Intronic Variant in CNTNAP2 Gene in a Boy With Remarkable Conduct Disorder, Minor Facial Features, Mild Intellectual Disability, and Seizures

Introduction: Mutations in the contactin-associated protein-like 2 (CNTNAP2) gene (MIM#604569) encoding for CASPR2, a cell adhesion protein of the neurexin family, are known to be associated with autism, intellectual disability, and other neuropsychiatric disorders. A set of intronic deletions of CNTNAP2 gene has also been suggested to have a causative role in individuals with a wide phenotypic spectrum, including Pitt-Hopkins syndrome, cortical dysplasia-focal epilepsy syndrome, Tourette syndrome, language dysfunction, and abnormal behavioral manifestations. Case presentation: A 10-years-old boy was referred to the hospital with mild intellectual disability and language impairment. Moreover, the child exhibited minor facial features, epileptic seizures, and notable behavioral abnormalities including impulsivity, aggressivity, and hyperactivity suggestive of the diagnosis of disruptive, impulse-control and conduct disorder (CD). Array comparative genomic hybridization (CGH) revealed a copy number variant (CNV) deletion in the first intron of CNTNAP2 gene inherited from a healthy father. Conclusions: A comprehensive description of the phenotypic features of the child is provided, revealing a distinct and remarkable alteration of social behavior not previously reported in individuals affected by disorders related to CNTNAP2 gene disruptions. A possible causative link between the deletion of a non-coding regulatory region and the symptoms presented by the boy has been advanced

Chromosome 15q BP4-BP5 Deletion in a Girl with Nocturnal Frontal Lobe Epilepsy, Migraine, Circumscribed Hypertrichosis, and Language Impairment

The 15q13.3 microdeletion (microdel15q13.3) syndrome (OMIM 612001) has been reported in healthy subjects as well as in individuals with a wide spectrum of clinical manifestations ranging from mild to severe neurological disorders, including developmental delay/intellectual disability, autism spectrum disorder, schizophrenia, epilepsy, behavioral problems and speech dysfunction. This study explored the link between this genomic rearrangement and nocturnal frontal lobe epilepsy (NFLE), which could improve the clinical interpretation. A clinical and genomic investigation was carried out on an 8-year-girl with a de novo deletion flanking the breakpoints (BPs) 4 and 5 of 15q13.3 detected by array comparative genomic hybridization analysis, affected by NFLE, migraine with aura, minor facial features, mild cognitive and language impairment, and circumscribed hypertrichosis. Literature survey of clinical studies was included. Nine years follow-up have displayed a benign course of the epileptic disorder with a progressive reduction and disappearance of the epileptic seizures, mild improvement of cognitive and language skills, partial cutaneous hypertrichosis regression, but stable ongoing of migraine episodes. A likely relationship between the BP4-BP5 deletion and NFLE with other symptoms presented by the girl is discussed together with a review of the literature on phenotypic features in microdel15q13.3

Need for palliative care from birth to infancy in pediatric patients with neurological diseases

Background Palliative care is a comprehensive treatment approach that guarantees comfort for pediatric patients and their families from diagnosis to death. The techniques used for neurological patients in the field of palliative care can enhance the quality of care provided to patients with neurological disorders and support their families. Purpose This study aimed to analyze the palliative care protocols in use in our department, describe the palliative course in the clinical setting, and propose the implementation of hospital palliative care for long-term prognosis of patients with neurological diseases. Methods This retrospective observational study examined the application of palliative care from birth to early infancy in neurological patients. We studied 34 newborns with diseases affecting the nervous system impairing prognosis. The study was conducted from 2016 to 2020 at the Neonatology Intensive Care Unit and the Pediatric Unit of the San Marco University Hospital in Catania, Sicily, Italy. Results Despite current legislation in Italy, no palliative care network has been activated to meet the needs of the population. In our center, given the vast number of patients with neurological conditions requiring palliative care, we should activate a straightforward departmental unit for neurologic pediatric palliative care. Conclusion The establishment of specialized reference centers that manage significant neurological illnesses is due to neuroscience research progress in recent decades. Integration with specialized palliative care is sparse but now seems essential

A new route to polyoxygenate C and D rings of steroids by oxidation of a D8,14-diene steroid with the methyltrioxorhenium-H2O2-urea system

In order to find new ways of introducing oxygenated functions in the 15-, 9- and 11-position on steroid rings and at the same time test the reactivity of a conjugated diene steroid toward methyltrioxorhenium (MTO)-catalyzed oxidation with the urea-hydrogen peroxide adduct (UHP), the reactions of 5α-cholesta-8,14-dien-3β-yl acetate 1 with the MTO-UHP system are performed in aprotic solvents. These oxidations are performed both at 0 °C and 25 °C in CHCl3 or diethyl ether as solvent and in the presence of pyridine ligand. From the reaction of diene 1 in CHCl3 we isolate two new sterols, 9β-hydroxy-15-oxo-5α-cholest-8(14)-en-3β-yl acetate 3 and 9α,11α,15α-trihydroxy- 5α-cholest-8(14)-en-3β-yl acetate 7, while oxidation in Et2O in the presence of pyridine ligand allows us to isolate the new epoxysteroid 9α,11α-epoxy-15α-hydroxy-5α-cholest-8(14)-en- 3β-yl acetate 13. The structure of all new steroids is secured on the basis of chemical evidence and interpretation of spectral data, which include H-H COSY, HMBC and NOESY experiments. These results represent a new and mild method for the functionalization of C and D rings from an 8,14-diene steroid, to give 15-oxygenated sterols, a class of compounds remarkable for their inhibitory action on sterol synthesis in animal cell culture systems

Developmental EEG hallmark or biological artifact? Glossokinetic artifact mimicking anterior slow dysrhythmia in two full term newborns

The aim of this paper is to describe an uncommon physiological EEG artifact in newborns caused by tongue movements (TM), mimicking anterior slow dysrhythmia (ASD). The subjects are two full-term newborns (39 weeks gestational age (GA)), admitted to the Neonatal Intensive Care Unit for respiratory distress. Both underwent polygraphic video-EEG recording in order to better characterize tremor-like movements of all four limbs that appeared 48 hours after birth. Multichannel video-EEG polygraphy was performed using the 10-20 electrode montage modified for neonates. Ninety minutes of EEG was recorded for each subject, capturing different behavioral states. Background EEG activity was normal for both subjects. During active sleep (AS), synchronous and symmetric slow activity was recorded over bifrontal head regions. For subject 1, bursts of monomorphic 2Hz delta waves, with an amplitude between 50-100μV lasting two seconds, were recorded and identified as anterior slow dysrhythmia. For subject 2, polymorphic 1-2Hz delta waves, 50-100μV in amplitude and lasting for 20 seconds, were recorded only during suction. After thorough analysis of simultaneous digital video recording synchronized with the EEG trace, this activity was thought to be compatible with glossokinetic artifact. Interpretation of neonatal EEG can be challenging; the background activity is frequently intermixed with physiological artifacts, such as ocular, muscle and movement artifacts, complicating the interpretation. Even continuous video-recording might not make the diagnosis immediately obvious. Therefore, when a rhythmic monomorphic pattern without evolution in amplitude or frequency is seen, we suggest that tongue movement artifact should be considered

Long-term follow-up and novel genotype-phenotype analysis of monozygotic twins with ATP1A3 mutation in Alternating Hemiplegia of Childhood-2

Alternating Hemiplegia of Childhood (AHC) is a rare disorder characterized by frequent, transient attacks of hemiplegia involving either side of the body or both in association to several other disturbances including dystonic spells, abnormal ocular movements, autonomic manifestations, epileptic seizures and cognitive impairment. The clinical manifestations usually start before the age of 18 months. Two forms of the disorder known as AHC-1 (MIM#104290) and AHC-2 (MIM#614820) depends on mutations in ATP1A2 and ATP1A3 genes respectively, with over 75% of AHC caused by a mutation in the ATP1A3 gene. Herewith, we report serial clinical follow-up data of monozygotic (MZ) twin sisters, who presented in early life bath-induced dystonia, signs of acute encephalopathy at the age of 2 years, hemiplegic spells, and motor dysfunction after the age of 3 years, and in young/adult frequent episodes of headache with drastic reduction of paroxysmal motor attacks. The molecular analysis revealed a known pathogenic variant p.Asn773Ser (rs606231437) in ATP1A3 gene associated with an unusual and moderate AHC-2 phenotype, with mild cognitive impairment and lack of epilepsy. The aim of this study is to analyze the clinical phases of the MZ twins, and to investigate the novel genotype-phenotype correlation

Pathogenic correlation between mosaic variegated aneuploidy 1 (MVA1) and a novel BUB1B variant: a reappraisal of a severe syndrome.

Funder: Università degli Studi di CataniaBACKGROUND: The BUB 1 mitotic checkpoint serine/threonine kinase B (BUB1B) gene encodes a key protein in the mitotic spindle checkpoint, which acts as a surveillance mechanism, crucial for the maintenance of the correct chromosome number during cell deviation. Mutations of BUB1B gene are linked to mosaic variegated aneuploidy 1 (MVA1) syndrome, a rare autosomal recessive disorder characterized by widespread mosaic aneuploidies, involving different chromosomes and tissues. MVA1 is clinically characterized by intrauterine growth restriction, post-natal growth retardation, and severe neurologic impairment including microcephaly, developmental delay/intellectual disability, epileptic seizures, and generalized hypotonia. Malignancies are also serious sequelae associated with the disorder. We reported on a case of two-year-old Italian girl with MVA1 who shows severe neurologic impairment, microcephaly and epileptic seizures. MATERIALS AND METHODS: Clinical data collection and genetic diagnosis of the patient were assessed. Mutational analysis covers the chromosomal microarray analysis, the gene methylation pattern studied using the methylation-specific multiplex ligation-dependent probe amplification, and the family-based Whole Exome Sequencing (WES). A literature research based on reported cases of MVA and premature chromatid separation was also included. RESULTS: Karyotyping has revealed 12% of mosaics in the patient who carries a novel variant in BUB1B gene (c.2679A > T, p.Arg893Ser) detected by WES. Thirty-one cases of MVA1 including the present report, and four prenatally diagnosed cases with MVA1 were selected and inspected. CONCLUSION: Clinical and genetic findings reported in the girl strongly suggest a new MVA1 genotype-phenotype correlation and lead to a reappraisal of a severe syndrome. Diagnosis and in-depth follow-up provided worthwhile data