of myoclonus in AS., Significance: Myoclonus in AS has not a cortical origin as previously hypothesised., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Nothing to disclose.

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.

Pathogenic variants in polynucleotide kinase 3'-phosphatase (PNKP) gene have been associated with two distinct clinical presentations: autosomal recessive microcephaly, seizures, and developmental delay (MCSZ; MIM 613402) and ataxia with oculomotor apraxia type 4 (AOA4; MIM 616267). More than 40 patients have been reported so far, and their clinical presentations revealed a continuum phenotypic spectrum ranging from congenital microcephaly and early-onset intractable seizures, to adult onset slowly progressive sensory-motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in PNKP gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early-onset MCSZ phenotype. Late in the disease progression, cerebellar ataxia and peripheral neuropathy were recognized. Patient 2, homozygous for a frameshift variant (p.Ala429Thrfs*42), presented a phenotype partially consistent with MCSZ including microcephaly and developmental delay, but without seizures. Patient 3 is one of the oldest patients described to date and presented polyneuropathy, and cerebellar signs. Biochemical tests showed abnormalities of cholesterol, albumin, or alpha-fetoprotein plasma levels. The clinical presentation of our patients encompassed early-to-adult-onset manifestations. For these cases, the long clinical follow-up allowed an in-depth phenotypic characterization and a better delineation of the natural history of patients carrying PNKP pathogenic variants., (© 2019 Wiley Periodicals, Inc.)

Spinal Tuberculosis in children is uncommon, even more so in cases of involvement of posterior vertebral elements, and its diagnosis is often delayed. Here we report the case of a young female presenting neuroradiological features and clinical symptoms suspicious for malignant tumor. Histological examination of biopsy specimen evidenced a Pott's disease. We highlight the importance of suspecting this disorder in children with both aspecific systemic and neurological symptoms, in order to reach a timely diagnosis for appropriate and targeted intervention, avoiding the risk of overtreatment and malpractice claims., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.

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.

Background: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs)., Methods: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria., Results: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs., Conclusion: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates., (© 2019 Wiley Periodicals, Inc.)

Overgrowth-intellectual disability (OGID) syndromes are characterized by increased growth (height and/or head circumference ≥+2 SD) in association with an intellectual disability. Constitutive EED variants have previously been reported in five individuals with an OGID syndrome, eponymously designated Cohen-Gibson syndrome and resembling Weaver syndrome. Here, we report three additional individuals with constitutive EED variants, identified through exome sequencing of an OGID patient series. We compare the EED phenotype with that of Weaver syndrome (56 individuals), caused by constitutive EZH2 variants. We conclude that while there is considerable overlap between the EED and EZH2 phenotypes with both characteristically associated with increased growth and an intellectual disability, individuals with EED variants more frequently have cardiac problems and cervical spine abnormalities, boys have cryptorchidism and the facial gestalts can usually be distinguished., (© 2019 Wiley Periodicals, Inc.)

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.

Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients' cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects., (© 2018 Wiley Periodicals, Inc.)

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions., (© 2018 Wiley Periodicals, Inc.)

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS., Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations., Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations., Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.