Clinical and molecular findings in 6 Turkish cases with Krabbe disease.

BACKGROUND: Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature. METHODS: Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantileonset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligationdependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis. RESULTS: GALC gene sequence analysis revealed four known mutations including c.1394C > T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G > C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G > A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases. CONCLUSIONS: We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests.

Development of Antiarrhythmic Therapy-Resistant Ventricular Tachycardia, Ventricular Fibrillation, and Premature Ventricular Contractions in a 15-Year-Old Patient.

Sudden cardiac arrest (SCA) is the sudden cessation of regular cardiac activity so that the victim becomes unresponsive, with no signs of circulation and no normal breathing. Asystole, ventricular tachycardia (VT), ventricular fibrillation (VF), and pulseless electrical activity are the underlying rhythm disturbances in the pediatric age group. If appropriate interventions (cardiopulmonary resuscitation-CPR and/or defibrillation or cardioversion) are not performed rapidly, this condition progresses to sudden death. There have not been many reported cases of the approach and treatment of cardiac arrhythmias after SCA. Herein, we would like to report a case of a 15-year-old female patient with dilated cardiomyopathy (DCM) who was admitted to our clinic a year ago, and while her left ventricular systolic functions were improved, SCA suddenly occurred. Since the SCA event occurred in another city, intravenous treatment of amiodarone was done immediately and was switch to continuous infusion dose of amiodarone until the patient arrived at our institution's pediatric intensive care unit (PICU) 3 hours later. During the patient's 20-day PICU hospitalization, she developed pulseless VT and VF from time to time. The patient's pulseless VT and VF attacks were brought under control by the use of a defibrillator and added antiarrhythmic drugs (amiodarone, flecainide, esmolol, and propafenone). Intriguingly, therapy-resistance bigeminy with premature ventricular contractions (PVCs) continued despite all these treatments. The patient did not have adequate blood pressure measured by invasive arterial blood pressure monitoring while having bigeminy PVCs. The intermittent bigeminy PVCs ameliorated rapidly after intermittent boluses of lidocaine. In the end, multiple antiarrhythmic therapies and intermittent bolus lidocaine doses were enough to bring her cardiac arrhythmias after SCA under control. This case illustrates that malign PVC's should be taken very seriously, since they may predispose to the development of VT or VF. Also, this case highlights the importance of close vigilance of arterial pressure tracings of patients with bigeminy PVCs which develop after SCA and should not be accepted as normal.

Importance of Thalamostriatal Pathway Associated With Neurocognitive Dysfunctions in Children With Neurofibromatosis Type 1: Diffusion Tensor Imaging Findings.

OBJECTIVE: To determine whether there is a difference between healthy control group and children with neurofibromatosis type 1 (NF1) in terms of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values in different regions of the brain associated with neurocognitive functions and to investigate the correlation between diffusion tensor imaging parameters and neurocognitive dysfunctions. METHODS: The study included 28 children with NF1 and 21 controls. Nine distinct areas related to cognitive functions were selected for the analysis. The ADC and FA values were compared. RESULTS: There was a significant difference between NF1 and healthy control in terms of ADC values obtained from all areas. The ADC values at obtained from thalamus and striatum were positively correlated with the full-scale intelligence quotient (IQ), verbal IQ, and performance IQ. CONCLUSIONS: We are speculated that the development of microstructural damage in the thalamostriatal pathway may lead to neurocognitive dysfunction.

A Snapshot of Pediatric Patients with COVID-19 in a Pandemic Hospital.

AIM: Reports describing coronavirus disease 2019 (Covid-19) in children are fewer than adult studies due to milder clinical picture. We aimed to share our experience at a single center with an emphasis on collective decision making. MATERIALS AND METHODS: A suspected case was defined as the presence of symptoms suggestive of COVID-19 and/or positive contact history. SARS-CoV-2 PCR positive patients were defined as confirmed COVID-19. Between March 12, 2020, and May 15, 2020, all children presenting with fever, cough, or respiratory difficulty were investigated for COVID-19. A total of 719 children were examined at outpatient clinics, and 495 were tested with polymerase chain reaction (PCR) for suspicion of COVID-19. A team was organized for monitoring and treating patients either as outpatients or hospitalization. Patients were evaluated in terms of age, gender, travel history, epidemiological history, clinical symptoms and signs, laboratory and radiological findings, treatment, and outcome. RESULTS: Sixty patients were hospitalized for suspicion of COVID-19. Forty-three patients were diagnosed as probable or confirmed COVID-19. 21 of 43 patients (48.8%) were PCR confirmed. The remaining 22 were diagnosed by epidemiologic history, clinical assessment, and computerized thorax tomography (CT) findings. The median age was 126 and 78.5 months in PCR positives and PCR negatives, respectively and the youngest patient was a 28 days old baby. Nineteen of the patients had an upper respiratory infection (44.1%). Although five patients had no clinical signs, chest X-ray, or CT revealed pneumonia. CONCLUSIONS: As previously reported, the clinical manifestations of COVID-19 in children are mostly mild. Even very young kids can become infected following exposure to sick family members. International and local guidelines are valuable for decision making since it is a new disease. A combination of chest disease, infectious diseases, and emergency care physicians approach will aid the appropriate management of cases.

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.

Expanding Clinical Phenotype of TRAPPC12-Related Childhood Encephalopathy: Two Cases and Review of Literature.

Biallelic mutations in the TRAPPC12 gene are responsible for early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS). To date, three different allelic variants have been reported. Next-generation sequencing allowed discovery of unique alternations in this gene with different phenotypes. We report two patients carrying TRAPPC12 variants, one previously reported and one unknown mutation, with severe neurodevelopmental delay and brain atrophy. Standard clinical examination and cranial imaging studies were performed in these two unrelated patients. In addition, whole-exome sequencing was performed, followed by Sanger sequencing for verification. The first patient, a 2-year-old boy, was found to be homozygous for the previously reported c.1880C > T (p.Ala627Val) mutation. He presented with a phenotype including severe progressive cortical atrophy, moderate cerebellar atrophy, epilepsy, and microcephaly, very similar to the previously reported cases. The second case, a 9-year-old boy, carried a novel homozygous c.679T > G (p.Phe227Val) variant and presented with mild cortical atrophy, severe cerebellar atrophy, and neither clinically manifest epilepsy nor microcephaly, which were previously considered typical findings in PEBAS with TRAPPC12 mutations. Our findings suggest that clinical and brain imaging findings might be more variable than previously anticipated; however, a larger number of observations would benefit for broader phenotypic spectrum.

The acute effects of physiotherapy on general movement patterns in preterm infants: A single-blind study.

BACKGROUND: The General Movement Assessment (GMA) is a video analysis method developed by Heinz Prechtl that examines the infant's spontaneous movements. In recent years, although many studies have been performed in preterm infants by applying GMA, few studies have shown the effects of early intervention on GMA. AIMS: Current study was planned to determine the acute effects of a single-session early physiotherapy approach on preterm infants' general spontaneous movements, and to reveal the change in Motor Optimality Scale (MOS) score including FMs. STUDY DESIGN: Prospective, single-blind study. SUBJECTS: Current study was carried out with 32 preterm infants at postterm 12-16 weeks. OUTCOME MEASURES: The infants included in the study were videotaped by a physiotherapist during 10-15 min before the physiotherapy session at postterm 12-16 weeks for GMA. After a single physiotherapy session, the same physiotherapist performed the same video footage second time. A blind evaluator assessed the videos taken before and after session and scored Motor Optimality Scale (MOS). RESULTS AND CONCLUSIONS: There was no statistically significant difference between MOS sub-category and total score of the infants before and after the session (p > 0.05). According to the results of present study, a single-session early physiotherapy intervention did not have an acute effect on the spontaneous movements of preterm infants at postterm 12-16 weeks. Future studies are needed to demonstrate the short and long-term effects of early physiotherapy approaches to risky infants.

Oxidant and antioxidant levels and DNA damage in tuberous sclerosis.

OBJECTIVE: The pathogenesis of inherited diseases is thought to involve oxidative stress and the associated DNA damage, which are also implicated in many other conditions including cancer. Tuberous sclerosis is a genetic disease with autosomal dominant inheritance pattern that is characterized by the development of hamartomas in multiple organ systems. Oxidative stress and the related DNA damage are also likely to play a significant role in the pathogenesis of this condition. Thus, our study aimed to assess total oxidant-antioxidant level, oxidative stress index and DNA damage in patients diagnosed with tuberous sclerosis. METHODS: The study included 30 patients with tuberous sclerosis between the ages of 0 and 16 years. The control group consisted of 29 age-matched healthy children. Blood samples obtained from each subject were centrifuged to separate the sera. The Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) were measured in serum samples with a Thermo Scientific Multiscan plate reader (FC, 2011-06, USA) at wavelengths of 240 nm and 520 nm, respectively. The measured TAS and TOS values were used to calculate the Oxidative Stress Index (OSI). In addition, the Comet Assay Method was used to determine DNA damage in the samples. Data were analyzed using SPSS software. RESULTS: Patients with tuberous sclerosis complex (TSC) and controls were compared with respect to TAS, TOS, and OSI. TAS was significantly lower (p < 0.01), while TOS and OSI were significantly higher (p < 0.01, for both) in patients as compared to controls. In addition, patients had significantly higher DNA damage as shown by the Comet Assay (p < 0.01). CONCLUSIONS: Increased oxidative stress and DNA damage may contribute to the pathogenesis of tuberous sclerosis.

Onychomadesis: A rare adverse effect in early-period valproic acid therapy.

Valproic acid is an effective, frequently used anticonvulsant drug. Typical adverse effects include weight gain, hair loss, and nausea. Hyperpigmentation, onycholysis, and onychomadesis are nail changes that can be seen after valproic acid use. Changes occur at the distal and proximal portions of the nail bed in onycholysis and onychomadesis, respectively. Onychomadesis is a very rare disease of childhood with the exception of systemic and genetic diseases. Here, we present a child aged 23 months, the youngest and the earliest isolated patient with onychomadesis, which occurred after valproic acid treatment and worried the family but resolved spontaneously. The improvement of this very rare adverse effect of antiepileptic drugs after cessation of valproic acid without treatment is emphasized.

The impact of epilepsy on preschool children and their families.

This study investigated the possible presence of sensory-motor developmental impairments in preschool children with epilepsy and explored epilepsy impact on their activities and quality of life and on the stress load of their family. Study participants were children aged 2-6years diagnosed with epilepsy without any other comorbidities (epi-only children). The instruments used for assessment included the Neurological, Sensory, Motor, Developmental Assessment (NSMDA) scale for sensory-motor development, the Impact of Childhood Neurologic Disability Scale (ICNDS), and the Impact of Pediatric Epilepsy Scale (IPES) for disease impact on disability and Quality of Life (QoL), as well as the Pediatric Outcomes Data Collection Instrument (PODCI) for functional health status, and the Parental Stress Scale (PSS) for the family stress load. Required data were obtained from direct testing or observation of children's activities and mother-supplied answers to questions. Eighty-two children were investigated. The NSMDA scores were in the normal development range 6-8. Significant moderate impact of the disease on disability and QoL was estimated with the ICNDS and IPES instruments. The PODCI scores were similar to healthy population levels except for the happiness dimension which was better for children with epilepsy. PSS were significantly above normal. The functional health and QoL of the children as well as their family stress were found to be positively correlated with increasing age. It is found that epilepsy does not degrade neuromotor development and functional health status of preschool epi-only children, though it has a significant impact on their neurological disability and QoL and the stress level of their families; this impact seems to decrease with age.

Clinical Significance of Human Metapneumovirus in Refractory Status Epilepticus and Encephalitis: Case Report and Review of the Literature.

Encephalitis is a complex neurological disease that is associated with significant morbidity and mortality, and the etiology of the disease is often not identified. Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. Few reports are available showing possible involvement of hMPV in development of neurologic complications. Here, we describe an infant, the youngest case in literature, with refractory status epilepticus and severe encephalitis in whom hMPV was detected in respiratory samples and review diagnostic workup of patient with encephalitis.

A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family.

A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents.

Prognosis and demographic characteristics of SSPE patients in Istanbul, Turkey.

AIM: SSPE is a rare progressive, invariably fatal long-term complication of measles infection. In this study, we assessed the demographic and prognostic characteristics of 64 consecutive SSPE patients diagnosed at a tertiary center. METHODS: The study had a retrospective design; data were obtained from patient records. RESULTS: The study includes 64 patients diagnosed with SSPE. There was history of consanguineous marriage in 27 (42.2%) patients. The average patient lifespan was 3.8years (45days-12years). The average patient age at diagnosis was 12.3 (range, 5-17)years. A statistically significant correlation was found between the age at diagnosis and lifespan (p=0.002). A statistically significant correlation was found between the incubation period and patient lifespan (p<0.001). No significant correlation was found between duration in the intensive care unit and lifespan (p=0.122). Routine physical therapy had no significant impact on the average lifespan (p=0.619). No significant difference was found between the vaccination dose and lifespan (p=0.651). CONCLUSIONS: High frequency of parental consanguinity in SSPE patients need to be evaluated as there might a genetic influence. Physical therapy and supportive treatments seems to have no affect on lifespan in SSPE patients. The age at diagnosis and incubation period might have an affect on prognosis and lifespan.

MRS features during encephalopathic crisis period in 11 years old case with GA-1.

Glutaric aciduria type-1 (GA-1) is a disorder of amino acid metabolism. The usual clinical-onset is an acute encephalopathic crisis in early childhood. There are only a few cases diagnosed in older age groups. MRI features of the disease are well defined. However, there are limited number of studies concerning advanced neuroimaging findings. We present DWI and MRS findings of an 11 year-old GA-1 patient admitted with an encephalopathic crisis. Diffusion restrictions in bilateral basal ganglia, corpus callosum and periventricular deep white matter were observed. In left occipital periventricular white matter and left basal ganglia, mild increased Cho/Cr and MI/Cr ratios and decreased NAA/Cr ratio were detected. Also inverted double lactate peak (TE: 135 ms) was present at 1.33 ppm in the left basal ganglia. In addition to these findings, a peak at 1.56 ppm above the baseline was seen on both short and long echo-time MRS in left occipital lobe deep white matter which may show accumulation of degradation products of amino acids in the GCDH enzyme deficiency.

Visual and brainstem auditory evoked potentials in infants with severe vitamin B12 deficiency.

BACKGROUND/AIM: Vitamin B12 plays an important role in the development of mental, motor, cognitive, and social functions via its role in DNA synthesis and nerve myelination. Its deficiency in infants might cause neuromotor retardation as well as megaloblastic anemia. The objective of this study was to investigate the effects of infantile vitamin B12 deficiency on evoked brain potentials and determine whether improvement could be obtained with vitamin B12 replacement at appropriate dosages. MATERIALS AND METHODS: Thirty patients with vitamin B12 deficiency and 30 age-matched healthy controls were included in the study. Hematological parameters, visual evoked potentials, and brainstem auditory evoked potentials tests were performed prior to treatment, 1 week after treatment, and 3 months after treatment. RESULTS: Visual evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) were found to be prolonged in 16 (53.3%) and 15 (50%) patients, respectively. Statistically significant improvements in VEP and BAEP examinations were determined 3 months after treatment. Three months after treatment, VEP and BAEP examinations returned to normal in 81.3% and 53.3% of subjects with prolonged VEPs and BAEPs, respectively. CONCLUSION: These results demonstrate that vitamin B12 deficiency in infants causes significant impairment in the auditory and visual functioning tests of the brain, such as VEP and BAEP.

An evaluation of serum paraoxonase together with arylesterase activities and oxidative stress in children with intractable epilepsy: a cross-sectional study.

Epilepsy is the most common chronic neurological illness in childhood and adolescence. The aim of this study was to investigate paraoxonase and arylesterase activities along with oxidative status parameters in children with intractable epilepsy. The study comprised 42 subjects with intractable epilepsy and a control group of 35 healthy subjects. Serum paraoxonase and arylesterase activities, and lipid hydroperoxide levels were determined. All paraoxonase and arylesterase activities were significantly lower in the intractable epilepsy subjects than in the controls (P<0.001), whereas lipid hydroperoxide levels were significantly higher (P<0.05). In conclusion, paraoxonase and arylesterase activities were decreased and the lipid hydroperoxide level was increased in patients with intractable epilepsy. These results showed that intractable epilepsy subjects may be more prone to the development of atherosclerosis.

May TLR4 Asp299Gly and IL17 His161Arg polymorphism be associated with progression of primary measles infection to subacute sclerosing panencephalitis?

SSPE is a progressive neurological disorder of children. Only some of the children who are infected with measles virus develop SSPE, which supports individual variation. TLR-2 and TLR-4 play an important role in innate immunity by recognizing envelope proteins of MV. Another important cytokine that plays an important role in orchestrating innate immune function is IL-17. The purpose of our study is to elucidate whether the TLR2, TLR4, IL17F and IL17A gene polymorphisms are susceptibility genes for the development of SSPE. Using the PCR-RFLP methods, the single nucleotide polymorphisms of TLR2 (Arg753Gln, Arg677Trp, -194 to -174 del), TLR4 (Asp299Gly and Thr399Ile) IL17F (His161Arg, Glu126Gly) and IL17A were studied in 54 patients with SSPE and 81 healthy controls. For Asp299Gly polymorphism of the TLR4 gene we found that there were no control individuals who were homozygous carriers of the Gly/Gly genotype, and the risk for SSPE increased at approximately 4.7 fold for the heterozygous carriers of the Asp/Gly genotype (OR 4.727, 95%-CI 1.192-18.742; P=0.01), when compared to healthy controls. Also our findings demonstrate that homozygosity for the Arg161 variant of the IL17F His161Arg polymorphism is inversely associated with development of SSPE (OR 0.114 95%-CI 0.026-0.494; P<0.001). In conclusion, it is suggested that variation in susceptibility to SSPE disease may be in part due to variations in TLR4 and IL17 function resulting from polymorphisms of TLR4 Asp299Gly and IL17F His161Arg.

Interictal serum S-100B protein levels in intractable epilepsy: a case-control study.

Epilepsy is the most common neurologic disorder of childhood. In approximately 6-14% of all patients with epilepsy, complete seizure control is difficult to achieve with current antiepileptic treatments. Several current studies have shown in both animals and people that the lengthening of epileptic seizures and frequent recurrence increases the likelihood of neuronal damage. S-100B protein is the most analyzed brain derived peripheral biochemical marker in brain damage. This study aimed to evaluate interictal serum S-100B protein levels in children diagnosed with intractable epilepsy. A group of 32 patients with intractable epilepsy and 25 healthy controls were recruited. Serum S-100B protein levels were measured using a commercially available electrochemiluminescence immunoassay (ECLIA kit, as supplied and according to the manufacturer's standards. The serum S-100B protein levels of the patient group in the study were found to be 0.094±0.011 µm/L, and 0.083±0.014 µm/L in the age-matched control group. The difference between the groups was determined to be statistically significant (P=0.004). In conclusions, it can be said that as the serum S-100B protein levels of the patients with focal epilepsy were high compared to those of the control group, this can be reliable peripheral biomarker for neuronal damage in patients with focal intractable epilepsy.