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Phosphomannomutase deficiency (PMM2-CDG) leads to cerebellar atrophy with ataxia, dysmetria, and intellectual deficits. Despite advances in therapy, the cognitive and adaptive profile remains unknown. Our study explores the adaptive profile of 37 PMM2-CDG patients, examining its association with parental stress and medical characteristics. Assessment tools included ICARS for the cerebellar syndrome and NPCRS for global disease severity. Behavioral and adaptive evaluation consisted of the Vineland Adaptive Behavior Scale and the Health of the Nation Outcome Scales. Psychopathological screening involved the Child Behavior Checklist and the Symptom Check-List-90-R. Parental stress was evaluated using Parental Stress Index. Results were correlated with clinical features. No significant age or sex differences were found. 'Daily living skills' were notably affected. Patients severely affected exhibited lower adaptive skill values, as did those with lipodystrophy and inverted nipples. Greater severity in motor cerebellar syndrome, behavioral disturbances and the presence of comorbidities such as hyperactivity, autistic features and moderate-to-severe intellectual disability correlated with greater parental stress. Our study found no decline in adaptive abilities. We provide tools to assess adaptive deficits in PMM2-CDG patients, emphasizing the importance of addressing communication, daily living skills, and autonomy, and their impact on parental stress in clinical monitoring and future therapies., (© 2023. The Author(s).)

Objective: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs., Methods: A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed., Results: Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent., Conclusion: This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs., Competing Interests: Declaration of Competing Interest Pablo Alonso-Singer has received research support from Eisai, and has served as a paid speaker for Eisai, Bial, UCB and Neuraxpharm. Maria José Aguilar has served as a paid speaker for Eisai, Bial, UCB and Neuraxpharm. Javier Oliva has served as a paid speaker for UCB. Andreu Massot-Tarrús has served as a paid speaker and consultant for Bial, Eisai, UCB Pharma and GW pharmaceuticals, and has received research support from Eisai and UCB Pharma. Joaquín Ojeda has served as a paid consultantforEisai and UCB, and has served as a paid speaker for Bial, Eisai, Pfizer, GSK and UCB Pharma, and has received research support from Alter, and travel support from Bial, Kern Pharma, Eisai and UCB. Ángel Aledo-Serranohas received research and educational support from Zogenix, GW, UCB, Bial, Eisai, Sanofi, Neuraxpharm, Arvelle and PTC. Pedro Bermejo has served as a paid speaker for Bial, Eisai, UCB, Cantabria, Kern, Juste, Cardiva2, St. Jude, Abbott, Esteve, Merck, Teva, Novartis, Lilly, Pfizer, Biogen, Ferrer, and Almirall, and as a paid consultant for Ferrer, AB-Biotics, Cardiva2, St. Jude, Abbott, UCB, Eisai, Merck, Sandoz and TFS, and has current collaborating contracts with UCB, MedAvante and Xana Neurodigital Therapies. Maria de Toledo received research and educational support from Eisai, GW, UCB, Bial and Exeltis. Beatriz G. Giráldez received educational support and has served as a paid-consultant for UCB, Bial, Eisai and Neuraxpharm. The remaining authors have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype-genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors., Methods: Paediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging., Results: Dysmorphology analysis of 31 patients (4-19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages., Conclusions: PMM2-CDG patients' DFs are consistent and inform about clinical severity when no clear phenotype-genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Phosphomannomutase deficiency (PMM2-CDG) causes a cerebellar syndrome that has been evaluated using the International Cooperative Ataxia Rating Scale (ICARS). However, no particular dysarthria tests have been used. Speech ICARS subscore subjectively assesses fluency and clarity of speech with two items. Repetition of syllables, traditionally used for characterization of ataxic speech, was validated in early-onset ataxia conditions. We assess the validity of the PATA test (SCA Functional Index [SCAFI]) in PMM2-CDG patients.PATA rates from 20 patients were compared with a control population were and correlated with ICARS and neuroimaging.There was a difference between the PATA rate in patients and controls. PATA rate increased with age in controls. In patients, the improvement of PATA rate with age was not significant. In patients, the PATA rate was negatively correlated with the total ICARS score and the Speech ICARS subscore. Regarding neuroimaging, midsaggital vermis relative diameter was positively correlated with PATA results. These last differences were also significant when the results are corrected by age.PATA rate provides an easy measure for a quantitative assessment of dysarthria that may help clinicians to monitor patients' evolution in a regular consultation. It could also be used in PMM2-CDG clinical trials implementing ICARS speech subscore information., Competing Interests: The authors declare that they have no competing interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction: Neurofibromatosis type 1 (NF1) is a genetic disorder with various clinical manifestations that affect the peripheral and central nervous system, as well as the skin, bones and endocrine and vascular system. There is still insufficient knowledge of neuropsychological effects of NF1 on children, and there is some controversy about the cognitive deficits that defines the cognitive profile of patients affected by this disorder., Aims: In this study an analysis is made of the neuropsychological performance of a group of patients affected by NF1, compared with a control group of healthy children., Subjects and Method: A comparison was made between the neuropsychological performance of a group of 23 boys and girls with a mean age of 8.7 years (+/-1.39) and diagnosed with NF1, and a control group consisting of 21 healthy children, with mean age of 8.9 years (+/- 1.41) and with similar socio-demographic characteristics. The Wechsler Intelligence Scale for Children (WISC) was applied to evaluate the subjects of both groups., Results: The group of patients affected with NF1 showed a lower performance in every primary index of WISC IV: Verbal Comprehension Index, Fluid Reasoning Index, Working Memory Index, Processing Speed Index, and full Scale IQ. Only in two subscales were no statistically significant differences observed: similarities and coding., Conclusion: The results show subtle and generalised neuropsychological alterations in the sample of children affected with NF1, which affect most of cognitive domains that have been evaluated. Proper specific and early neuropsychological treatment should be provided in order to prevent the high risk for these children of presenting learning difficulties and school failure., (Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Juvenile neuronal ceroid lipofuscinosis (JNCL, NCL3, Batten disease) is usually caused by a 1.02-kb deletion in the CLN3 gene. Mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). We report the clinical course and molecular studies in 24 patients with JNCL collected from 1975 to 2010 with the aim of assessing the natural history of the disorder and phenotype/genotype correlations., Patients and Methods: Patients were classified into the groups of vJNCL with mutations in the CLN1 gene and/or granular osmiophilic deposit (GROD) inclusion bodies (n = 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene and/or fingerprint (FP) profiles (n = 13). Psychomotor impairment included regression of acquired skills, cognitive decline, and clinical manifestations of the disease. We used Kaplan-Meier analyses to estimate the age of onset of psychomotor impairment., Results: Patients with vJNCL showed learning delay at an earlier age (median 4 years, 95% confidence interval [CI] 3.1-4.8) than those in the cJNCL group (median 8 years, 95% CI 6.2-9.7) (P = 0.001) and regression of acquired skills at a younger age. Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. There may be a Gypsy ancestry for V181L missense mutation in the CLN1 gene., Conclusions: The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Further studies of genotype/phenotype correlation will be helpful for understanding the pathogenesis of this disease.

Introduction: Cutaneous hemangioma and vascular malformation are two vascular abnormalities frequently associated with absence or hypoplasia of one or both carotid and/or vertebral arteries, presence of persistent embryonic arteries, especially the trigeminal, cerebellar malformations, and coarctation of the aortic arch and/or congenital cardiopathy. This disease is known as Pascual-Castroviejo type II syndrome (P-CIIS) and by the acronym PHACE., Material and Methods: Three patients (two females and one male) with facial hemangioma are studied during the first years of age by magnetic resonance angiography (MRA) and their vascular evolution to adult age followed through several MRA controls., Results: All the three patients showed persistence of the trigeminal artery associated to other intra- and extracranial vascular abnormalities of type hemangioma or hemangiomatous arteries that presented progressive involution with decreased arterial caliber without appearing cerebrovascular stroke or hypoxic zones because, at the same time, collateral vascularization appeared through connections between the embryonic arteries and the peripheral branches of the internal carotids or connections between branches of the external and internal carotids. Only one patient had obstruction of a branch of the left middle cerebral artery after 3 days, with gastroenteritis with elevated fever at 17 months of life that caused parenchymal infarct in the left cerebral region supplied by the obstructed artery., Conclusions: The presence of embryonic arteries, especially the trigeminal, and connections between branches of the internal and external carotids, mainly through the internal maxillary and ophthalmic arteries, ensure the cerebral supply in the P-CIIS despite the progressive involvement of the cerebral arteries.

Objective: Presentation of 8 patients with subependymal giant-cell astrocytomas (SGCA) associated with tuberous sclerosis complex (TSC)., Material and Methods: There are 8 patients, 6 males and 2 females with TSC, who presented with the tumour between the neonatal period and 24 years., Results: All patients showed bilateral hypersignalised areas in zones close to the foramen of Monro. Three of the patients were admitted urgently due to blindness and increased intracranial pressure. Incomplete removal of the tumour has always been bad solution as it resulted in the death of the patient (in one case) or further surgery operation in the short term. Only one patient developed the tumour suddenly from pre-existing subependymal nodules from the childhood and they had to be removed at 24 years of age. By contrast, 32 patients with TSC and images of subependymal nodules whose CT or MR progress was followed up for between 10 and 30 years did not develop a tumour. One patient had to be operated four times over 20 years., Conclusions: SGCA associated with TSC is a severe complication which as likely to develop and careful monitoring is required from neonatal age with periodicclinical and imaging studies in order to avoid its irreversible complications. Hydrocephaly, blindness and even the death can be the main consequences. Reintervention of the recurrent tumour is often necessary.

Aim: To present seven tumors of the cerebral hemispheres in 6 children with neurofibromatosis type 1 (NF1)., Patients and Methods: Six patients (three males and three females) of 600 cases of a series with NF1 showed features of cerebral hemispheres tumor (seizures, headache and hemiparesis). They were studied neurologically, by EEG and by image (MR and/or spectroscopic-MR) because of these features or simply because having NF1., Results: All the patients had the two diagnostic criteria of the NF1. Six patients had seven tumors (it was because one of them had one tumor in every frontal lobe, both with the same image characteristics), but they did not were removed and they were not studied histologically. The histological study was made to the other five patients and showed that the histological nature corresponded to pilocytic astrocytoma in one patient, neuroepitelial dysembryoplastic tumor in one, polymorphe xanthoastrocytoma in one, neuroectodermic hamartoma in one, and inflammatory chronic non-granulomatose lesion in one., Conclusion: The prevalence of the tumors in the cerebral hemispheres is very low (1%) in the patients with NF1. The tumors commonly are histologically benign, and they can be found in peripheral or deep region of the cerebral hemispheres. Identity of the tumors by MR study commonly is easy and the treatment is surgical in most cases. However, urgent treatment very seldom is necessary in these tumors, and most frequently is possible to take the attitude of 'wait and see' before to decide the definite treatment.

Introduction: It is known as segmental neurofibromatosis type 1 (NF1) a type of NF1 characterized by the features circumscribed to one or more body cutaneous and/or subcutaneous segments. This entity is recognized from recently and it is related with somatic mosaicism., Patients and Methods: 43 patients (29 females and 14 males) with ages below 16 years were retrospectively studied. Image study of the affected region of the body was performed in all patients to discard a subjacent organic disease, and a neurofibroma was histologically demonstrated in some cases. Somatic or gonosomal mosaicism was not investigated in any of the patients., Results: Only 8 patients showed cutaneous lesion--7 with café-au-lait spots (3 of freckles type, 4 of large spots, of which, 3 were bilateral and 1 unilateral ) and 1 presented neurofibromas-. The other cases (81%) had cutaneous lesion with subjacent lesion (neurofibromas and bone dysplasia in most cases). The subcutaneous lesions were seen in all parts of the body without a preferent location. In cases with only cutaneous lesion, the clinical features were seen on the trunk skin., Conclusion: Segmental NF1 is considered to be the result of a somatic or gonosomal mosaicism and still is underdiagnosed. Features of segmental NF1 can be found in as many regions of the body as NF1 without mosaicism. The types of segmental NF1 that were seen less frequently in this series were those with only cutaneous features (café-au-lait spots and neurofibromas). Types with subcutaneous features that involved subjacent organs were seen in 81% of patients. Familial patients, with NF1 or segmental NF1 was shown in 15 patients (35%) and bilateral lesion in 4 cases (9.3%).

Patients and Methods: From a series of 530 patients with neurofibromatosis type 1 (NF1), we performed a retrospective assessment of the long-term neurologic, visual, neuroimaging and evolution of 80 patients (15%) with optic pathway gliomas (OPG). All the 80 patients, 58 (72.5%) females and 22 (27.5%) males were diagnosed during childhood (below age 16 years), range 13 months to 15 years (average: 4.6 years)., Results: Image studies showed the distribution of the lesions among optic nerves, chiasm, tracts and radiations demonstrated that only 25% of the tumors involved only one optic nerve and 11.5% were located only in the chiasm, while 40% involved one or both optic nerves and chiasm, tracts and radiations. Two patients showed pilocytic astrocytoma in the histological study. Late diagnosis (after 7 years of age) of OPG was made in three patients and late progression was evident in three others who required surgical resection, radiotherapy or chemotherapy., Conclusions: All patients were diagnosed during childhood (below 16 years of age). Incidence was double in girls than in boys. Despite the apparent tumoral agressivity of the magnetic resonance and magnetic resonance spectroscopy images, histological findings corresponded to benign pilocytic astrocytoma. Some tumors follow the growth after 7 years. Continued monitoring of patients with NF1 into adulthood is advisable.

Partial trisomy of the long arm of chromosome 19 is a rare aneusomy. Only six cases of pure duplications have been previously reported, two of which were prenatally detected. Here we describe the clinical manifestations in a 15-month-old girl with a de novo dup(19)(q12q13.2) and the application of array-based comparative genomic hybridization with a resolution of approximately 1 Mb to characterize the duplicated segment. Seven clones were found duplicated, and the size of the fragment was determined to be 10.8 Mb. The scarce number of patients reported and the difficulty of accurately defining the duplicated segment when conventional cytogenetic methods are applied hamper the delineation of a clinical phenotype for duplication of chromosome 19q. To our knowledge this is the fifth live born reported with a pure dup(19), and the first report in which the duplicated segment has been accurately characterized by means of array CGH.

Introduction: Benign myoclonic epilepsy in infants is a rare condition that belongs to the group of epilepsies and generalised epileptic syndromes. Doubts have recently arisen as to whether it is really benign, with some reports of cases of compromised psychomotor development when therapy is started late. The differential diagnosis can be associated with epileptic and non-epileptic diseases, and it is important to preclude it from the former due to their severity. Lombroso and Fejerman's benign myocloni are the non-epileptic diseases that create most problems as far as the differential diagnosis is concerned. Congenital defects of the cranial vault are quite rare and are sometimes associated with other malformations. Exceptionally they appear in isolation, and familial cases have been reported., Case Report: Here we describe the case of a female infant, who had been subject to a follow-up in the Children's Neurology department from the age of 7 months and who had been diagnosed as suffering from unspecific bone erosion of the cranial vault and benign myoclonic epilepsy in infants. Psychomotor development has taken place within the range of parameters that can be considered to be normal and the patient is currently 25 months old., Conclusions: From the clinical point of view, in this case we can rule out the most severe epileptic situations. This is a clinical case that is atypical, not only because of the coexistence of two rare diagnoses, but also due to the clinical features and electroencephalographic manifestations. Both situations are very uncommon and there is no apparent relationship between them.

Aim: To present a series of infantile patients with aqueductal stenosis associated with neurofibromatosis type 1 (NF1)., Patients and Methods: Nineteen patients with ages below 16 years, 11 girls and 8 boys, with NF1 presented hydrocephalus due to aqueductal stenosis. All patients, except one who died before the imaging study was performed and was diagnosed by autopsy, were studied by pneumoencephalography (since 1965 to 1974), computerized tomography (CT) (since 1975 to 1984), magnetic resonance (MR) or MR and CT (since 1985 to 2004) (two children had been studied by pneumoencephalography some years before) most times to discard optic pathway tumor and, in few patients, because of intracranial hypertension., Results: All patients showed three ventricular hydrocephalus with aqueductal stenosis. Eleven patients showed optic pathway tumor. One patient had a benign aqueductal tumor that impaired the normal flow of cerebrospinal fluid. Neurological features of hydrocephalus occurred very rapidly in some patients and after several years of evolution in others. Two boys showed precocious puberty. All patients were treated with shunt., Conclusions: In our series, aqueductal stenosis occurred in about 5% of children with NF1. Aqueductal stenosis and hydrocephalus were identified at a short age because many patients were studied suspecting optic pathway tumor. Eleven patients (about 60%) associated optic pathway tumor and aqueductal stenosis.