Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

Evaluation of seizure semiology, genetics, magnetic resonance imaging, and electroencephalogram findings in children with Rett syndrome: A multicenter retrospective study.

OBJECTIVES: This study aimed to evaluate seizure semiology, electroencephalogram (EEG), magnetic resonance imaging (MRI), and genetic findings, as well as treatment choices in Rett syndrome (RTT). METHODS: A retrospective analysis was conducted on one hundred and twenty cases diagnosed with RTT with a genetic mutation. Data were obtained from nine participating centers. RESULTS: In this study, 93.3 % of patients were female, with typical RTT found in 70 % of cases. Genetic etiology revealed MECP2, FoxG1, and CDKL5 in 93.8 %, 2.7 %, and 1.8 % of cases, respectively. Atypical RTT clinics were observed in 50 % of male cases, with the first EEG being normal in atypical RTT cases (p = 0.01). Generalized tonic-clonic and myoclonic epilepsy were the most common seizure semiologies, while absence and focal epilepsy were less prevalent. Valproate, levetiracetam, lamotrigine, and clobazam were the most commonly used antiepileptic drugs, affecting the severity and frequency of seizures (p = 0.015, p=<0.001, p = 0.022, and p=<0.001, respectively). No significant differences were observed in EEG findings. The initiation of anti-seizure medications significantly altered seizure characteristics (Table 4). A ketogenic diet and vagal nerve stimulation (VNS) correlated with a 50 % improvement in cognitive function, while steroid treatment showed a 60 % improvement. Remarkably, seizures were substantially reduced after VNS application. CONCLUSION: This study underscores the importance of genetic diagnosis in RTT cases with a clinical diagnosis. These preliminary results will be further validated with the inclusion of clinically diagnosed RTT cases in our ongoing study.

Autism in Turkey: demographics, behavior problems, and accompanying medical conditions in a sample of Turkish youth with autism spectrum disorder.

Autism spectrum disorder (ASD) is an etiologically heterogeneous neurodevelopmental condition that eludes a single explanation or cure. Epidemiological studies reveal risk factors, relevant comorbidities, and behavioral correlates to reach a better understanding of ASD. To contribute such data from an understudied ASD population, this paper presents epidemiological data from a Turkish sample of individuals with ASD (n = 911, 748 boys (82.1%) and 163 girls (17.9%) between 1 and 18 years of age). Average age at diagnosis was 31.06 ± 11.88 months, and the male-to-female ratio was 4.6:1. Three in 4 individuals with ASD had obsessive behaviors, and 1 in 4 had allergic conditions, inappropriate sexual behaviors, self-harming behaviors, and harmful behaviors towards others. One in 3 received a dietary treatment for at least 3 months; almost half received vitamin supplements; the majority (70%) did not experience constipation; and 2 in 3 were picky eaters. This paper presents data on the age of diagnosis, gender ratios, accompanying behaviors, and dietary interventions in Turkish individuals with ASD, which are topics of current research interest about ASD. Such data from non-Western populations may supplement epidemiological knowledge gained from Western populations to help reach a more comprehensive understanding of this condition with many unknowns.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.

OBJECTIVE: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. METHODS: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. RESULTS: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. CONCLUSION: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Demographic characteristics of SMA type 1 patients at a tertiary center in Turkey.

UNLABELLED: The aim of this study was to demonstrate demographics of 39 consecutive Spinal Muscular Atrophy (SMA) type 1 patients diagnosed genetically in a tertiary center between June 2006 and June 2009. There was history of consanguineous marriage in 27 (69%) patients. The average patient lifespan was 251 days (30-726 days). The average patient age at diagnosis was 129 days (33-297 days). A statistically significant correlation was found between the age at diagnosis and the lifespan (p = 0.00). No significant correlation was found between the time spent in intensive care and the lifespan (p = 0.43). Routine physical therapy was found to have no significant impact on the lifespan average (p = 0.17). The cause of death in all of our patients was respiratory issues. Genetic counseling was given to 35 families. A second child with SMA was born in three out of the 14 families who declined prenatal diagnosis. CONCLUSION: A national program is needed in Turkey for SMA prevention and creation of expert teams for the management of these patients.

Evaluation of the North Star Ambulatory Assessment scale and cardiac abnormalities in ambulant boys with Duchenne muscular dystrophy.

AIM: We evaluated ambulatory patients with Duchenne muscular dystrophy from the cardiovascular standpoint and studied the correlation between the results of electrocardiographic (ECG) findings, left ventricular ejection fraction (LVEF), troponin T and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and patients' North Star Ambulatory Assessment scores. METHODS: Fifty patients of ages 6-12 (8.9 ± 2.8) were enrolled in this cross-sectional study. Cardiac evaluation included electrocardiography, echocardiography and cardiac enzyme tests. RESULTS: North Star scores ranged from 6/34 to 34/34. Twenty-eight patients (56%) had ECG changes. The most frequently seen ECG abnormalities were short PR interval (14%, n= 7), right ventricular hypertrophy (16%, n= 8), prolonged QTc interval (10%, n= 5), prominent Q wave (10%, n= 5) and T wave inversion (44%, n= 22). In 10 patients (20%), LVEF was below 55%, troponin T and NT-proBNP levels were significantly elevated (P= 0.003 and P < 0.001, respectively). When North Star scores were compared to patients' age, enzyme levels, ECG and echocardiographic results, we discovered negative correlation with age (P < 0.001) and troponin T levels (P= 0.02) and positive correlation with LVEF (P= 0.02). CONCLUSION: Patients with North Star scores of ≤16 are more at risk of developing cardiomyopathies. Troponin T is a cardiac index that can be used for evaluating myopathic patients and it seems to be correlated with the proBNP levels and LVEF values.

Thyroid hormones in children on antiepileptic therapy.

The aim of this study was to evaluate the thyroid function alterations in a group of epileptic children taking antiepileptic drugs (AEDs). Patients demographic data and the free throxine (fT4) and thyroid-stimulating hormone (TSH) levels at the beginning of the treatment and at the third, sixth and ninth months of AED treatment were recorded retrospectively. A total of 106 children, 59 males and 47 females, were enrolled in the study. Mean patient age was 3.7 years, ranging between 3 months and 14 years. In total, 54% of patients were on valproic acid (VPA), 16% phenobarbital (PB), 14% were on carbamazepine (CBZ), 6% were on oxcarbazepine (OXC), 5% were on levetiracetam, and 5% were on topiramate therapy. There were no significant differences in average fT4 values between the drug groups. But the mean fT4 levels of the patients on VPA therapy showed a clear decrease within the observation period. No significant difference in average TSH values between the groups was detected in the beginning and in the third and sixth month. However, in the ninth month, a significant increase in TSH values was found in the VPA group (p = 0.007). In the patients taking VPA, average TSH values rose progressively while staying within normal limits. During follow-up, thyroid dysfunction were found in 21 patients (19.6%). A statistically significant relationship was found between severe electroencephalography (EEG) findings and thyroid dysfunction (p = 0.041). It was concluded that epileptic children with severe EEG findings and using VPA could have thyroid dysfunction. These patients should be followed up closely by thyroid function tests during treatment.

Changes in EEG complexity with neurofeedback and multi-sensory learning in children with dyslexia: A multiscale entropy analysis.

Multiscale entropy analysis (MSE) is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. MSE has been successfully applied in the literature when measuring autism traits, Alzheimer's, and schizophrenia. However, until now, there has been no research on MSE applied to children with dyslexia. In this study, we have applied MSE analysis to the EEG data of an experimental group consisting of children with dyslexia as well as a control group consisting of typically developing children and compared the results. The experimental group comprised 16 participants with dyslexia who visited Ankara University Medical Faculty Child Neurology Department, and the control group comprised 20 age-matched typically developing children with no reading or writing problems. MSE was calculated for one continuous 60-s epoch for each experimental and control group's EEG session data. The experimental group showed significantly lower complexity at the lowest temporal scale and the medium temporal scales than the typically developing group. Moreover, the experimental group received 60 neurofeedback and multi-sensory learning sessions, each lasting 30 min, with Auto Train Brain. Post-treatment, the experimental group's lower complexity increased to the typically developing group's levels at lower and medium temporal scales in all channels.

A mobile app that uses neurofeedback and multi-sensory learning methods improves reading abilities in dyslexia: A pilot study.

Reading comprehension is difficult to improve for children with dyslexia because of the continuing demands of orthographic decoding in combination with limited working memory capacity. Children with dyslexia get special education that improves spelling, phonemic and vocabulary awareness, however the latest research indicated that special education does not improve reading comprehension. With the aim of improving reading comprehension, reading speed and all other reading abilities of children with dyslexia, Auto Train Brain that is a novel mobile app using neurofeedback and multi-sensory learning methods was developed. With a clinical study, we wanted to demonstrate the effectiveness of Auto Train Brain on reading abilities. We compared the cognitive improvements obtained with Auto Train Brain with the improvements obtained with special dyslexia training. Auto Train Brain was applied to 16 children with dyslexia 60 times for 30 minutes. The control group consisted of 14 children with dyslexia who did not have remedial training with Auto Train Brain, but who did continue special education. The TILLS test was applied to both the experimental and the control group at the beginning of the experiment and after a 6-month duration from the first TILLS test. Comparison of the pre- and post- TILLS test results indicated that applying neurofeedback and multi-sensory learning method improved reading comprehension of the experimental group more than that of the control group statistically significantly. Both Auto Train Brain and special education improved phonemic awareness and nonword spelling.

Clinical features of nine patients with alternating hemiplegia of childhood.

AIM: To define clinical features of patients with alternating hemiplegia of childhood. METHODS: We retrospectively reviewed the clinical presentation and course of the disease in patients diagnosed between January 2003 and December 2008 at the Pediatric Neurology Department of the Istanbul Medical Faculty. RESULTS: The nine patients had a mean age of 6.6 months (2-15 months) at the onset of symptoms. Paroxysmal eye movements were the early symptom of five patients. All patients had recurrent alternating hemiplegic episodes and relief of symptoms while sleeping. Duration of events varied widely from few minutes to several days and was associated with slowly progressive neurological deterioration. Flunarizine might decrease frequency of events but is not effective to neurological deterioration. Amantadine as an alternative agent is used in add-on therapy, but epileptogenic side effect prevented the evaluation of long-term efficacy. CONCLUSION: Trials on new agents like amantadine are necessary for more effective control of the disease.

Rapidly progressive subacute sclerosing panencephalitis presenting with acute loss of vision.

A 10-year-old male presented with vision loss and behavioral changes. He had midpoint pupils with no reaction to light and normal funduscopic examination. Cranial magnetic resonance imaging revealed bilateral cortical lesions at parieto-occipital lobes. Elevated measles antibody titers in the cerebrospinal fluid confirmed the diagnosis of subacute sclerosing panencephalitis. Despite oral inosiplex and supportive care, patient developed generalized seizures with frequent myoclonic jerks and rapidly progressed into coma. Cortical blindness in subacute sclerosing panencephalitis can be an early indicator for fulminant course.

CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature.

INTRODUCTION: Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. OBJECTIVE: In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. MATERIALS AND METHODS: The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3-2 mg/kg/day). The median duration of treatment was 6.5 months (3-28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. RESULTS: The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents' reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20-70% of the patients. CONCLUSION: Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

A Rare Cause of Autistic Regression in a Boy with Down Syndrome: Hashimoto Encephalopathy.

BACKGROUND: Hashimoto encephalopathy (HE) is a rare condition associated with autoimmune thyroid disease. We aimed to report the youngest patient with Down syndrome and HE with an unusual presentation. CASE REPORT: Six years and six months old boy with Down syndrome admitted due to loss of speech. His physical development was appropriate for his age and had no goiter. Neurological examination revealed the absence of eye contact and stereotypic movements. Autism spectrum disorder was considered based on his result on Gilliam autism evaluation scale. He had subclinical hypothyroidism with markedly elevated anti-thyroid peroxidase antibody level, rare spikes in the frontocentral area were found in electroencephalography, and cranial magnetic resonance imaging was normal. Neurologic improvement was observed to a treatment with glucocorticoid and thyroid hormone. CONCLUSION: HE might be considered in patients with Down syndrome along with progressive cognitive decline and autistic regression.

Impact of eating habits and nutritional status on children with autism spectrum disorder.

OBJECTIVES: Obesity is common among children with Autism Spectrum Disorder (ASD). They suffer more feeding problems than children with normal developmental milestones. Several kinds of diet are recommended for children with ASD. This study determines the frequency of eating disorders and obesity among such children. We investigate the predisposing factors of eating disorders and examine the effects of consumed food on autism scores. METHODS: In this single-centre, cross-sectional study, 46 children with ASD aged between 2 and 10 years were included. Anthropometric measurements were recorded and Brief Autism Mealtime Behavior Inventory (BAMBI), Autism Behavior Checklist (ABC), and Food Frequency Questionnaire (FFQ) forms were filled in by their parents. RESULTS: The rates of being overweight and obese were 10.9% and 28.3%, respectively. Food selectivity was observed in 84.8% of the children, and BAMBI food refusal scores were significantly higher for those aged between 2 and 5 years (p = 0.03). Autism scores and consumption of milk, yoghurt, oily seeds, rice/pasta, and fruits (p < 0.05) were significantly correlated. There were also significant differences between these scores and the frequency of consuming eggs, legumes, and other cereals (p < 0.05). CONCLUSION: Obesity was more common in children with ASD than typically developed children. Despite the high rate of food selectivity, our findings confirmed that food selectivity could be considered independent of obesity. Further, the diet of patients with ASD must include more fruits, yogurt, eggs, legumes, other cereals, less milk, and less rice/pasta.

Play interactions of parents toward children with autism spectrum disorder: NeuroPLAY parent play behavior assessment scale.

PROBLEM: The aim of this study is to analyze the changes that NeuroPLAY, which is an intensive early intervention method for children with autism spectrum disorder (ASD) and ages of 12-42 months, has created in the play skills of the parents of children with ASD by using method strategies. METHODS: The study cohort includes 91 children ages ranging from 18 to 42 months old. The study is designed for repetitive measurements performed pre- and post-intervention. Within the scope of the study, children's ASD symptoms were evaluated with the Childhood Autism Rating Scale (CARS) and changes in the play skills of parents were evaluated using NeuroPLAY Parental Play Behavior Assessment Scale (NPPBAS). RESULTS: The NPPBAS score at the beginning of the intervention was 12.55; repeated measurements (46.22 after 3 months, 45.95 after 6 months, and 48.53 after 12 months) were observed to increase core. The older age of the parents in the intervention program is associated with lower final NPPBAS scores. However, it was determined that the CARS score, which is an indicator of the autism spectrum, will decrease after intervention regardless of the parents' age. CONCLUSION: The results showed that NeuroPLAY led to significant improvement in play behaviors of the parents.

Pontine Tegmentum Lesions Accompanying Myelitis During an Enterovirus Outbreak: Differential Diagnosis and Outcome.

AIM: To investigate etiology and prognostic significance of pontine tegmentum lesions accompanying a cluster of acute flaccid myelitis. METHOD: We retrospectively examined patients from 6 centers in Turkey who manifested encephalitis or myelitis associated with dorsal pontine lesions on magnetic resonance imaging (MRI) between July 2018 and February 2019. RESULTS: Twenty-two patients were evaluated. Ten of 22 (45%) presented with acute paralysis and 12 of 22 (55%) with brainstem symptoms only. Reverse transcription polymerase chain reaction for enterovirus was positive in 2 patients' respiratory tract. Other etiologic factors were detected in 10 cases. On follow-up, patients presenting with symptoms of myelitis developed motor sequalae although spinal cord lesions on MRI resolved in 5 of 9 (55%). Encephalitic symptoms, present in 17 cases, recovered in 13 (76%), and brain MRI showed complete or near-complete resolution in 11 of 14 (78%). CONCLUSION: Various etiologic agents can be detected in patients with pontine involvement, even in a series collected during an outbreak of EV-D68. Encephalitis has a fair outcome but clinical recovery is slow and motor sequalae are frequent in spinal involvement, irrespective of follow-up spinal MRI findings.

Neonatal hypoxic ischemic encephalopathy: an update on disease pathogenesis and treatment.

INTRODUCTION: Hypoxic ischemic encephalopathy (HIE) is the most important reason for morbidity and mortality in term-born infants. Understanding pathophysiology of the brain damage is essential for the early detection of patients with high risk for HIE and development of strategies for their treatments. Areas covered: This review discusses pathophysiology of the neonatal HIE and its treatment options, including hypothermia, melatonin, allopurinol, topiramate, erythropoietin, N-acetylcyctein, magnesium sulphate and xenon. Expert commentary: Several clinical studies have been performed in order to decrease the risk of brain injury due to difficulties in the early diagnosis and treatment, and to develop strategies for better long-term outcomes. Although currently standard treatment methods include therapeutic hypothermia for neonates with moderate to severe HIE, new supportive options are needed to enhance neuroprotective effects of the hypothermia, which should aim to reduce production of the free radicals and to have anti-inflammatory and anti-apoptotic actions.

Nicolau syndrome after intramuscular benzathine penicillin treatment.

Nicolau syndrome (livedoid dermatitis) is a very rare complication of intramuscular injections and manifests as excruciating pain immediately after injection. We describe a 3-year-old boy with diagnosis of Nicolau syndrome after intramuscular benzathine penicillin injection to the midanterior part of the left thigh. He was treated with hyberbaric oxygen and pentoxyphilline in addition to supportive treatment and recovered with no sequelae.

Vestibular neuritis caused by enteroviral infection.

Vestibular neuritis is characterized by the sudden onset of nausea, vomiting, and spontaneous horizontal or horizonto-rotatory nystagmus. The etiology of the disease is multifactorial. Mumps, rubella, herpes simplex virus type 1, cytomegalovirus, and Epstein-Barr virus may have a role in the disease. Enteroviruses are among the other rare causes. This report presents a 7-year-old male admitted with nausea, vomiting, rotatory vertigo, horizonto-rotatory nystagmus with positive Romberg's sign and positive head-thrust test. Cranial magnetic resonance imaging and audiometry of the patient were normal. He was diagnosed with vestibular neuritis, and steroid therapy was initiated. At the second month of follow-up, all symptoms had regressed. To the best of our knowledge, this case report describes the first pediatric patient in whom enteroviral ribonucleic acid is documented both in cerebrospinal fluid and in nasopharyngeal material in active disease. This finding supports the possible role of enteroviruses in the etiology of vestibular neuritis.