A novel mutation in COL4A1 gene: a possible cause of early postnatal cerebrovascular events.

COL4A1 is located in humans on chromosome13q34 and it encodes the alpha 1 chain of type IV collagen, a component of basal membrane. It is expressed mainly in the brain, muscles, kidneys and eyes. Different COL4A1 mutations have been reported in many patients who present a very wide spectrum of clinical symptoms. They typically show a multisystemic phenotype. Here we report on the case of a patient carrying a novel de novo splicing mutation of COL4A1 associated with a distinctive clinical picture characterized by onset in infancy and an unusual evolution of the neuroradiological features. At three months of age, the child was diagnosed with a congenital cataract, while his brain MRI was normal. Over the following years, the patient developed focal epilepsy, mild diplegia, asymptomatic microhematuria, raised creatine kinase levels, MRI white matter abnormalities and brain calcification on CT. During the neuroradiological follow-up the extension and intensity of the brain lesions progressively decreased. The significance of a second variant in COL4A1 carried by the child and inherited from his father remains to be clarified. In conclusion, our patient shows new aspects of this collagenopathy and possibly a COL4A1 compound heterozygosity.

Septo-optic dysplasia in childhood: the neurological, cognitive and neuro-ophthalmological perspective.

AIM: We set out to describe 17 patients with septo-optic dysplasia (SOD), focusing on the little-explored neurological, cognitive, and neuro-ophthalmological components. A further aim was to identify possible clinical correlations and phenotypic characteristics within the diagnostic spectrum. METHOD: We collected clinical-instrumental data (from the history, general and neurological examination, developmental assessment, and neuro-ophthalmological, neuroradiological, neurophysiological, and endocrinological evaluations) on nine males and eight females (mean age 34.4mo, SD 31.6; range 4mo-9y 6mo) diagnosed with SOD who were referred to our Centre of Child Neuro-ophthalmology between 1999 and 2010. RESULTS: We observed a heterogeneous clinical spectrum characterized by nervous system, visual, and endocrine dysfunctions; optic nerve involvement was present in all 17 children, midline brain defects in 14, and cortical developmental malformations in seven. Developmental/cognitive delay and relational and communication difficulties were observed in eight and seven children, respectively, and reduced visual acuity and oculomotor dysfunction were observed in all. Pituitary hormone deficiencies were present in nine children. INTERPRETATION: Nervous system involvement emerged as a key feature of SOD. As part of a holistic approach to the disease, particular attention should be paid to this aspect. The emergence of new clinical correlations and correlations between clinical features and three SOD subtypes opens the way for better clarification of this disease and, therefore, more targeted diagnosis, follow-up, and care of affected children.

Epileptic Phenotype and Cannabidiol Efficacy in a Williams-Beuren Syndrome Patient With Atypical Deletion: A Case Report.

Epilepsy is a rare clinical manifestation in Williams-Beuren syndrome patients. However, some studies report the presence of infantile spasms and epilepsy in patients carrying larger deletions. Herein, we describe a 13-year-old female affected by Williams-Beuren syndrome and pharmacoresistant epilepsy reporting a de novo large heterozygous 7q11.21q21 deletion (19.4 Mb) also including the YWHAG gene. Studies indicate that cannabidiol is effective as adjunctive therapy for seizures associated with tuberous sclerosis complex, and it is under investigation also in focal cortical dysplasia. When treated with cannabidiol, our patient showed a significant reduction in seizure frequency and intensity, and improved motor and social skills. We hypothesized that CBD could exert a gene/disease-specific effect.

Patterns of Presentation of SARS-CoV-2 Infection in Children. Experience at the Italian Epicentre of the Pandemic.

Background: COVID-19, a disease caused by the new coronavirus SARS-CoV-2, spread worldwide, and Bergamo was one of the most affected areas in Europe. Following the first outbreak, more than half of the population of the Bergamo province had been infected. We aimed to describe the patients admitted to our unit shortly after the first outbreak. Methods: we retrospectively reviewed the notes of all pediatric patients diagnosed with COVID-19. We enrolled patients with positive swabs or serology and classified them based on the pattern and the timing of presentation after the first outbreak. This setting was considered a reliable reflection of the consequences of unmitigated SARS-CoV-2 circulation. Results: We diagnosed 35 patients over a 3-month period and we identified six patterns presenting in two temporal phases: Early phase, Group 1 (median of 20 days from epidemic start, IQR: 15-27): neonatal sepsis (n.7), pneumonia (n.5), flu-like symptoms (n.2). Late phase, Group 2 (59:51-66 days, p < 0.001): MIS-C (n.18), neurological manifestations (n.3). Group 1 differed from Group 2 for younger age (1 vs. 8 years, p = 0.02), lower C-reactive protein (0.9 vs. 16.6 mg/dl, p = 0.008), procalcitonin (0.16 vs. 7.9 ng/ml, p = 0.008) and neutrophil count (3,765 vs. 6,780/µl, p = 0.006), higher rate of positive swabs (14/14 vs. 9/21, p < 0.001), higher lymphocyte count (3,000 vs. 930/µl, p = 0.006) and platelet count (323,000 vs. 210,000/µl, p = 0.009). Conclusions: Following an outbreak of unmitigated SARS-CoV-2 diffusion, infected children may present with clinical patterns suggesting two temporal clusters, the first characterized by markers of direct viral injury, the second suggesting an immune-mediated disease.

Neurodevelopmental outcome of preterm very low birth weight infants admitted to an Italian tertiary center over an 11-year period.

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome.

A Different Brain: Anomalies of Functional and Structural Connections in Williams Syndrome.

We describe the results of a functional and structural brain connectivity analysis comparing a homogeneous group of 10 young adults with Williams Syndrome (WS; 3 females, age 20. 7 ± 3.7 years, age range 17.4-28.7 years) to a group of 18 controls of similar age (3 females, age 23.9 ± 4.4 years, age range 16.8-30.2), with the aim to increase knowledge of the structure - function relationship in WS. Subjects underwent a 3T brain MRI exam including anatomical, functional (resting state) and structural (diffusion MRI) sequences. We found convergent anomalies in structural and functional connectivity in the WS group. Altered Fractional Anisotropy (FA) values in parieto-occipital regions were associated with increased connectivity in the antero-posterior pathways linking parieto-occipital with frontal regions. The analysis of resting state data showed altered functional connectivity in the WS group in main brain networks (default mode, executive control and dorsal attention, sensori-motor, fronto-parietal, ventral stream). The combined analysis of functional and structural connectivity displayed a different pattern in the two groups: in controls the highest agreement was found in frontal and visual areas, whereas in WS patients in posterior regions (parieto-occipital and temporal areas). These preliminary findings may reflect an altered "wiring" of the brain in WS, which can be driven by hyper-connectivity of the posterior regions as opposed to disrupted connectivity in the anterior areas, supporting the hypothesis that a different brain (organization) could be associated with a different (organization of) behavior in Williams Syndrome.

Encephalopathies with intracranial calcification in children: clinical and genetic characterization.

BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. CONCLUSIONS: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

"Acquired" Dandy-Walker malformation and cerebellar hemorrhage: Usefulness of serial MRI.

BACKGROUND/PURPOSE: Neuroimaging plays a fundamental role in the diagnosis of Dandy Walker malformation (DWM), a posterior fossa anomaly that is usually associated with genetic abnormalities, but may rarely be ascribed to acquired causes. Here, we report the clinical history and neuroimaging studies of a child with a complex cardiac malformation, developmental delay, and oculomotor anomalies whose neuroimaging findings were consistent with an acquired form of DWM. METHODS/RESULTS: Fetal MRI at gestational weeks 27 and 31 showed cerebellar and vermis hypoplasia and fourth ventricle enlargement, together with hemosiderin deposits on the cerebellar hemispheric surface, but without significant vermian rotation. Postnatal MRIs at 5 days and 13 months revealed progressive counter-clockwise rotation of the hypoplastic cerebellar vermis with cystic dilation of the fourth ventricle, eventually leading to a full-blown DWM. CONCLUSION: This case strengthens the opinion that DWM is a heterogeneous condition, and may support the hypothesis that acquired meningeal abnormalities in the form of cortico-pial hemosiderosis may play a role in the development of DWM. This case also demonstrates that serial neuroimaging plays a key role in the correct diagnosis of posterior fossa malformations, whose prognosis is difficult to establish on second trimester fetal MRI and requires longer clinical follow-up.