Effect of Piracetam and Iron Treatment on Heart Rate Variability in Patients With Breath-Holding Spell.

BACKGROUND: Breath-holding spells are a benign condition primarily seen in 3% to 5% of healthy children aged between six months and five years. Although no specific treatment is recommended due to its benign nature, iron and piracetam are used in severe or recurrent cases. We planned to compare the heart rate variability (HRV) before and after treatment with 24-hour Holter monitoring in patients receiving iron and piracetam treatment and investigate the treatment's effectiveness. METHODS: Twenty-five patients who applied to the outpatient clinic between 2013 and 2015 due to breath-holding spells were included in the study. The patients who received piracetam and iron therapy and underwent 24-hour rhythm Holter monitoring were evaluated retrospectively. RESULTS: Fourteen (56%) of these patients were evaluated as having cyanotic-type and 11 (44%) patients were assessed as having pale-type breath-holding spells. A significant difference was found only between hourly peak heart rate and total power in the group receiving iron treatment. Significant differences were also found among the minimum heart rate, mean heart rate, the standard deviation of RR intervals, the mean square root of the sum of the squares of their difference between adjacent RR intervals, spectpow, and low frequency before and after the treatment in the patients who started piracetam treatment (P < 0.05). CONCLUSIONS: Our study is critical as it is the first to investigate the effects of treatment options on various HRV in patients with breath-holding spells. There were statistically significant changes in HRV parameters in patients receiving piracetam, and the number of attacks decreased significantly. Piracetam treatment contributes positively to the breath-holding spell with regard to efficacy and HRV, therefore it can be used to treat breath-holding spells.

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

The Value of Electroencephalogram (EEG) Findings in the Evaluation and Treatment Management of Pediatric Acute Liver Failure.

Background Pediatric acute liver failure (PALF) is still life-threatening and requires urgent care. The presence of encephalopathy is a clinical diagnosis, but it is more difficult to diagnose in children than in adults, and an electroencephalogram (EEG) can be invaluable. The role of EEG in managing the treatment of patients with PALF, other than the identification of encephalopathy, is unknown. This study aimed to investigate patients' EEGs, which may guide in choosing the most appropriate treatment in encephalopathy children. A further aim was to investigate a new score method, based on the laboratory results, which might indicate the presence of encephalopathy in cases with PALF. Methods Medical data of 33 PALF patients followed in our clinic were reviewed retrospectively. This study included 33 patients, whose EEG recording was taken on the first day of supportive treatment due to liver failure in the pediatric intensive care unit (PICU). The EEG findings were categorized into three classes: normal, epileptic and non-epileptic paroxysmal, and background encephalopathic patterns including widespread slowing and voltage suppression. Result This retrospective study included 13 male and 20 female patients with a mean age at presentation of 4.82±4.81 months whose EEG was performed on the first day of supportive therapy for liver failure in the PICU. The EEG findings were categorized into three groups: normal, epileptic and non-epileptic paroxysms, and encephalopathic patterns including diffuse background slowing and voltage suppression. Comparing EEG findings and treatments, we found that the normal EEG group responded well to liver-supporting therapy and the rate of plasmapheresis treatment was significantly higher in the diffuse slowing group. Patients with diffuse slowing of the EEG were 9.6 times more likely to receive plasmapheresis. We found that above a cut-off of ≥7.5 for the TAI (total bilirubin, albumin, and international normalized ratio (INR)) score used in our study, the risk of developing encephalopathy increased 14.4-fold. Conclusions In PALF, EEG findings can provide findings that will help clinicians in determining treatment selection and prognosis, as well as detecting epileptic focus and encephalopathy. The TAI score can be used to assess the risk of encephalopathy in cases of PALF, when it is challenging to identify encephalopathy or when an EEG is not possible.

Emotional Dysregulation and Temperament-Character Traits in Adolescents With Functional Neurological Symptom Disorder (Conversion Disorder).

ABSTRACT: The purpose of this study was to evaluate emotion dysregulation and temperament-character traits in adolescents with functional neurological symptom disorder (FNSD). Forty adolescents with FNSD and 40 healthy adolescents were evaluated by a semiconstructed diagnosis interview, Temperament and Character Inventory (TCI), Difficulties in Emotion Regulation Scale (DERS), Regulation of Emotions Questionnaire (REQ), and Children's Somatization Inventory-24 (CSI-24). The external and internal dysfunctional emotion regulation scores of REQ, all subscales of DERS, except the awareness subscale, and CSI-24 scores were significantly higher in FNSD patients compared with healthy controls. There were significant differences between the groups in terms of harm avoidance and reward dependence subscale scores of TCI. Multiple logistic regression analysis showed that the external dysfunctional emotion regulation strategy, somatization, and reward dependence are significant predictors of FNSD. Our results provide evidence that adolescents with FNSD experience emotional dysregulation and that the differential value of some temperament-character traits in the diagnosis of FNSD.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study.

BACKGROUND: Various etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. METHODS: Cases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. RESULTS: The study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1-12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others". The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. CONCLUSION: Our results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri­ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Sleep quality and depression in mothers of children with epilepsy and its relation to their children's sleep.

OBJECTIVE: This study aimed to evaluate the relationship between sleep disturbances in children with epilepsy (CWE) and maternal sleep quality and depression severity. METHODS: A Cross-sectional study was conducted in pediatric sleep disturbances using questionnaires on mother-reported sleep of CWE [Children's Sleep Habits Questionnaire (CSHQ)], maternal sleep quality [Pittsburgh Sleep Quality Index (PSQI)], and maternal depression status [Self-Rating Depression Scale (SDS)]. 114 dyads consisting of CWE and their mothers were included in this study. RESULTS: Over three-quarters (78.9 %) of mothers reported poor sleep quality (total PSQI score ≥ 5), and nearly a third (29.8 %) met clinical criteria for moderate or severe depression levels. The mothers' total PSQI scores were between 5.93 ±â€¯2.44 (range: 2-16 points). The most affected PSQI subcomponents were sleep latency (AUC = 0.826p < 0.001) and daytime dysfunction (AUC = 0.800p < 0.001). The majority of children (88.6 %) were stated by their mothers to have sleep-related problems. The total CSHQ scores of the children were between 49.06 ±â€¯9.20 (range: 33-86 points). The most affected CSHQ subcomponents were detected sleep anxiety (AUC = 0.856, p < 0.001), bedtime resistance (AUC = 0.818, p < 0.001) and daytime sleepiness (AUC = 0.807, p < 0.001). There was a statistically significant positive correlation between maternal sleep quality and depression severity (rho = 0.842; p < 0.001). A statistically significant positive moderate correlation was detected between sleep problems in CWE and maternal sleep quality and depression severity (rho = 0.406; p < 0.001, rho = 0.399; p < 0.001, respectively). As a result of multiple stepwise logistic regression analysis, the presence of seizures during sleep and generalized epileptiform discharges on electroencephalography were associated risk factors with poor maternal sleep quality (OR:6.6, p = 0.014; OR:11.5, p = 0.018, respectively). A borderline insignificant relationship was observed between a less than 50 % decrease in seizure frequency and the poor maternal sleep quality (OR:20.59p = 0.059). Seizures during sleep was associated risk factor with children's sleep disturbances (OR:7.2, p = 0.02). CONCLUSIONS: Sleep problems in CWE may lead to negative consequences such as sleep quality and/or depression in mothers. Interventions planned to correct sleep disturbances in mothers suggest that children's sleep problems should be optimally managed.

Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

The Importance of Long-Term Video Electroencephalography Monitoring in the Differential Diagnosis of Epilepsy in Children.

OBJECTIVE: Epilepsy is a condition in which abnormal, recurring, and excessive neuronal discharges caused by many different disorders in the central nervous system are observed. The rate of detecting epileptiform activity in the first interictal electroencephalography (EEG) of patients with epilepsy is around 40%, even when routine activation methods are applied. Video recordings simultaneously with EEG recordings enable the establishment of correlations between abnormalities. PATIENTS AND METHODS: The long-term video-EEG monitoring (VEM) reports and images of 87 patients hospitalized in the video EEG service in the Pediatric Neurology Clinic of Inönü University between 2016 and 2020 were retrospectively analyzed in this study. Demographic information of the patients, such as age, gender, diagnosis/history, and length of hospital stay, was analyzed. RESULTS: A total of 87 patients were included in the study. Of the patients, 54 (62.1%) were male and 33 (37.9%) were female. The mean age was 107.57 ± 64.40 months. While 10 (11.5%) patients followed up with non-epileptic paroxysmal events (NEPE) were taking antiepileptic drugs (AEDs), AED treatments were discontinued after VEM. The diagnosis of 18 (20.69%) patients changed after VEM. The medications of 27 (31%) patients who took AEDs before VEM were discontinued after VEM. During VEM, sleep movement, psychogenic seizures, infantile masturbation, and tic disorder were observed in 19 (41.3%), 17 (36.9%), three (6.5%), and three (6.5%) patients, respectively. CONCLUSION: In conclusion, VEM is the gold standard diagnostic method used to distinguish between epilepsy and NEPEs. After VEM, the clinical diagnosis of patients can change, and unnecessary drug administration may be prevented. Psychogenic nonepileptic seizures and NEPEs are common in the pediatric population; however, they are often overlooked.

Effectiveness of zonisamide in childhood refractory epilepsy.

INTRODUCTION: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy. METHOD: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients. RESULTS: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant. CONCLUSION: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.

Evaluation of micronutrient levels in children with cerebral palsy.

BACKGROUND: Many studies evaluating the nutritional status of children with cerebral palsy (CP) have focused on energy requirements and protein intake. The present work aimed to assess nutritional status and micronutrient levels of children with (CP). METHODS: This multicenter, cross-sectional and observational study was conducted in 10 different cities in Turkey. Data were available for 398 participants. Anthropometric measurements, feeding mode, nutritional status, and micronutrient levels were evaluated. RESULTS: The study was conducted with 398 participants (303 patients and 95 healthy controls). Statistical analysis showed that according to the Gomez Classification, weight-for-age (WFA) revealed malnutrition in 92.6% of children with CP, based on Centers for Disease Control and Prevention percentiles. Measurements of micronutrient levels showed that zinc levels were low in patients, whereas vitamin A levels were low in controls. Phosphorous and manganese levels were significantly lower in malnourished children than in typical children. The results revealed that children consuming enteral nutrition solutions had higher selenium and lower zinc levels than non-consumers. CONCLUSIONS: Malnutrition is not only a protein- or calorie-based problem; micronutrient deficiencies might cause severe health problems. Children with chronic neurological disabilities must be carefully evaluated for these issues. Therefore, nutritional interventions should be adapted to nutrition.

The PURPLE N study: objective and perceived nutritional status in children and adolescents with cerebral palsy.

PURPOSE: To obtain information on characteristics, management, current objective nutritional status and perception of nutritional status of children with cerebral palsy (CP) from healthcare professionals (HCPs) and caregivers. MATERIALS AND METHODS: A detailed survey of several items on eight main topics (general characteristics, motor function, comorbidities, therapies, anthropometry, feeding mode and problems and perceived nutritional status) was developed and tested for the study. Correlation between nutritional status and Gross Motor Function Classification System (GMFCS) levels was assessed using continuous variables (Z-scores for weight-for-age, height-for-age, weight-for-height, and body mass index-for-age), and categorical variables (being malnourished, stunted, or wasted). HCP and caregiver perceptions of the child's nutritional status as well as agreement between perceived and objective nutritional status and agreement between perceived nutritional status and concerns about the nutritional status were analyzed. RESULTS: Data were available for 497 participants from eight European countries. Poorer nutritional status was associated with higher (more severe) GMFCS levels. There was minimal agreement between perceived and objective nutritional status, both for HCPs and caregivers. Agreement between HCP and caregiver perceptions of the child's nutritional status was weak (weighted kappa 0.56). However, the concerns about the nutritional status of the child were in line with the perceived nutritional status. CONCLUSIONS: The risk of poor nutritional status is associated with more severe disability in children and adolescents with CP. There is a mismatch between HCP and caregiver perceptions of participants' nutritional status as well as between subjective and objective nutritional status. Our data warrant the use of a simple and objective screening tool in daily practice to determine nutritional status in children and adolescents with CP. Clinical trial registration: ClinicalTrials.gov Identifier: NCT03499288 (https://clinicaltrials.gov/ct2/show/NCT03499288). IMPLICATIONS FOR REHABILITATIONUse of the ESPGHAN recommendations and simple screening tools in daily practice is needed to improve nutritional care for individuals with CP.Attention should be paid to the differences in the perception of nutritional status of individuals with CP between professionals and caregivers to improve appropriate referral for nutritional support.Objective measures rather than the professional's perception need to be used to define the nutritional status of individuals with CP.

High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Clinical and genetic characterization of PYROXD1-related myopathy patients from Turkey.

Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease.

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans.

Clinical features and the role of magnetic resonance imaging in pediatric patients with intracranial hypertension.

Increased intracranial hypertension (IIH) is a defined clinical condition; however, an unsolved pathophysiologic background usually creates problems in its diagnosis and proper approach. The aim of this study was to emphasize the clinical conditions and brain magnetic resonce imaging (MRI) clues of pediatric patients, especially this clinical entity with high morbidity. Here, we review the etiology, clinical presentation, brain MRI findings, and prognosis of IIH in children. The symptoms' onset age ranged from 9 months to 16 years. Headache (81%), vomiting (37%), and diplopia (33.3%) were the most frequent symptoms. The most common etiologic factors were found to be obesity and dural venous sinus thrombosis. Cerebrospinal fluid (CSF) opening pressure had mean a mean value of 615.2 ± 248 mm H2O. A significant relationship was found between visual field impairment and height of CSF pressure (p < 0.001). Optic nerve sheath enlargement (88.8%) and optic nerve tortuosity (85.1%) were found as the most common brain MRI findings. Slit-like ventricle (37%), venous sinus thrombosis (29.6%), posterior globe sclera flattening (29.6%), empty sella (25.9%), and intraocular protrusion of the optic nerve (14.8%) were the other findings. A significant relationship was found between CSF opening pressure and the presence of optic nerve tortuosity (p = 0.002), and distension of the optic nerve sheath (p = 0.006). All patients received acetazolamide, only one patient underwent lumboperitoneal shunt, and only one received steroids. In children, IIH can present with different etiologies and symptoms. Brain MRI provides crucial clues in diagnosis. Urgent diagnosis and treatment planning are required to protect vision functions.

Acute Ataxia in Childhood: Clinical Presentation, Etiology, and Prognosis of Single-Center Experience.

BACKGROUND: Acute ataxia is a common reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. Its incidence is between 1/100,000 and 1/500,000. Its most common reason is infections. OBJECTIVE: The aim of this study was to examine the clinical presentation, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute ataxia. METHODS: An evaluation was made of patients younger than 18 years diagnosed with acute ataxia in our tertiary pediatric neurology clinic between 2009 and 2016. RESULTS: Thirty-nine children were included in the analysis. Sex, age, diagnoses, treatment options, and clinical and radiological findings were evaluated. Acute postinfectious cerebellar ataxia was the most common diagnosis (21/39 [51.2%]). No agent could be identified in viral serological examination in 34 patients (87.2%). Rotavirus was identified in 2 (10.5%) of the acute postinfectious cerebellar ataxia cases, and varicella-zoster virus, herpes simplex virus, and hepatitis A positivities were each identified in 1 case. In 20 (51.2%) of 39 patients, varying treatments were applied according to the primary etiology. CONCLUSIONS: Acute ataxia is a significant neurological problem in childhood. In this study, Rotavirus was the most common infectious agent. It may be related to vaccination. This study can be considered of value as the most comprehensive study conducted to date on this subject in the eastern region of Turkey.

A Novel SCN1A Mutation: A Case Report.

INTRODUCTION: Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy with delayed psychomotor development and increased premature mortality. The seizures triggered by fire have been gradually decreased over time, and finally they start to occur without fever at the age of 2-3 years. Along with its initiation of myoclonic seizures in the early period, other types such as atypical absence, versive, and complex partial seizures occur between 1 and 4 years of age. CASE REPORT: A 3-year-old male patient with refractory epilepsy and neuromotor developmental retardation was admitted to our clinic. The patient initially had seizures in the afebrile period, when he was 4 months old, and he had a total of five seizures by the age of 1 year. Neuromotor developmental retardation developed over time in patients with normal neuromotor development in the early stages of his life. His cranial magnetic resonance imaging and metabolic test findings were normal. The SCN1A mutation was investigated, and a new variant mutation of SCN1A, homozygous (p.Y1599Ffs*19-c.4796delA) was detected. The patient's family was also screened and this new mutation was detected as heterozygous mutation. The patient had hepatomegaly. The etiology of hepatomegaly was investigated but no cause was found. CONCLUSION: Variant mutations of DS should be kept in mind and diagnostic genetic testing should be done in patients with neuromotor developmental retardation starting with afebrile seizures. In DS, hepatomegaly is not an expected condition. Maybe this new mutation might have caused hepatomegaly.