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

BACKGROUND: 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.

West syndrome: a comprehensive review.

Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.

Grisel's syndrome caused by Mycoplasma pneumoniae infection: a case report and review of the literature.

BACKGROUND: Grisel's syndrome is a non-traumatic subluxation of the atlantoaxial joints, which is caused by an inflammatory process involving the upper neck. Torticollis, neck pain, and reduced neck mobility are the main clinical signs of presentation. Predisposing factors are trauma, hyperlaxity of the transverse and alar ligaments of the atlantoaxial joints, and surgical interventions carried out in this area. Several viral and bacterial pathogens have been reported as causative events of Grisel's syndrome, including Epstein-Barr virus, Kawasaki disease, Streptococcus pyogenes, Staphylococcus aureus, and other infectious agents. Grisel's syndrome linked to Mycoplasma pneumoniae infection as the trigger has not previously been reported. Mycoplasma pneumoniae is a small prokaryotic microbe and a frequent etiologic factor of respiratory tract infections and, less frequently, of extrapulmonary body organs. The recognition of the Grisel's syndrome is based on clinical and neuroradiological investigations, and early diagnosis and specific treatment are crucial to the successful outcome of the disease. RESULTS: We report the case of an 8-year-old girl with Grisel's syndrome caused by an upper respiratory tract infection due to Mycoplasma pneumoniae. Diagnostic suspicion and treatment of Grisel's syndrome were established quickly by anamnestic and clinical data and confirmed by radiological findings. The girl was immediately treated with specific antibiotic therapy and cervical immobilization, thus preventing the most dangerous complications of the disorder. CONCLUSION: Mycoplasma pneumoniae, among the other infectious agents, may be cause of scute torticollis and Gresel's syndrome.

Pyridoxine Add-On Treatment for the Control of Behavioral Adverse Effects Induced by Levetiracetam in Children: A Case-Control Prospective Study.

BACKGROUND: Few studies on adult and pediatric patients have shown pyridoxine efficacy as additional therapy for those receiving levetiracetam (LEV) to prevent and mitigate behavioral adverse effects (BAEs). OBJECTIVE: The aim of our study was to analyze the safety and efficacy of pyridoxine supplementation in the prevention of LEV adverse effects, including suicidal ideation. METHODS: This randomized, case-control trial included patients receiving LEV as monotherapy treatment. Patients were subdivided into 2 groups, according to whether they were treated with LEV only (group 1) or LEV with supplemental pyridoxine (group 2). RESULTS: In both cohorts, the most frequent BAEs were irritability/aggression followed by depression and confusion. Those patients (92%) who initiated pyridoxine after 1 month of LEV treatment did not need to change or suspend LEV ( P < 0.001), and BAE improved after 9.06 ± 3.05 days of pyridoxine supplementation. None of the patients complained of symptoms of pyridoxine toxicity, and no new adverse effects of LEV off-label were reported. CONCLUSIONS: In our study, we found pyridoxine to be safe and effective in controlling LEV-induced BAEs in children.

Molecular Dynamic Simulations to Determine Individualized Therapy: Tetrabenazine for the GNAO1 Encephalopathy E246K Variant.

INTRODUCTION: GNAO1 encephalopathy is characterized by severe hypotonia, psychomotor retardation, epilepsy, and movement disorders. Genetic variations in GNAO1 have been linked to neurological symptoms including movement disorders like dystonia. The correlation between the E246K mutation in the Gα subunit and aberrant signal transduction of G proteins has been established but no data are reported regarding the efficacy of medical treatment with tetrabenazine. METHODS: Molecular modeling studies were performed to elucidate the molecular mechanisms underlying this mutation. We developed drug efficacy models using molecular dynamic simulations that replicated the behavior of wild-type and mutated proteins in the presence or absence of ligands. RESULTS AND DISCUSSION: We demonstrated that the absence of the mutation leads to normal signal transduction upon receptor activation by the endogenous ligand, but not in the presence of tetrabenazine. In contrast, the presence of the mutation resulted in abnormal signal transduction in the presence of the endogenous ligand, which was corrected by the drug tetrabenazine. Tetrabenazine was identified as a promising therapeutic option for pediatric patients suffering from encephalopathy due to an E246K mutation in the GNAO1 gene validated through molecular dynamics. This is a potential first example of the use of this technique in a rare neurological pediatric disease.

PYRIDOXINE-dependent epilepsy (PDE): An observational study of neonatal cases on the role of pyridoxine in patients treated with standard anti-seizure medications.

BACKGROUND: The main objective of this study was to evaluate the neurological consequences of delayed pyridoxine administration in patients diagnosed with Pyridoxin Dependent Epilepsies (PDE). MATERIALS AND METHODS: We reviewed 29 articles, comprising 52 genetically diagnosed PDE cases, ensuring data homogeneity. Three additional cases were included from the General Pediatric Operative Unit of San Marco Hospital. Data collection considered factors like age at the first seizure's onset, EEG reports, genetic analyses, and more. Based on the response to first-line antiseizure medications, patients were categorized into four distinct groups. Follow-up evaluations employed various scales to ascertain neurological, cognitive, and psychomotor developments. RESULTS: Our study includes 55 patients (28 males and 27 females), among whom 15 were excluded for the lack of follow-up data. 21 patients were categorized as "Responder with Relapse", 11 as "Resistant", 6 as "Pyridoxine First Approach", and 2 as "Responders". The neurological outcome revealed 37,5 % with no neurological effects, 37,5 % showed complications in two developmental areas, 15 % in one, and 10 % in all areas. The statistical analysis highlighted a positive correlation between the time elapsed from the administration of pyridoxine after the first seizure and worse neurological outcomes. On the other hand, a significant association was found between an extended latency period (that is, the time that elapsed between the onset of the first seizure and its recurrence) and worse neurological outcomes in patients who received an unfavorable score on the neurological evaluation noted in a subsequent follow-up. CONCLUSIONS: The study highlights the importance of early recognition and intervention in PDE. Existing medical protocols frequently overlook the timely diagnosis of PDE. Immediate administration of pyridoxine, guided by a swift diagnosis in the presence of typical symptoms, might improve long-term neurological outcomes, and further studies should evaluate the outcome of PDE neonates promptly treated with Pyridoxine.

The Use of Midazolam as an Antiseizure Medication in Neonatal Seizures: Single Center Experience and Literature Review.

BACKGROUND: Existing therapeutic alternatives for neonatal crises have expanded in recent decades, but no consensus has been reached on protocols based on neonatal seizures. In particular, little is known about the use of midazolam in newborns. AIM: The aim of our study is to evaluate the response to midazolam, the appearance of side effects, and their impact on therapeutic decisions. METHODS: This is a STROBE-conformed retrospective observational study of 10 patients with neonatal seizures unresponsive to common antiseizure drugs, admitted to San Marco University Hospital's neonatal intensive care (Catania, Italy) from September 2015 to October 2022. In our database search, 36 newborns were treated with midazolam, but only ten children met the selection criteria for this study. RESULTS: Response was assessed both clinically and electrographic. Only 4 patients at the end of the treatment showed a complete electroclinical response; they were full-term infants with a postnatal age greater than 7 days. Non-responders and partial responders are all premature (4/10) or full-term neonates who started therapy in the first days of life (<7th day) (2/10). CONCLUSION: Neonatal seizures in preterm show a lower response rate to midazolam than seizures in full-term infants, with poorer prognosis. Liver and renal function and central nervous system development are incomplete in premature infants and the first days of life. In this study, we show that midazolam, a short-acting benzodiazepine, appears to be most effective in full-term infants and after 7 days of life.

A Young Boy with 21q21.1 Microdeletion Showing Speech Delay, Spastic Diplegia, and MRI Abnormalities: Original Case Report.

Chromosome 21q deletion syndrome is a rare disorder affecting the long arm of chromosome 21 and manifesting with wide phenotypic features depending on the size and position of the deleted region. In the syndrome, three distinct deleted regions have been distinguished: region 1, from the centromere to approximately 31.2 Mb (21q11.2-q22.11); region 2, from 31.2 to 36 Mb (21q22.11-q22.12); and region 3, from 36 to 37.5 Mb to the telomere (21q22.12-q22.3). The clinical features are highly variable manifesting with mild, poorly recognizable signs or with severe symptoms including craniofacial dysmorphism, growth failure, developmental delay, behavioral/affective abnormalities, and systemic malformations. We report here the case of a young boy with speech delay, mild spastic diplegia, and brain anomalies on magnetic resonance imaging (MRI). The genetic analysis displayed a microdeletion of the long arm of chromosome 21 approximately extending up to 1.08 Mb. Clinical presentation of the patient and cases of 21q21 deletion reported by the literature are discussed.

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.

Impressive efficacy of the ketogenic diet in a KCNQ2 encephalopathy infant: a case report and exhaustive literature review.

Background: KCNQ2 encephalopathy is characterized by neonatal-onset epilepsy and developmental impairment, due to "de novo" KCNQ2 pathogenic variants. According to literature data, sodium channel blocking agents appear to be the best treatment options for the disease. Reports describing the use of ketogenic diet (KD) in the KCNQ2 pediatric population are limited. The non-conservative amino acid substitution p.Ser122Leu in KCNQ2 is associated with a broad spectrum of inheritance modalities, clinical phenotypes and outcomes; no previous reports of the same variant treated with KD are available in literature. Case Description: We described a 22-month-old female with seizure onset on day 2 of life. At three months of age, she presented refractory status epilepticus (SE) that did not respond to midazolam and carbamazepine, which was added once a "de novo" p.Ser122Leu KCNQ2 variant was demonstrated. KD was the only treatment that led to cessation of seizures. The baby maintained seizures remission and achieved neurodevelopmental milestones. Conclusions: To define an overt genotype-phenotype correlation for KCNQ2 pathogenic variants is a challenge; we propose the KD as a valuable treatment for refractory seizures and impaired neurodevelopment in infants harboring "de novo" mutations in the KCNQ2 gene.

Case report: Structural brain abnormalities in TUBA1A-tubulinopathies: a narrative review.

Introduction: Tubulin genes have been related to severe neurological complications and the term "tubulinopathy" now refers to a heterogeneous group of disorders involving an extensive family of tubulin genes with TUBA1A being the most common. A review was carried out on the complex and severe brain abnormalities associated with this genetic anomaly. Methods: A literature review of the cases of TUBA1A-tubulopathy was performed to investigate the molecular findings linked with cerebral anomalies and to describe the clinical and neuroradiological features related to this genetic disorder. Results: Clinical manifestations of TUBA1A-tubulinopathy patients are heterogeneous and severe ranging from craniofacial dysmorphism, notable developmental delay, and intellectual delay to early-onset seizures, neuroradiologically associated with complex abnormalities. TUBA1A-tubulinopathy may display various and complex cortical and subcortical malformations. Discussion: A range of clinical manifestations related to different cerebral structures involved may be observed in patients with TUBA1A-tubulinopathy. Genotype-phenotype correlations are discussed here. Individuals with cortical and subcortical anomalies should be screened also for pathogenic variants in TUBA1A.

Simple febrile seizures: new cut off for the duration of the crises.

BACKGROUND: Our study aimed to identify a new cut-off for febrile seizure (FS) with a good prognosis, thereby replacing the 15 min described in the standard definition of simple febrile seizure (SFS). METHODS: Our study was a retrospective observational study (from January 2018 to December 2018) on children admitted to the Pediatric emergency room of the Santobono-Pausilipon Hospital, Naples, Italy, Pediatric Unit of Latina, Rome, Italy, and Policlinico-Vittorio-Emanuele University Hospital, Catania, Italy, for fever, which developed SFS during the hospitalization. All included patients had their seizures classified as SFS according to the international criteria for epilepsy. We assumed a duration cut-off, and we analyzed the EEG results, neurological follow-up at 12 months, and the recurrence of the febrile seizures the following year. Then, with another calculation, we identify an optimal cut-off of 6 min. Finally, we divided the population into two groups: children with seizures having a duration greater than or less than 6 min. RESULTS: We found that the population with FS with a duration greater than 6 min presented EEG alteration at follow-up visits, neurological disorders, and a recurrence of FS during the following year. CONCLUSIONS: We suggest to introduce a new cut-off for the duration of FS that better represents the benign nature of a simple febrile event.

Fever-Associated Seizures or Epilepsy: An Overview of Old and Recent Literature Acquisitions.

In addition to central nervous system infections, seizures and fever may occur together in several neurological disorders. Formerly, based on the clinical features and prognostic evolution, the co-association of seizure and fever included classical febrile seizures (FS) divided into simple, complex, and prolonged FS (also called febrile status epilepticus). Later, this group of disorders has been progressively indicated, with a more inclusive term, as "fever-associated seizures or epilepsy" (FASE) that encompasses: (a) FS divided into simple, complex, and prolonged FS; (b) FS plus; (c) severe myoclonic epilepsy in infancy (Dravet syndrome); (d) genetic epilepsy with FS plus; and (e) febrile infection-related epilepsy syndrome (FIRES). Among the FASE disorders, simple FS, the most common and benign condition, is rarely associated with subsequent epileptic seizures. The correlation of FS with epilepsy and other neurological disorders is highly variable. The pathogenesis of FASE is unclear but immunological and genetic factors play a relevant role and the disorders belonging to the FASE group show to have an underlying common clinical, immunological, and genetic pathway. In this study, we have reviewed and analyzed the clinical data of each of the heterogeneous group of disorders belonging to FASE.

Neonatal neurologic emergencies requiring access to paediatric emergency units: a retrospective observational study.

Herein, authors present a retrospective, multi-center study to determine the number of accesses to Pediatric Emergency Unit (PEU) of patients within 28 days of life, admitted to (1) the Acute and Emergency Pediatric Unit, San Marco University Hospital, Catania, Italy; (2) Garibaldi Hospital for Emergency Care, Catania, Italy; (3) Cannizzaro Hospital for Emergency Care, Catania, Italy. We included neonates admitted for neurologic problems, from January 2015 to December 2020, to the 1-Acute and Emergency Access of the San Marco University Hospital, Catania, Italy [observation center 1 (OC1)]; 2-Garibaldi Hospital for Emergency Care, Catania, Italy (Observation Center 2-OC2); 3-Cannizzaro Hospital for Emergency Care, Catania, Italy (Observation Center 3-OC3). For each patient, we evaluated the severity of urgency, by studying the admission triage-coloured codes, the clinical data at admission and the discharge diagnosis. Neonates who had access to PEU were 812 in the OC1, 3720 in the OC2, and 748 in the OC3 respectively; 69 (8.4%), 138 (3.7%), and 55 (7.4%) was the proportion of neonatal accesses for neurological conditions. We observed that in the study period, the three hospitals had an important decrease of pediatric accesses to their PEU, but the proportion of neonates who had access to the OC1 for neurologic diseases, with respect to the total neonatal accesses, remained stable. We found that the most frequent neurologic disease for which newborns had access to PEU was Cyanosis, (46.1% of all neonatal accesses). Apnea was the second most frequent cause, with a number of 76 accesses (29%). In the literature there are numerous studies on the assessment of diseases that most frequently concern the pediatric patient in an emergency room, but there are very few references on neonatal accesses for urgent neurologic diseases. Therefore, appropriate training is required to avoid unnecessary tests without overlooking potentially serious conditions.

Alternating Hemiplegia of Childhood: neurological comorbidities and intrafamilial variability.

BACKGROUND: Alternating of Childhood (AHC) is an uncommon and complex disorder characterized by age of onset before 18 months with recurrent hemiplegia of one or either sides of the body or quadriplegia. The disorder is mainly caused by mutations in ATP1A3 gene, and to a lesser extent in ATP1A2 gene. In AHC neurological co-morbidities are various and frequently reported including developmental delay, epilepsy, tonic or dystonic spells, nystagmus,autonomic manifestations with intrafamilial variability. CASE PRESENTATION: Clinical and genetic findings of a couple of twins (Family 1: Case 1 and Case 2) and a couple of siblings (Family 2: Case 3 and Case 4) coming from two different Italian families affected by AHC were deeply examined. In twins of Family 1, a pathogenic variant in ATP1A3 gene (c.2318A>G) was detected. In siblings of Family 2, the younger brother showed a novel GRIN2A variant (c.3175 T > A), while the older carried the same GRIN2A variant, and two missense mutations in SCNIB (c.632 > A) and KCNQ2 (1870 G > A) genes. Clinical manifestations of the four affected children were reported along with cases of AHC drawn from the literature. CONCLUSIONS: Hemiplegic episode is only a sign even if the most remarkable of several and various neurological comorbidities in AHC affected individuals. Molecular analysis of the families here reported showed that clinical features of AHC may be also the result of an unexpected genetic heterogeneity.

Graph theory in paediatric epilepsy: A systematic review.

Graph theoretical studies have been designed to investigate network topologies during life. Network science and graph theory methods may contribute to a better understanding of brain function, both normal and abnormal, throughout developmental stages. The degree to which childhood epilepsies exert a significant effect on brain network organisation and cognition remains unclear. The hypothesis suggests that the formation of abnormal networks associated with epileptogenesis early in life causes a disruption in normal brain network development and cognition, reflecting abnormalities in later life. Neurological diseases with onset during critical stages of brain maturation, including childhood epilepsy, may threaten this orderly neurodevelopmental process. According to the hypothesis that the formation of abnormal networks associated with epileptogenesis in early life causes a disruption in normal brain network development, it is then mandatory to perform a proper examination of children with new-onset epilepsy early in the disease course and a deep study of their brain network organisation over time. In regards, graph theoretical analysis could add more information. In order to facilitate further development of graph theory in childhood, we performed a systematic review to describe its application in functional dynamic connectivity using electroencephalographic (EEG) analysis, focussing on paediatric epilepsy.

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.

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.

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.

7q31.32 partial duplication: First report of a child with dysmorphism, autistic spectrum disorder, moderate intellectual disability and, epilepsy. Literature review.

INTRODUCTION: Duplication of long arm of chromosome 7(q) is uncommon. It may occur as "pure", isolated anomaly or in association with other mutations involving the same or other chromosomes. "Pure" chromosome 7q duplication has recently been classified by segment involved: the interstitial, proximal, or distal segment of the arm. Attempts to correlate genotype with phenotype in each group has yielded questionable results even though intellective disability and minor dysmorphic features of variable types are typically seen. MATERIAL AND METHODS: In a young boy showing minor facial dysmorphism, language delay, autistic spectrum disorder, epileptic seizures, behavioral disturbances and irritability an array-CGH analysis was carried out. RESULTS: Array-CGH analysis found in the proband a de novo variant of partial duplication of 7q31.32 (122.254.792-122.376.908). DISCUSSION: A very few cases of partial 7q duplication have been reported thus far mainly presenting with clinical signs of dysmorphic features, large head, developmental delay, epileptic seizures and skeletal anomalies. To our knowledge, this is the first report of a case of a de novo variant of 7q31.32 duplication, showing dysmorphic anomalies and neurologic impairment including ASD and seizures. In the 7q31.32 region is located the gene CADPS2, which has been associated to autistic spectrum disorder and other neurologic disorders. In the child, a genotype-phenotype correlation may be hypothesized. Further similar reports may be useful to confirm this observation.