Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Early diagnostic clues of mucolipidosis type II: Significance of radiological findings.

Mucolipidosis type-II (ML-II) is an ultra-rare disorder caused by deficiency of N-acetylglucosaminyl-1-phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few known about the natural history of ML-II. In this study, we presented the natural course of 24 patients diagnosed with ML-II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML-II were different from typical dysostosis multiplex such as femoral cloaking, rickets-like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML-II and disappears in the first year. Cloaking, rickets-like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.

A Retrospective Cohort Study of Traumatic Brain Injury in Children: A Single-Institution Experience and Determinants of Neurologic Outcome.

Introduction: Traumatic brain injury (TBI) has become a significant cause of death and morbidity in childhood since the elucidation of infectious causes within the last century. Mortality rates in this population decreased over time due to developments in technology and effective treatment modalities. Aim of the study: This retrospective cohort study aimed to describe the volume, severity and mechanism of all hospital-admitted pediatric TBI patients at a university hospital over a 5-year period. Material and Methods: This was a single-center, retrospective cohort study including 90 pediatric patients with TBI admitted to a tertiary care PICU. The patients' demographic data, injury mechanisms, disease and trauma severity scores, initiation of enteral nutrition and outcome measures such as hospital stay, PICU stay, duration of mechanical ventilation, mortality, and Glasgow Outcome Scale (GOS) were also recorded. Late enteral nutrition was defined as initiation of enteral feeding after 48 hours of hospitalization. Results: Of the 90 patients included in the cohort, 60% had mild TBI, 21.1% had moderate TBI and 18.9% had severe TBI. Their mean age was 69 months (3-210 months). TBI was isolated in 34 (37.8%) patients and observed as a part of multisystemic trauma in 56 (62.2%). The most commonly involved site in multisystemic injury was the thorax (33.3%). The length of hospitalization in the late enteral nutrition group was significantly higher than that in the early nutrition group, while the PICU stay was not significantly different between the two groups. The multiple logistic regression analysis found a significant relationship between GOS-3rd month and PIM3 score, the presence of diffuse axonal injury and the need for CPR in the first 24 h of hospitalization. Conclusion: Although our study showed that delayed enteral nutrition did not affect neurologic outcome, it may lead to prolonged hospitalization and increased hospital costs. High PIM3 scores and diffuse axonal injury are both associated with worse neurologic outcomes.

Posttraumatic epilepsy in critically ill children with traumatic brain injury.

PURPOSE: The aim of this study was to determine the clinical, laboratory, and radiological factors related with posttraumatic epilepsy (PTE). METHODS: The study is a multicenter descriptive cross-sectional cohort study. Children who followed up for TBI in the pediatric intensive care unit between 2014 and 2021 were included. Demographic data and clinical and radiological parameters were recorded from electronic case forms. All patients who were in the 6-month posttraumatic period were evaluated by a neurologist for PTE. RESULTS: Four hundred seventy-seven patients were included. The median age at the time of trauma was 66 (IQR 27-122) months, and 298 (62.5%) were male. Two hundred eighty (58.7%) patients had multiple traumas. The mortality rate was 11.7%. The mean duration of hospitalization, pediatric intensive care unit hospitalization and mechanical ventilation, Rotterdam score, PRISM III score, and GCS at admission were higher in patients with epilepsy (p < 0.05). The rate of epilepsy was higher in patients with severe TBI, cerebral edema on tomography and clinical findings of increased intracranial pressure, blood transfusion in the intensive care unit, multiple intracranial hemorrhages, and intubated patients (p < 0.05). In logistic regression analysis, the presence of intracranial hemorrhage in more than one compartment of the brain (OR 6.13, 95%CI 3.05-12.33) and the presence of seizures (OR 9.75, 95%CI 4.80-19.83) were independently significant in terms of the development of epilepsy (p < 0.001). CONCLUSIONS: In this multicenter cross-sectional study, intracranial hemorrhages in more than one compartment and clinical seizures during intensive care unit admission were found to be independent risk factors for PTE development in pediatric intensive care unit patients with TBI.

Peripheral facial nerve palsy in children: clinical manifestations, treatment and prognosis.

Background: Sudden onset of unilateral weakness of the upper and lower muscles of one side of the face is defined as peripheral facial nerve palsy. Peripheral facial nerve palsy is often idiopathic and sometimes it could be due to infectious, traumatic, neoplastic, and immune causes. This study aimed to report the clinical manifestation, evaluation, and prognosis in children with peripheral facial nerve palsy. Methods: 57 children under 18 years of age diagnosed with peripheral facial nerve palsy at Çukurova University, Balcali Hospital, between January 2018 and September 2021, were included in the study. Results: The mean age of the children at the time of diagnosis was 9.6 ± 7, 4 years. Thirty-two (56.1%) of the patients were female and 25 (43.9%) were male. A total of 57 patients were diagnosed with peripheral facial nerve palsy and categorized into many groups by etiology: idiopathic Bell's palsy in 27 (47.5%), infectious in 11 (19.2%), traumatic in 6 (10.5%), and others (due to congenital, immune, neoplastic, Melkersson-Rosenthal syndrome, drug toxicity, and iatrogenic causes) in 13 (22.8%). Forty-six of the children achieved full recovery under oral steroids within 1-7 months. Four patients with acute leukemia, myelodysplastic syndrome, Mobius syndrome and trauma did not recover and two patients (schwannoma, trauma) showed partial improvement. Five patients could not come to follow-up control. Conclusion: Peripheral facial nerve palsy is a rare condition in children with different causes. It could be idiopathic, congenital, or due to infectious, traumatic, neoplastic, and immune reasons. So, when a child presents with facial palsy, a complete clinical history and a detailed clinical examination are recommended. Giving attention to the red flag is very important. Peripheral facial nerve palsy in children is considered to have a good prognosis.

Evaluation of the relationship between NIRS (near-infrared spectroscopy) and optic nerve sheath diameter measurement in children with increased intracranial pressure: a pilot study.

BACKGROUND: The increased intracranial pressure (ICP) syndrome may emerge depending on many different neurological factors and the early diagnosis and treatment are important for the prevention of neurologic damage and related mortality. In recent years, the follow-up of increased ICP with non-invasive methods has been rising. In this study, our objective was to determine the significance and any possible correlation between Optic Nerve Sheath Diameter (ONSD) and Near Infrared Spectroscopy (NIRS) in children with increased ICP. METHODS: Patients who were hospitalized in our pediatric ICU at Çukurova University Medical Faculty between June 2018 and June 2019 due to the suspicion of increased ICP were included in this study. The demographic characteristics of patients, diagnosis at admission, results of the cranial CT and MRI examinations, and results of the simultaneous ONSD and NIRS measurements were recorded. RESULTS: A total of 36 patients were included in our study. With respect to the diagnosis, non-traumatic causes were at the forefront in 30 patients (83.3%), and the most common causes were meningoencephalitis (n = 9; 25%) and non-traumatic bleeding (n = 7; 19.4%). Six of the patients were under the age of one year (16.7%), and the mean values of ONSD and NIRS were 4.8 ± 0.7 mm and 71.1 ± 12.4% respectively in this group. Fourteen patients were in the one to ten year age group and the mean values of ONSD and NIRS were 6.1 ± 0.6 mm and 72.7 ± 9.3% respectively. Sixteen patients were over ten years of age (44.4%), and the mean values of ONSD and NIRS were 5.6 ± 0.7 mm and 74.2 ± 16% respectively. There was no correlation between the ONSD and NIRS values (r:0.307; p = 0.068). CONCLUSION: Our study showed that ONSD measurements were helpful in children with increased ICP and reflected the increase in ICP. However, our study also demonstrated that ONSD was not in correlation with the NIRS monitoring. We believe that there is a need for further studies focused on the use of ONSD and NIRS in the monitoring of increased ICP.

The outcome of 41 Late-Diagnosed Turkish GA-1 Patients: A Candidate for the Turkish NBS.

BACKGROUND: Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. METHOD: This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. RESULTS: The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. CONCLUSION: All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.

Evaluation of Pediatric Brain Death and Organ Donation: 10-Year Experience in a Pediatric Intensive Care Unit in Turkey.

OBJECTIVE: We aimed to investigate the rate of brain death (BD) determinations and organ donations (OD) in our tertiary pediatric intensive care unit (PICU), and to report the data on the demographic pattern and supplementary descriptive data on BD declarations. METHODS: The study was designed as a retrospective, single-center, descriptive cohort study. We evaluated all children who were determined to meet the criteria for BD in our tertiary PICU between January 2011 and December 2020. RESULTS: During study period, BD was identified in 24 patients among 225 total deaths (10.7%). Their median age was 85 months (8-214) and the male-to-female ratio was 1 : 1. The most common diagnosis was meningoencephalitis in 25%, followed by traumatic intracranial hemorrhage (16.7%). The median time from admission to PICU until BD diagnosis was 6.5 days. The time from the first BD physical examination to the declaration of BD was 27.5 hours. There was no statistically important difference between donors and non-donors. The apnea test (AT) was the most performed ancillary method (100%), followed by electroencephalogram (EEG) (66.7%), and magnetic resonance angiography or computed tomography angiography (MRA/ CTA) (54.2%). Hyperglycemia developed in 79.2% of the cases, and 70.8% developed diabetes insipidus (DI). Five patients (20.8%) were organ donors in study group. In the study, 13 solid organ and 4 tissue transplantations were performed after OD. CONCLUSION: Awareness of the incidence and etiology may contribute to the timely diagnosis and declaration of brain death, and with the help of good donor care, may help in increasing OD rates in the pediatric population.

Congenital myasthenic syndrome in Turkey: clinical and genetic features in the long-term follow-up of patients.

Congenital Myasthenic Syndromes (CMS) are rare disorders that occur as a result of defects in the structure and in the function of neuromuscular junctions. Molecular genetic diagnosis is important to select the most suitable therapeutic option and treatment. Eight patients with congenital myasthenic syndromes who presented to the Çukurova University Pediatric Neurology Department Outpatient Clinic between June 2015 and May 2018 were reviewed. Mutations in the acetylcholine receptor (subunits in epsilon) (CHRNE) in three and mutations in the collagenic tail of endplate acetylcholinesterase (COLQ) gene in five patients were identified; p.W148 mutation was detected to be homozygous in four, c.1169A > G novel mutation in COLQ gene was homozygous in one, c452_454delAGG mutation was homozygous in the other patient, IVS7 + 2T > C(c.802 + 2T > C) mutation was homozygous in a patient and compound heterozygous mutations of c.865C > T(p.Leu289Phe) and c.872C > G(p.A2916)(p.Arg291Gly) in the CHRNE gene in the last patient. The parents of all the evaluated patients were consanguineous. Ptosis, ophthalmoplegia, generalized hypotonia, bulbar weakness, and respiratory crisis were the main findings at the time of presentation. Pyridostigmine is the first-line drug therapy in primary AChR deficiency. Beta adrenergic agonists, ephedrine, and albuterol are the other treatment options for CMS subtypes caused by mutations in COLQ. This study points out the genetic and phenotypic features of CMS patients in the Turkish population and it also reports previously unreported mutations in the literature. CHRNE and COLQ gene mutations are common in the Turkish population. Patients can get serious benefits and recover after the treatment. The treatment should be planned according to genetic tests and clinical findings.

Effect of Levetiracetam Usage on Serum Creatine Phosphokinase Concentration in Patients with Epilepsy.

BACKGROUND: Levetiracetam (LEV) is a widely used antiepileptic drug (AED) in the treatment of various type of seizures, including generalized epileptic seizure as well as focal seizures, and it is generally well tolerated. Common side effects of LEV are somnolence, asthenia, dizziness, mood changes, kidney dysfunction, minor infections, and thrombocytopenia. Recently, increased creatine phosphokinase (CPK) concentration or rhabdomyolysis after LEV administration has been reported. The goal of the study was to evaluate clinical risk factors associated with increased CPK concentration or rhabdomyolysis in LEV administration. MATERIALS AND METHODS: One hundred and sixty children were enrolled. The risk factors were retrospectively analyzed. RESULTS: Among the 160 patients, 84 (52.5%) were boys and 76 (47.5%) were girls, and the mean age was 85.95 ± 49.03 months (9-188 months). Of the 160 patients, 66 (41.3%) were treated with monotherapy, and 94 (58.8%) with polytherapy. We detected increased CPK concentration or rhabdomyolysis in three patients (1.9%). The CPK values of these three patients were 943, 1504, and 5046, respectively. No significant differences were observed in the serum CPK concentration between the patients treated with LEV. CONCLUSION: We detected that LEV may cause increased CPK concentration or rhabdomyolysis. When treating patients with LEV, clinicians should closely monitor serum CPK level. To the best of our knowledge, this is the first study of elevated CPK concentration or rhabdomyolysis associated with LEV therapy in children.

Clinical Features and Molecular Genetics of Autosomal Recessive Ataxia in the Turkish Population.

BACKGROUND: Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of inherited neurodegenerative disorders. The aim of this study was to present the clinical and genetic features of patients with ataxia complaints and those genetically diagnosed with ARCAs. MATERIALS AND METHODS: Thirty-one children with ARCA were retrospectively analyzed. RESULTS: Fourteen (45.2%) were boys and 17 (54.8%) were girls with the mean age at onset of symptoms of 46.13 ± 26.30 months (12-120 months). Of the 31 patients, 21 (67.7%) were from consanguineous marriages. Eight patients had Friedreich's ataxia, five had ataxia telangiectasia, three had L-2-hydroxyglutaric aciduria, three had Joubert syndrome, two had neuronal ceroid lipofuscinosis, two had megalencephalic leukoencephalopathy with subcortical cysts, two had ataxia with ocular motor oculomotor apraxia type 1, one had cytochrome c oxidase deficiency, one had autosomal recessive spastic ataxia of Charlevoix-Saguenay, one had Niemann-Pick type C, one had congenital disorders of glycosylation, one had adrenoleukodystrophy, and one had cobalamin transport disorder. CONCLUSION: The prevalence of hereditary ataxia can vary among countries. The consanguineous marriage is an important finding in these diseases. These genetic tests will increase the number of ARCA patients diagnosed.

Mitochondrial Membrane Protein-Associated Neurodegeneration: A Case Series of Six Children.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders with a progressive extrapyramidal syndrome and excessive iron deposition in the brain, particularly in the globus pallidus and substantia nigra. Mitochondrial membrane protein-associated neurodegeneration (MPAN), a subtype of NBIA, is caused by mutation in the orphan gene C19orf12. A slowly progressive gait disorder from generalized dystonia and spasticity and cognitive impairment constitute the main features of MPAN. The C19orf12 p.Thr11Met mutation is frequent among Turkish patients with MPAN. Here, we report the clinical manifestations and genetic study results of six Turkish patients with MPAN due to different mutations from previous.

Different Clinical Manifestations of Three Prime Repair Exonuclease 1 Mutation: A Case Series.

Three prime repair exonuclease 1 (TREX1) degrades single- and double-stranded DNA with 3'-5' exonuclease activity. TREX1 mutations are related to type 1 interferon-mediated autoinflammation owing to accumulated intracellular nucleic acids. Several cases of systemic lupus erythematosus, Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), and retinal vasculopathy-cerebral leukodystrophy caused by TREX1 mutations have been reported, so far. In this report, we described five patients with TREX1 mutations from three families with three different disorders, which include AGS, FCL, and FCL with central nervous system vasculitis.

A homozygote novel L451W mutation in CECR1 gene causes deficiency of adenosine deaminase 2 in a pediatric patient representing with chronic lymphoproliferation and cytopenia.

Deficiency of Adenosine Deaminase 2 (DADA2) is a monogenic autoinflammatory disorder characterized by livedo reticularis, skin ulcers, subcutaneous rash, aphthous ulcers, and leukocytoclastic vasculitis, neurological signs such as early onset stroke and polyneuropathy. A minority of DADA2 patients suffer from severe cytopenia and lymphoproliferation. Herein, we report an adolescent patient, followed up as having a hematological disorder for many years, eventually diagnosed as having DADA2. In view of the presence of elevated acute phase reactants, hepatosplenomegaly, low IgM level, lymphopenia, anemia, and neutropenia, and a subtle neurological involvement we considered DADA2 diagnosis. The diagnosis was confirmed by identification of a novel L451W mutation in CECR1 gene. The patient has been successfully treated with etanercept, monthly intravenous immunoglobulin replacement, and low-dose methylprednisolone. In conclusion, although the absence of skin and neurological findings, low IgM levels, and persistent lymphopenia should lead the physicians to consider DADA2 in patients with particularly complicated hematological abnormalities.

Dynamic thiol/disulphide homeostasis in children with neurofibromatosis type 1 and tuberous sclerosis.

Neurofibromatosis type 1 (NF1) and tuberous sclerosis (TSC) are autosomal dominant neurocutaneous diseases. Epilepsy, malignancy and other neurological complications are common in both diseases. We aimed to investigate the thiol/disulphide balance as an oxidative stress marker in children who suffer from NF1 and TSC. Twenty-two patients with NF1, 20 TCS, and 22 healthy control subjects were included in the study. The total thiol, native thiol, and disulphide levels were measured and the disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were calculated and compared in three groups. The mean age and sex distribution of the patients with TSC and NF1 and the healthy control were similar. The total thiol, native thiol, and disulfide level was lower in TSC and NF1 group than the healthy control group. There were no significant differences among disulphide/native thiol and disulphide/total thiol ratios of three groups. We detected that the total thiol, native thiol, and disulfide levels were lower in TSC and NF1 group than the healthy control group. These results indicate that dynamic thiol-disulphide homeostasis can be used as a marker of oxidative stress in clinical trials with TSC and NF1.