Eating disorders in young patients with neurofibromatosis type 1

Aim: We describe the association of neurofibromatosis type 1 (NF1) and feeding and eating disorders (FED) in five patients admitted to our third level centre for both FED and NF1. Methods: Case series of five adolescent females with NF1 treated for FED. Results: We collected data from five patients with NF1 aged between 14 and 22 years, all females. The onset of eating disorder symptoms occurred between 13 and 19 years of age and was characterised by food intake restriction, associated with physical hyperactivity in three out of five cases. One patient also reported self-injurious acts and episodic binges. Patients received diagnoses of anorexia nervosa (AN, n = 2), atypical AN (n = 1), bulimia nervosa (n = 1), unspecified feeding and eating disorder (n = 1). Conclusion: The current literature reports a single case of an adult with NF1 and comorbid AN, focusing on the dermatological features of NF1. Our article describes a case series of five patients in developmental age affected by NF1 and FED. Clinical and psychological features of NF1 may play a role in the pathogenesis of FED when these two conditions co-occur. The dermatological alterations of NF1 may contribute to body image distortion that characterises AN. Further research is required to systematically screen populations of patients with NF1 for the presence of FED

Relationship between Sensory Alterations and Repetitive Behaviours in Children with Autism Spectrum Disorders: A Parents' Questionnaire Based Study

The relationship between sensory profile and repetitive behaviours in autism spectrum disorder (ASD) has long been known. However, there is no consensus on the type of relationship that exists between them. This monocentric retrospective-prospective observational study aimed (a) to detect a clinical correlation between the severity of repetitive behaviours and the alterations of sensory profile in a sample of 50 children diagnosed with ASD; (b) to evaluate how different patterns of stereotypies and sensory alterations correlate with each other and with the main clinical-instrumental variables in the same sample. We enrolled 29 children in the retrospective phase of the study and 21 in the prospective phase. The Repetitive Behaviour Scale-Revised (RBS-R) and the Short Sensory Profile (SSP) were administered to the caregivers, and clinical-instrumental data were collected. SSP and RBS-R total scores directly correlated with a high significance rate. Among the subscales, the strongest correlations involved "Visual/Auditory Sensitivity", related to "Stereotyped Behaviour" and "Sameness Behaviour". "Under-Responsive/Seeks Sensation" related to "Stereotyped Behaviour". Sex and intellectual disability significantly influenced both the stereotypies and the sensory alterations of the examined population. In conclusion, this study provides new insights into the relationship between sensory alterations and repetitive behaviours in ASD children by using direct medical observation and parent observation

VNS in drug resistant epilepsy: preliminary report on a small group of patients

<p>Abstract</p> <p>Background</p> <p>In 1997 Vagus Nerve Stimulation (VNS) received approval from the US Food and Drug Administration (FDA) as an adjunctive therapy in the treatment of medically intractable partial epilepsy in people aged 12 years and older who are ineligible for resective epilepsy surgery. Although the exact mechanisms of action are unknown, the use of VNS with children has increased, including those younger than 12 years of age, or those with generalized epilepsy.</p> <p>Methods</p> <p>We describe the outcome for the first group of nine patients, aged 8-28 years, who had pharmaco-resistant epilepsy and were treated with VNS. During the follow up, we gradually and slowly increased the parameters of the stimulation in order to assess the efficacy of VNS even at parameters which would usually be considered "non-therapeutic", along with possible side effects and changes in quality of life.</p> <p>Results</p> <p>At the last follow, up 1 patient was "seizures free", 3 were "very good responders", 3 were "good responders" and 2 were "non responders". We obtained an initial seizure reduction with low stimulation parameters, the highest current reached being 2.00 mA. This observation supports the possibility that, for younger patients, lower stimulation intensities than those commonly used in clinical practice for adults can be therapeutic. We also wanted to underline the reduction in seizure frequency (~91,7%) and the reduction in seizure duration (> 50%) in the patients affected by drug-resistant absence epilepsy. Adverse effects were mild, tolerable and, in most of cases, easily resolved by adjusting the stimulation parameters. Hoarseness of voice was the most frequent side effect. The improvements in the quality of life are relevant and seem to be independent of the VNS effect in controlling seizures.</p> <p>Conclusions</p> <p>Our small experience seems to confirm the efficacy and safety of VNS in drug resistant partial and generalized epilepsy in developing age groups.</p

Expanding the Clinical Spectrum of UBTF-Related Neurodevelopmental Disorder

Objectives: UBTF1 gene encodes for Upstream Binding Transcription Factor, an essential protein for RNA metabolism. A recurrent de novo variant (c.628G&gt;A; p.Glu210Lys) has recently been associated with a childhood-onset neurodegenerative disorder characterized by motor and language regression, ataxia, dystonia, and acquired microcephaly. In this study, we report the clinical, metabolic, molecular genetics and neuroimaging findings and histologic, histochemical, and electron microscopy studies in muscle samples of 2 patients from unrelated families with a neurodevelopmental disorder. Methods: Data were retrospectively analyzed by medical charts revision. Results: Patient 1, a 16-year-old boy, presented a childhood-onset slowly progressive neurodegenerative disorder mainly affecting language skills, behavior, and motor coordination. Patient 2, a 22-year-old woman, presented with a severe and rapidly progressive disease with dystonic tetra paresis, acquired microcephaly, and severe cognitive deficit complicated by pseudobulbar syndrome characterized by involuntary and uncontrollable outbursts of laughing, dysphagia requiring tube feeding, and nocturnal hypoventilation treated with noninvasive ventilation. Both patients carried the recurrent previously described UBTF1 de novo variant and had signs of mitochondrial dysfunction at muscle biopsy. The metabolic profile of patient 2 also revealed a decrease in CSF biopterin. Discussion: These case reports add new insights to the UBTF1 disease spectrum instrumental to improving the diagnostic rate in neurodevelopmental disorders

Neurodevelopmental Correlates of Brain Magnetic Resonance Imaging Abnormalities in Extremely Low-birth-weight Infants

Objective: To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely low-birth-weight (ELBW) infants over the first 2&nbsp;years. Methods: ELBW infants born from 2009 through 2018 and undergoing brain magnetic resonance imaging (MRI) at TEA were enrolled in this retrospective cohort study. MRI scans were reviewed using a validated quali-quantitative score, including several white and gray matter items. Neurodevelopment was assessed at 6, 12, 18, and 24&nbsp;months using the Griffiths scales. The independent associations between MRI subscores and the trajectories of general and specific neurodevelopmental functions were analyzed by generalized estimating equations. Results: One hundred-nine ELBW infants were included. White matter volume reduction and delayed myelination were associated with worse general development (b = -2.33, P&nbsp;=&nbsp;.040; b = -6.88, P&nbsp;=&nbsp;.049 respectively), social skills (b = -3.13, P&nbsp;=&nbsp;.019; b = -4.79, P&nbsp;=&nbsp;.049), and eye-hand coordination (b = -3.48, P&nbsp;=&nbsp;.009; b = -7.21, P&nbsp;=&nbsp;.045). Cystic white matter lesions were associated with poorer motor outcomes (b = -4.99, P&nbsp;=&nbsp;.027), while white matter signal abnormalities and corpus callosum thinning were associated with worse nonverbal cognitive performances (b = -6.42, P&nbsp;=&nbsp;.010; b = -6.72, P&nbsp;=&nbsp;.021, respectively). Deep gray matter volume reduction correlated with worse developmental trajectories. Conclusions: Distinctive MRI abnormalities correlate with specific later developmental skills. This finding may suggest that TEA brain MRI may assist with neurodevelopmental prediction, counseling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates

Identification of the DNA methylation signature of Mowat-Wilson syndrome

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis

Identification of the DNA methylation signature of Mowat-Wilson syndrome

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis

The Clinical Impact of Methotrexate-Induced Stroke-Like Neurotoxicity in Paediatric Departments: An Italian Multi-Centre Case-Series

IntroductionStroke-like syndrome (SLS) is a rare subacute neurological complication of intrathecal or high-dose (&gt;= 500 mg) Methotrexate (MTX) administration. Its clinical features, evoking acute cerebral ischaemia with fluctuating course symptoms and a possible spontaneous resolution, have elicited interest among the scientific community. However, many issues are still open on the underlying pathogenesis, clinical, and therapeutic management and long-term outcome. Materials and MethodsWe retrospectively analyzed clinical, radiological and laboratory records of all patients diagnosed with SLS between 2011 and 2021 at 4 National referral centers for Pediatric Onco-Hematology. Patients with a latency period that was longer than 3 weeks between the last MTX administration of MTX and SLS onset were excluded from the analysis, as were those with unclear etiologies. We assessed symptom severity using a dedicated arbitrary scoring system. Eleven patients were included in the study. ResultsThe underlying disease was acute lymphoblastic leukemia type B in 10/11 patients, while fibroblastic osteosarcoma was present in a single subject. The median age at diagnosis was 11 years (range 4-34), and 64% of the patients were women. Symptoms occurred after a mean of 9.45 days (+/- 0.75) since the last MTX administration and lasted between 1 and 96 h. Clinical features included hemiplegia and/or cranial nerves palsy, paraesthesia, movement or speech disorders, and seizure. All patients underwent neuroimaging studies (CT and/or MRI) and EEG. The scoring system revealed an average of 4.9 points (+/- 2.3), with a median of 5 points (maximum 20 points). We detected a linear correlation between the severity of the disease and age in male patients. ConclusionsSLS is a rare, well-characterized complication of MTX administration. Despite the small sample, we have been able to confirm some of the previous findings in literature. We also identified a linear correlation between age and severity of the disease, which could improve the future clinical management

Cyclic Vomiting Syndrome in Children

Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset have been also described. The etiopathogenesis is largely unknown, but it is likely to be multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering environmental stimulus are involved. CVS is characterized by acute, stereotyped and recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity and return to baseline health between episodes. A distinction with other differential diagnoses is a challenge for clinicians. Although extensive and invasive investigations should be avoided, baseline testing toward identifying organic causes is recommended in all children with CVS. The management of CVS requires an individually tailored therapy Management of acute phase is mainly based on supportive and symptomatic care. Early intervention with abortive agents during the brief prodromal phase can be used to attempt to terminate the attack. During the interictal period, non-pharmacologic measures as lifestyle changes and the use of reassurance and anticipatory guidance seem to be effective as a preventive treatment. The indication for prophylactic pharmacotherapy depends on attack intensity and severity, the impairment of the QoL and if attack treatments are ineffective or cause side effects. When children remain refractory to acute or prophylactic treatment, or the episode differs from previous ones, the clinician should consider the possibility of an underlying disease and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities and specific sub-phenotype. This review was developed by a joint task force of the Italian Society of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society of Pediatric Neurology (SINP) to identify relevant current issues and to propose future research directions on pediatric CV

A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism

Funding: Royal Society grant RG110387 (S.P.)Loss-of-function mutations in the SPART gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. SPART encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the SPART gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca2+ homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in SPART leads to a profound bioenergetic imbalance.PreprintPeer reviewe