Evaluation of Molecular and Clinical Findings in Children With Neurofibromatosis Type 1: Identification of 15 Novel Variants.

BACKGROUND: Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease and is caused by mutations in the NF1 gene. The most common clinical features of NF1 are pigmentary abnormalities such as café-au-lait spots and inguinal or axillary freckling, cutaneous and plexiform neurofibromas, hamartomas of the iris, optic gliomas, and bone lesions. The aim of this retrospective study was to define the clinical and molecular characteristics of a pediatric sample of NF1, as well as the mutational spectrum and genotype-phenotype correlation. METHODS: The study included 40 children with clinically suspected NF1. The patients were screened for NF1 mutations by DNA-based sequencing. In addition, all the patients were studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications or deletions in NF1. The demographic, clinical, and genetic features of the children were characterized. RESULTS: A total of 40 children with NF1 were included. Of those, 28 were female and 12 were male. The mean age was 8.91 years. An NF1 variant was discovered in 28 of 40 patients (70%). Among these mutations, intronic mutations were the most frequently detected mutations; 15 of these variants had not been previously reported. Only one patient had a whole NF1 gene deletion. CONCLUSIONS: This study expands the spectrum of mutations in the NF1 gene. This study also showed that genetic screening using both next-generation sequencing and MLPA had a positive effect on diagnosis and genetic counseling in patients with suspected NF1.

A randomized controlled study: Evaluating the efficacy of a mobile application developed for mothers who have children with epilepsy in Turkiye.

PURPOSE: This study was conducted for the purposes of developing the Mobile Epilepsy Education Package (MEEP) for mothers who have children with epilepsy, and evaluating the efficacy of such a package. DESIGN AND METHODS: The research consisted of a randomized, controlled experimental study. DISCERN measuring tool was used to evaluate the content of MEEP. The evaluation of the package was conducted with a total of 60 mothers-30 participants in the intervention group and 30 controls. This study was conducted in the Pediatric Neurology Outpatient Clinic of a hospital with mothers who had children with epilepsy, ages 3-6. A Description Form, the Epilepsy Knowledge Scale for Parents, and Parental Anxiety over Seizures Scale were used in the data collection. RESULTS: The general quality evaluation of MEEP according to the experts was rated 70.35 ± 6.20, with interrater agreement at a good level. Knowledge and anxiety scores were similar in the groups prior to the mobile application. Following the application, a significant increase was seen in the level of knowledge about epilepsy among the intervention group mothers (p < .001), while a significant decrease was observed in anxiety over seizures (p = .009). CONCLUSIONS: MEEP, which was developed to evaluate mothers' levels of knowledge about epilepsy and their state of anxiety over seizures, resulted in an increase in knowledge and reduced anxiety. PRACTICE IMPLICATIONS: A simple-to-use, easy-to-access and low-cost mobile application has been developed that facilitates epilepsy diagnosis, follow-up and treatment, increases mothers' knowledge levels, and reduces anxiety levels.

The factors affecting neurodevelopmental outcomes in HIE.

BACKGROUND: Hypoxic ischemic encephalopathy (HIE) has different neurological outcomes. AIM: We wanted to see if there was any developmental delay in neonates with hypoxia ischemic encephalopathy who were given therapeutic hypothermia. STUDY DESIGN: Retrospective cohort study. METHODS: The Denver developmental screening test II (DDST-II) was performed to newborns who had been applied to therapeutic hypothermia. RESULTS: There were 69 male and 36 female newborns. The mean 1-min and 5-min Apgar scores were 4.72 ± 2.51 and 7.03 ± 2.017, respectively. The mean pH and mean base excess were 6.92 ± 0.1 and -18.05 ± 5.72, respectively. The most common risk factors were meconium staining (17.1%). There were 67 patients with Stage I, 20 with Stage II, and 18 with Stage III. Diffusion restriction was seen in 13 patients. 28 patients had seizures. In aEEG, 12 patients had burst suppression. Three (2.9%) infants died during hospitalization. 19 patients missed follow-up appointments. Thirteen patients had abnormal development according to DDST-II. Seven patients had gross motor function delays and were diagnosed with cerebral palsy. Three had language skill delays, but two of them had speech disorders after two years of age. Two had delayed milestones. Two had delays in fine motor skills but did not have any sequels after two years of age. A significant difference was found between seizures and the severity of Sarnat stage, intubation in the delivery room with developmental delay. Apgar scores were significantly lower in patients with CP. CONCLUSION: We should closely follow-up neonates who had low Apgar scores, seizures, a high Sarnat stage, were intubated in the delivery room.

Clinical, neuroimaging and genetic findings in children with hereditary ataxia: single center study.

BACKGROUND: The genetics of hereditary ataxia (HA) are complex and multigenic. The diversity of genes that cause ataxia varies considerably between populations. We aimed to investigate the clinical, neuroimaging, and genetic findings of HA in children from a tertiary center in Turkey. METHODS: The clinical and neuroimaging evaluations of patients, laboratory investigations, and molecular genetic evaluations of those with ataxia were performed at the pediatrics, pediatric neurology, and genetics outpatient clinics between October 2020 and October 2021. With repeated expansions in the ATXN 1, 2, 3, 7, and 8 genes for spinocerebellar ataxia (SCA) and FXN genes for Friedreich's ataxia (FA), whole-exome sequencing (WES) was used to analyze every patient. RESULTS: 25 patients from 24 families had ataxia and an unsteady gait as their main symptoms. The patients had a mean age of 8.5 ± 3.78 years, and the symptoms had begun at a mean age of 2 ± 0.62 years; five of these were males and three were females. A genetic cause of ataxia was found in 8/25 patients (32%). Seven of the eight gene mutations detected in the patients were novel mutations. Spinocerebellar ataxia was found in 16% of cases (n = 4), L-2-Hydroxyglutaric aciduria was found in 12% of cases (n = 3), and ataxia-telangiectasia was found in 4% of cases (n = 1). CONCLUSION: Our research adds to the body of knowledge by describing the clinical and genetic traits of HA patients in our area and by finding unusual gene changes linked to ataxia.

Identification of Novel Gene Variants in Children With Drug-Resistant Epilepsy: Expanding the Genetic Spectrum.

BACKGROUND: Resistance to antiseizure drugs is an important problem in the treatment of individuals with epilepsy. Identifying the molecular etiology of drug-resistant epilepsy (DRE) is crucial for better management of epilepsy. Here, we explore the utility of whole exome sequencing (WES) in identifying causative gene variants in children with DRE. METHODS: Forty-five children with DRE who underwent WES tests were included. Genetic examination of all patients included chromosomal analysis and clinical chromosomal microarray followed by WES. The identified variants by WES analysis were classified for pathogenicity based on the American College of Medical Genetics and Genomics guidelines and in silico protein prediction tools. RESULTS: The overall diagnostic yield was 55.5% (25 of 45). A total of 26 variants spanning 22 genes were identified in 25 patients. Of note, only 19 of these genes were examined as novel. Ten patients (22.2%) had a pathogenic or likely pathogenic variant. There was a trend associated with a diagnostic genetic test result in girls compared with boys in DRE (P = 0.028). CONCLUSION: Our findings expand the mutational spectrum of genes related to DRE. To form disease-specific treatment in children with DRE, the WES analysis should be included in the diagnostic algorithm because of its high diagnostic efficiency.

Lethal encephalitis in a pediatric patient with SARS-CoV-2.

BACKGROUND: SARS-CoV-2 mostly affects the respiratory system. Some studies have reported neurological disorders associated with SARS-CoV-2. Despite an increase in reported instances, encephalitis caused by COVID-19 infection is still poorly understood. CASE: We reported a rare presentation of SARS-CoV-2 in a 15-year-old patient. He had a fulminant course with encephalitis. He had mild symptoms of a COVID-19 infection five months ago and recovered without any sequel. Despite appropriate treatment, the patient had a devastating course. CONCLUSIONS: This was a severe presentation of SARS-CoV-2 with central nervous system manifestations.

Novel NR2F1 variant identified by whole-exome sequencing in a patient with Bosch-Boonstra-Schaaf optic atrophy syndrome.

Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an extremely rare autosomal dominant disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, hearing loss, and optic nerve atrophy. This syndrome is caused by loss-of-function variants in the nuclear receptor subfamily 2 group F member 1 (NR2F1) gene. To date, approximately 80 patients have been reported with BBSOAS. Here, we describe a 3-year-old infant with delayed development, intellectual disability, strabismus, nystagmus, and optic atrophy with well-characterized features associated with BBSOAS. Whole-exome sequencing revealed a novel heterozygous missense mutation (NM_005654.6:c.437G>A, p.Cys146Tyr) in the NR2F1 gene. This missense variant is predicted to be deleterious by the protein prediction tools (SIFT, PolyPhen-2, and MutationTaster). To the best of our knowledge, this is the first patient with BBSOAS reported from Turkey.

Presentation of an Infant with Chromosome 18p Deletion Syndrome and Asymmetric Septal Hypertrophy.

The frequency of 18p deletion syndrome is estimated to be ∼1/50,000 live births and is more commonly associated with certain clinical features including short stature, intellectual disability, and facial dysmorphism. Physical examination of our patient revealed a short stature, intellectual disability, facial dysmorphism (microcephaly, ptosis, epicanthus, low nasal bridge, protruding ears, long philtrum, and thin lips), and clinodactyly of the fifth finger. The peripheral karyotype was 46, XX, del (18) (p11.32p11.2). DNA microarray analysis revealed a de novo 13.9-Mb deletion at 18p11.32p.11.21. Echocardiography revealed asymmetric septal hypertrophy. Congenital cardiac abnormalities are present very rarely in this syndrome. This finding suggests that one locus or loci that play a role in cardiac development is located in this chromosomal region. Although rare, cardiac hypertrophies should be kept in mind when evaluating a patient with phenotypic anomalies and genetic results compatible with an 18p deletion syndrome.

Viral etiological causes of febrile seizures for respiratory pathogens (EFES Study).

BACKGROUND: Febrile seizure is the most common childhood neurological disorder, is an important health problem with potential short- and long-term complications, also leading to economic burden and increased parental anxiety about fevers and seizures occurring in their children. There are no routine recommendation to detect etiological causes of FS for neurological perspective, further knowledge about the etiological causes of FS in children will support preventive measures and follow-up strategies. The aim of this study is to evaluate the percentage of respiratory viruses in children with FS. METHODS: This prospective multicenter study, entitled "Viral etiological causes of febrile seizures for respiratory pathogens (EFES Study)" examined representative populations in eight different cities in Turkey between March 1, 2016 and April 1, 2017. Nasopharyngeal swabs were taken from all children at presentation. A respiratory multiplex array was performed to detect for influenza A and B; respiratory syncytial virus A and B; human parainfluenza virus 1-2-3 and 4; human coronavirus 229E and OC43; human rhinovirus; human enterovirus; human adenovirus; human bocavirus; human metapneumovirus. RESULTS: During the study period, at least one virus was detected in 82.7% (144/174) of children with FS. The most frequently detected virus was adenovirus, followed by influenza A and influenza B. Detection of more than one virus was present in 58.3% of the children with FS, and the most common co-existence was the presence of adenovirus and influenza B. In children younger than 12 months, Coronavirus OC43 was the most common, while influenza A was most frequently observed in children older than 48 months (p < 0.05). Human bocavirus was common in children who experienced complex FS, while respiratory syncytial virus (RSV) A was more common in children who experienced simple FS. Influenza B virus was the most common virus identified in children who were experiencing their first incidence of FS (p < 0.05). CONCLUSIONS: This study indicates that respiratory viruses are important in the etiology of FS in children. The results show that antibiotics must be prescribed carefully in children with FS since the majority of cases are related to viral causes. Widespread use of the existing quadrivalent influenza vaccine might be useful for the prevention of FS related to the flu. Further vaccine candidates for potential respiratory pathogens, including RSV, might be helpful for the prevention of FS.

Hot Water Epilepsy Successfully Treated With Daily Clobazam.

Hot water epilepsy (HWE) is a rare form of reflex epilepsy precipitated by a bath or shower in hot water. Although the condition is benign and a decreased bath temperature will help, antiepileptic drugs may be needed in some cases. Prophylactic clobazam is currently the first choice treatment option. Here we report the case of a 10-year-old boy with HWE successfully treated with daily doses of clobazam. Daily clobazam was preferred over prophylactic clobazam because of the patient's frequent bathing and parental concern. Daily clobazam is a novel treatment option for HWE and seems to be a good choice where antiepileptic drugs are necessary.

Hemi-meningitis with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare lymphoproliferative disorder. HLH may occur as a complication of Epstein-Barr virus (EBV), particularly in patients with immunodeficiencies. Herein, we describe a 16-year-old girl with neurological complications associated EBV-induced HLH. Her cerebral magnetic resonance imaging (MRI) showed contrast-enhanced axial T1-weighted images with enhancement of meningeal surface in the right hemisphere that was consistent with right hemi-meningitis. Hydrocephalus, dilated subdural spaces, delayed myelination, edema, diffuse parenchymal atrophy, calcifications, diffuse/patchy white matter abnormalities have all been previously described with HLH. To the best of our knowledge, this is the first case of hemi-meningitis associated with HLH. We suggest that clinicians should consider HLH with vascular disorders when they determine unilateral meningitis on a brain MRI.

Ptosis during hematologic malignancy in children.

Neurological symptoms such as ptosis may develop due to either chemotherapeutic agents or involvement of the central nervous system (CNS) during hematologic malignancy. It is difficult to make this distinction according to clinical symptoms and magnetic resonance imaging findings. If the neurologic symptoms are increased, it is a warning of CNS involvement. Herein are described the clinical and neuroimaging features of three patients with hematologic malignancy who presented with ptosis.

Akathisia in association with herpes simplex encephalitis relapse and opercular syndrome in children.

We report a 2-year-old boy with herpes simplex virus type 1 encephalitis (HSE) and opercular syndrome who presented with clinical relapse characterized by chorea-like involuntary movements that suggest akathisia. The patient initially presented with multiple focal seizures that cause epilepsia partialis continua, polymerase chain reaction (PCR) for herpes simplex virus type 1 was positive. He developed hypersalivation, speech and swallowing difficulties within 30days. Based on these findings the patient was diagnosed as having opercular syndrome due to HSE. He developed akathisia on 44th day of admission as a relapse and he was successfully treated with propranolol. Opercular syndrome might be seen HSE in children and it may cause neurological suquela. Akathisia might be seen after encephalitic process as a symptom of relapse, however diagnosis of akathisia is difficult in young children. It should be noted that because propranolol effective for these involuntary movements. It can be add additional choice of treatment in these patients.

Clinical and Neuroimaging Findings of Sydenham's Chorea.

OBJECTIVE: Sydenham's chorea (SC) is thought to be an autoimmune disorder. MRI is generally used to exclude other causes of chorea. There are no typically defined MRI features of SC. In this study we aimed to determine clinical and neuroimaging findings of SC. METHODS: In this study 17 patients with acute SC were retrospectively evaluated. Sydenham's chorea was diagnosed according to the 1992 revision of the Jones criteria. The other causes of chorea were excluded. Cranial MRI was performed in all patients during the acute phase of SC. Walking, speech and swallowing disorders, muscle weakness, behavioral disorders, treatment, symptom recovery time and recurrence were evaluated. Findings : The patients' mean age was 11.2 years. Behavioral changes, muscle weakness and dysphagia occurred in 70%, 64% and 23% of the patients, respectively. Nonspecific signal hyperintensities were observed in the white matter, brain stem and caudate nucleus in 47% of patients. Two patients who had chorea paralytica were treated successfully with a high dose of intravenous methylprednisolone. CONCLUSION: Nonspecific hyperintense white matter abnormalities may be due to the inflammatory process associated with a longer duration of clinical signs. To explain the MRI findings and the pathogenesis of SC, comprehensive studies are needed.

Mycoplasma pneumoniae infection with neurologic complications.

BACKGROUND: Extrapulmonary complications of Mycoplasma pneumoniae (M. pneumoniae) infection include encephalitis, optic neuritis, acute psychosis, stroke, cranial nerve palsies, aseptic meningitis and also it may be implicated in immune mediated neurological diseases such as acute demyelinating encephalomyelitis, Guillain-Barre syndrome and transverse myelitis. CASE PRESENTATION: We present five cases with acute neurological diseases after M. pneumoniae infection. The clinical presentations were characterized by encephalitis in 2 patients, Gullain-Barre syndrome in 2 patients, transverse myelitis in 1 patient. M. pneumoniae infection was detected in serum by serological method. Only two patients had respiratory symptoms preceding M. pneumoniae infection. Brain MRI revealed hyperintensities on corpus striatum and mesencephalon in one patient with encephalitis, the other had front parietal coalescent periventricular white matter lesions on T2 images. The patient with transverse myelitis had cervical, dorsal and lumbar scattered hyperintense lesions on T2 images. Two patients were treated with high dose steroid, the other two patients received treatment with intravenous immune globuline. CONCLUSION: M. pneumoniae may reveal different neurologic complications with different radiologic findings.

Co-existence of acute transverse myelitis and Guillain-Barré syndrome associated with Bartonella henselae infection.

Cat scratch disease (CSD) is a benign, self-limiting condition associated with Bartonella henselae. Neurological manifestations are uncommon. Acute transverse myelitis and Guillain-Barré syndrome have been reported rarely with CSD. This report describes a 12-year-old boy with acute transverse myelitis and Guillain-Barré syndrome associated with CSD.

Breath holding spells: point prevalence and associated factors among Turkish children.

BACKGROUND: Breath holding spells (BHS) are known as paroxysmal non-epileptic disorder. There are two subtypes of BHS: cyanotic and the pallid. BHS have been reported to occur in 0.1-4.6% of children in Western countries. Although it is easy to diagnose in its typical form, the data on prevalence of BHS are insufficient in developing countries. METHODS: This study was performed in Turkey's Eskisehir province. A total of 1000 randomly selected 0-6-year-old children were invited to family health centers. A specific questionnaire was given to parents. Children who had a history BHS were referred to the hospital to for investigation of medical history and neurological examinations. RESULTS: A total of 933 children participated and were included in analysis. Thirty-four children (3.6%) had had BHS. Children's birthweight, parent consanguinity and mothers' education status significantly affected the frequency of BHS. Increase in birth sequence decreases the risk of BHS 0.65-fold. Fathers' education status also affected the prevalence of BHS, with the risk of BHS being 0.39-fold less if the father had completed high school or some higher education. And, as the age of the fathers increased, the risk that their children would have BHS was 1.14-fold higher. CONCLUSIONS: Although the calculated prevalence rate was compatible with previous studies, positive family history for BHS, birth sequence, parents' education status and fathers' age were identified as risk factors associated with BHS.

A new nonsense mutation in the NF1 gene with neurofibromatosis-Noonan syndrome phenotype.

PURPOSE: Neurofibromatosis-Noonan syndrome is a rare autosomal dominant disorder which combines neurofibromatosis type 1 (NF1) features with Noonan syndrome. NF1 gene mutations are reported in the majority of these patients. METHOD: Sequence analysis of the established genes for Noonan syndrome revealed no mutation; a heterozygous NF1 point mutation c.7549C>T in exon 51, creating a premature stop codon (p.R2517X), had been demonstrated. RESULT: Neurofibromatosis-Noonan syndrome recently has been considered a subtype of NF1 and caused by different NF1 mutations. CONCLUSION: We report the case of a 14-year-old boy with neurofibromatosis type 1 with Noonan-like features, who complained of headache with triventricular hydrocephaly and a heterozygous NF1 point mutation c.7549C>T in exon 51.