Short- vs long-term assessment of heart rate variability: Clinical significance in Dravet Syndrome.

PURPOSE: Heart rate variability (HRV) is a promising prognostic biomarker in Dravet Syndrome (DS), but different studies are not always comparable, limiting its clinical application. In fact, multiple HRV parameters, analyzed over different timescales and in different states are reported. The aim of this study was to assess which HRV parameter is more reproducible and clinically significant, analyzing differences between wake and sleep. METHOD: Patients with DS, with available 24 h-ECG Holter-derived HRV, were screened to evaluate if they had EEG-derived ECG traces available within one month before/after the Holter. A 5-minute period in the awake and sleep state were analyzed and correlated with the 24 h-HRV. Several relevant clinical features such as age, a recent history of status epilepticus (SE), and frequent generalized tonic-clonic seizures (GTCS) were correlated to HRV parameters with multiple linear regression models. RESULTS: Thirty-oneawake recordings and 22 sleep recordings were included. HF was the parameter with the highest correlation in awake (Rho 0.745, p < 0.001) and in sleep (Rho 0.727, p < 0.001). Age was a significant factor in simple models for most of the parameters except RMSSD. A recent history of SE was associated with a significant reduction of HRV, both in simple and multiple regressions for all parameters except for awake LF and for sleep RMSSD and PNN50. Frequent GTCS were associated with a significant decrease in sleep RMSSD, HF, and LF, also when correcting for the effect of age and history of SE. When compared pairwise, a significant increase in sleep was seen for HF (median + 24.45 ms2, IQR -7.51/+172.18 ms2, p = 0.036; increase in 15/22 patients). CONCLUSION: A moderate degree of correlation between long- and short-term HRV was seen both in sleep and in awake, and a strong correlation for awake HF. HF, both in awake and sleep, was significantly associated with high seizure burden, including SE and frequent GTCS.

Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome.

BACKGROUND: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1. It was mainly described in children. METHODS: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. RESULTS: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1. All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. CONCLUSIONS: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset.

BACKGROUND: JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC). CASE REPORT: Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene. CONCLUSION: Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.

BACKGROUND: Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases. CASE PRESENTATION: In the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father. CONCLUSIONS: Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

Wernicke Encephalopathy Caused by Avoidance-Restrictive Food Intake Disorder in a Child: A Case-Based Review.

BACKGROUND: Wernicke encephalopathy (WE) is an acute and potentially fatal neuropsychiatric disorder resulting from thiamine deficiency: its etiology and clinical presentation can be heterogeneous and arduously recognized, especially in children and adolescents. CASE PRESENTATION: An 8-year-old girl arrived to the emergency room with ataxic gait, nystagmus, and mental confusion after a 10-day history of repeated severe vomiting; her recent clinical history was characterized by restricted nutrition due to a choking phobia, which caused substantial weight loss. Brain magnetic resonance imaging revealed a bilaterally increased T2 signal in the medial areas of the thalami and cerebral periaqueductal region. Diagnosis of WE based on clinical and neuroradiological findings was established and confirmed after labwork showing low serum thiamine. Following psychiatric evaluation, the patient was also diagnosed with avoidance-restrictive food intake disorder (ARFID), which required starting cognitive behavioral therapy and introducing aripiprazole. The patient displayed improvement of the radiological findings after one month and complete resolution of her neurological symptoms and signs. CONCLUSIONS: Eating disorders like ARFID might forerun acute signs of WE; this possibility should be considered even in pediatric patients, especially when atypical neurological pictures or feeding issues come out.

Childhood Trauma and Self-harm in Youths with Bipolar Disorders.

BACKGROUND: Bipolar disorders (BD) in youth are associated with a high risk of self-harm behaviors. Childhood trauma (CT) is a relevant environmental stressor that is related to both BD diagnosis and self-harm in adulthood. It is not yet established whether CT may impact self-harm risk in youth. Therefore, the aim of this study was to investigate the distribution patterns of CT in youth BD with and without self-harm. METHODS: We assessed 273 participants (aged 13-25 years), 96 youths with BD according to DSM-5 criteria and 177 healthy controls (HC). History of CT was obtained using the Childhood Trauma Questionnaire (CTQ). The association between CT and self-harm was tested using multivariate statistical models. RESULTS: Over 45% of participants with BD reported lifetime self-harm. The BD Self-harm group reported more emotional abuse, emotional neglect, sexual abuse, and physical abuse than HC. The BD No-Self-harm group reported more emotional abuse than HC. The BD Self-harm group reported more emotional abuse and neglect than the BD No-Self-harm group. The BD Self-harm group also reported separated parents, hospitalizations, smoking, use of antiepileptics, antipsychotics and lithium. Emotional abuse was an independent predictor of self-harm in youths with BD. CONCLUSION: Findings support the importance of assessing CT, in particular emotional abuse, in youth with BD at risk for self-harm.

Status epilepticus in BRAF-related cardio-facio-cutaneous syndrome: Focus on neuroimaging clues to physiopathology.

OBJECTIVE: Cardio-facio-cutaneous syndrome (CFC) is a genetic disorder due to variants affecting genes coding key proteins of the Ras/MAPK signaling pathway. Among the different features of CFC, neurological involvement, including cerebral malformations and epilepsy, represents a common and clinically relevant aspect. Status epilepticus (SE) is a recurrent feature, especially in a specific subgroup of CFC patients with developmental and epileptic encephalopathy (DEE) and history of severe pharmacoresistant epilepsy. Here we dissect the features of SE in CFC patients with a particular focus on longitudinal magnetic resonance imaging (MRI) findings to identify clinical-radiological patterns and discuss the underlying physiopathology. METHODS: We retrospectively analyzed clinical, electroencephalogram (EEG), and MRI data collected in a single center from a cohort of 23 patients with CFC carrying pathogenic BRAF variants who experienced SE during a 5-year period. RESULTS: Seven episodes of SE were documented in 5 CFC patients who underwent EEG and MRI at baseline. MRI was performed during SE/within 72 hours from SE termination in 5/7 events. Acute/early post-ictal MRI findings showed heterogenous abnormalities: restricted diffusion in 2/7, focal area of pcASL perfusion change in 2/7, focal cortical T2/FLAIR hyperintensity in 2/7. Follow-up images were available for 4/7 SE. No acute changes were detected in 2/7 (MRI performed 4 days after SE termination). SIGNIFICANCE: Acute focal neuroimaging changes concomitant with ictal EEG focus were present in 5/7 episodes, though with different findings. The heterogeneous patterns suggest different contributing factors, possibly including the presence of focal cortical malformations and autoinflammation. When cytotoxic edema is revealed by MRI, it can be followed by permanent structural damage, as already observed in other genetic conditions. A better understanding of the physiopathology will provide access to targeted treatments allowing to prevent long-term adverse neurological outcome. PLAIN LANGUAGE SUMMARY: Cardio-facio-cutaneous syndrome is a genetic disorder that often causes prolonged seizures known as status epilepticus. This study has a focus on electroclinical and neuroimaging patterns in patients with cardio-facio-cutaneous syndrome. During these status epilepticus episodes, we found different abnormal brain imaging patterns in patients, indicating various causes like brain malformations and inflammation. Understanding these patterns could help doctors find specific treatments, protecting cardio-facio-cutaneous syndrome patients from long-term brain damage.

Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in MFSD8.

Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in MFSD8 in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including EXOSC9, SPATA5 and MFSD8. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted MFSD8 sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.

Specific Learning Disorders (SLD) and Behavior Impairment: Comorbidity or Specific Profile?

INTRODUCTION: Specific Learning Disorder (SLD) is a neurodevelopmental disorder characterized by difficulties in perceiving and processing verbal and non-verbal information. It is usually accompanied by impaired academic skills leading to school dropout and emotional disturbances, resulting in significant distress and behavioral problems. METHODS: A cognitive, academic, and emotional-behavioral assessment was performed at T0 and T1 in children and adolescents with SLD. Participants received psychotherapy and speech therapy treatment from T0 to T1. RESULTS: In SLD, the most compromised cognitive functions were working memory and writing skills. An impact on academic abilities was found. Children and adolescents with SLD experience greater anxiety and depression levels compared to their control peers. CONCLUSIONS: SLD may adversely influence psychological well-being. To counteract such a consequence, more specific cognitive and academic skill-oriented strategies should be taken into consideration.

Visual Function in Children with GNAO1-Related Encephalopathy.

BACKGROUND: GNAO1-related encephalopathies include a broad spectrum of developmental disorders caused by de novo heterozygous mutations in the GNAO1 gene, encoding the G (o) subunit α of G-proteins. These conditions are characterized by epilepsy, movement disorders and developmental impairment, in combination or as isolated features. OBJECTIVE: This study aimed at describing the profile of neurovisual competences in children with GNAO1 deficiency to better characterize the phenotype of the disease spectrum. METHODS: Four male and three female patients with confirmed genetic diagnosis underwent neurological examination, visual function assessment, and neurovisual and ophthalmological evaluation. Present clinical history of epilepsy and movement disorders, and neuroimaging findings were also evaluated. RESULTS: The assessment revealed two trends in visual development. Some aspects of visual function, such as discrimination and perception of distance, depth and volume, appeared to be impaired at all ages, with no sign of improvement. Other aspects, reliant on temporal lobe competences (ventral stream) and more related to object-face exploration, recognition and environmental control, appeared to be preserved and improved with age. SIGNIFICANCE: Visual function is often impaired, with patterns of visual impairment affecting the ventral stream less.

A systematic review on gender dysphoria in adolescents and young adults: focus on suicidal and self-harming ideation and behaviours.

INTRODUCTION: Gender dysphoria (GD) is characterized by the incongruence between one's experienced and expressed gender and assigned-sex-at-birth; it is associated with clinically significant distress. In recent years, the number of young patients diagnosed with GD has increased considerably. Recent studies reported that GD adolescents present behavioural and emotional problems and internalizing problems. Furthermore, this population shows a prevalence of psychiatric symptoms, like depression and anxiety. Several studies showed high rates of suicidal and non-suicidal self-injurious thoughts and behaviour in GD adolescents. To increase understanding of overall mental health status and potential risks of young people with GD, this systematic review focused on risk of suicide and self-harm gestures. METHODS: We followed the PRISMA 2020 statement, collecting empirical studies from four electronic databases, i.e., PubMed, Scopus, PsycINFO, and Web of Science. RESULTS: Twenty-one studies on GD and gender nonconforming identity, suicidality, and self-harm in adolescents and young adults met inclusion criteria. Results showed that GD adolescents have more suicidal ideation, life-threatening behaviour, self-injurious thoughts or self-harm than their cisgender peers. Assessment methods were heterogeneous. CONCLUSION: A standardised assessment is needed. Understanding the mental health status of transgender young people could help develop and provide effective clinical pathways and interventions.

Metabolic Profile of Patients with Smith-Magenis Syndrome: An Observational Study with Literature Review.

Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9-32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS 'deleted' patients may show a dyslipidemic pattern, while SMS 'mutated' patients are more likely to develop early-onset obesity along with hyperinsulinism.

Outpatient care for adolescents' and young adults' mental health: promoting self- and others' understanding through a metacognitive interpersonal therapy-informed psychological intervention.

Introduction: Psychological distress may result in impairment and difficulty understanding oneself and others. Thus, addressing metacognitive issues in psychotherapy may improve psychopathology in adolescents and young adults (AYAs). We aimed to compare metacognitive interpersonal therapy (MIT)-informed psychotherapy with other treatment-as-usual (TAU) therapies. Methods: We administered the Global Assessment of Functioning (GAF) scale, the Clinical Global Impressions-Severity (CGI-S) scale, and the Brief Psychiatric Rating Scale (BPRS) at baseline (BL) and at treatment termination (the endpoint was at 6 months and any last results obtained before that term were carried forward in analyzes). Patients received concomitant psychiatric and psychological treatment. Results: Sixty AYAs were involved in the study. There was a significant reduction in symptomatology after the intervention. Twelve patients (17%) dropped out; treatment adherence was 83%. In the MIT group, 2 patients dropped out (11%), and in the TAU group, 9 patients dropped out (19%). All scales showed a significant reduction in symptoms between baseline (BL) and the 6-month endpoint: GAF (χ2 = 6.61, p < 0.001), BPRS (χ2 = 6.77, p < 0.001), and CGI (χ2 = 7.20, p < 0.001). There was a greater efficacy for the MIT group in terms of symptom reduction on the BPRS (t = 2.31; p < 0.05). Conclusion: The study confirmed the efficacy of early and integrated care in adolescence and suggested greater symptom reduction for a psychotherapeutic intervention focused on stimulating mentalization skills. The study indicates the usefulness of this type of approach in the treatment of adolescent psychopathology. Due to the small sample size, the results need replication.

Hereditary Hyperekplexia: A New Family and a Systematic Review of GLRA1 Gene-Related Phenotypes.

Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms.

Fighting autoinflammation in FIRES: The role of interleukins and early immunomodulation.

Febrile infection-related epilepsy syndrome (FIRES) is a challenging condition with unfavorable outcome in most cases. Preliminary evidence suggests that some interleukins, in particular IL-1 Receptor Antagonist (IL-1RA), could be elevated due to a functional deficiency of anti-inflammatory pathways. Therefore, treatment strategies acting on innate immunity could represent a targeted treatment. We describe the case of an 11-year-old child with super-refractory status epilepticus (SE), lasting more than two months. After being treated aggressively with antiseizure medications, anesthetics and empiric treatment for autoimmune encephalitis without success, she responded to anakinra and ketogenic diet. Escalation of the therapy was supported by the finding of a very high serum level of IL-1RA. This immunomodulatory approach allowed to discharge the child from intensive care 48 days after the SE onset. After more than one year follow-up the patient has moderate intellectual disability but with good language skills; she is seizure free and without motor deficits. This case suggests that serum IL-1RA serum levels may help to support treatment escalation. Moreover, anakinra and ketogenic diet represent encouraging immunomodulatory strategies which deserve further studies and could potentially have a synergistic effect. Finally, structured neuropsychological testing is an important outcome measure that will help to define the effectiveness of different treatment strategies.

Heart rate variability alterations in Dravet Syndrome: The role of status epilepticus and a possible association with mortality risk.

PURPOSE: Preliminary data suggest that patients with Dravet Syndrome (DS) have a reduced heart rate variability (HRV). This seems particularly evident in patients who experienced sudden unexpected death in epilepsy (SUDEP). This study aims at confirming these findings in a larger cohort and at defining clinical, genetic or electroencephalographic predictors of HRV impairment in DS patients. METHODS: DS patients followed at our Institution performed a 24h-ECG Holter to derive HRV parameters. We used as control population patients with epilepsy (PWEs) and healthy controls (HCs). In DS patients, we assessed the impact of different clinical, neurophysiological and genetic features on HRV alterations through multiple linear regression. After a mean follow-up of 7.4 ± 3.2 years since the HRV assessment, all DS patients were contacted to record death or life-threatening events. RESULTS: 56 DS patients had a significantly reduced HRV compared to both HCs and PWEs. A recent history of status epilepticus (SE) was the only significant predictor of lower HRV in the multivariate analysis. At follow-up, only one patient died; her HRV was lower than that of all the controls and was in the low range for DS patients. CONCLUSION: We describe for the first time an association between SE and HRV alterations in DS. Further studies on other SCN1A-related phenotypes and other epilepsies with frequent SE will help clarify this finding. Compared to the literature, our cohort showed better HRV and lower mortality. Although limited, this observation reinforces the role of HRV as a biomarker for mortality risk in DS.

Cortical Visual Impairment in CDKL5 Deficiency Disorder.

BACKGROUND: CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene cyclin-dependent kinase-like 5. Cerebral visual impairment (CVI) is frequent in patients with CDD. In addition to being recognized as a specific feature of the pathology, it has been suggested that visual impairment may correlate with neurodevelopmental outcome and epilepsy severity, but no systematic behavioral visual assessment has been performed. The aim of our study was to evaluate clinical and electrophysiological profile of CVI in patients with CDD, to correlate various aspects of visual function to neurodevelopmental and epileptic features. METHODS: The study included all patients with CDD from the National Pathology Registry. All patients underwent neurological examination, a disease-specific functional assessment, structured clinical evaluation of visual functions, including pattern reversal visual evoked potential (VEP), and a detailed monitoring of epileptic features, including video-EEG. RESULTS: All the 11 patients recorded in the CDKL5 national registry, 10 females and one male, age range of 1.5 to 24 years (mean 9, SD 7.7, median 6.5), were enrolled. Visual function is impaired in all patients; in particular, visual fields, visual acuity, contrast sensitivity, and stereopsis were consistently abnormal whereas other aspects, such as fixing and tracking, were relatively preserved. Pattern reversal VEP was abnormal in nearly 80% of our patients. No correlation was found among CVI severity, age, level of psychomotor development, EEG abnormalities, and pathology stages even if an overall less abnormal EEG pattern was more often associated with better visual results. CONCLUSION: In conclusion, CVI can be considered as a major feature of CDD with a diffuse involvement in several behavioral and electrophysiological aspects. Larger cohorts will help to better clarify the possible prognostic role of EEG severity in predicting both visual and developmental abnormalities.

Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations.

OBJECTIVE: Cardiofaciocutaneous syndrome (CFCS) is a rare developmental disorder caused by upregulated signaling through the RAS-mitogen-activated protein kinase (MAPK) pathway, mostly resulting from de novo activating BRAF mutations. Children with CFCS are prone to epilepsy, which is a major life-threatening complication. The aim of our study was to define the natural history of epilepsy in this syndrome and exploring genotype-phenotype correlations. METHODS: We performed an observational study, including 34 patients with molecularly confirmed diagnosis (11 males, mean age: 15.8 years). The mean follow-up period was 9.2 years. For all patients, we performed neurological examination, cognitive assessment when possible, neuroimaging, electrophysiological assessment and systematic assessment of epilepsy features. Correlation analyses were performed, taking into account gender, age of seizure onset, EEG features, degree of cognitive deficits, type of mutation, presence of non-epileptic paroxysmal events and neuroimaging features. RESULTS: Epilepsy was documented in 64% of cases, a higher prevalence compared to previous reports. Patients were classified into three groups based on their electroclinical features, long-term outcome and response to therapy. A genotype-phenotype correlation linking the presence/severity of epilepsy to the nature of the structural/functional consequences of mutations was observed, providing a stratification based on genotype to improve the clinical management of these patients.

Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case.

The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1-26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.