A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.

PURPOSE: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. METHODS: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. RESULTS: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. CONCLUSION: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Surgical approaches to upper thoracic Pott's disease with spinal instability during childhood: two cases.

PURPOSE: Tuberculosis is a common disease worldwide that is caused by Mycobacterium tuberculosis. Tuberculosis is primarily a pulmonary disease, but extrapulmonary manifestations are not uncommon, especially in children and adolescents. METHODS: We present two pediatric patients who underwent surgery in our clinic for Pott's disease in the upper thoracic region. The patients were investigated to describe their age, complaints, neurological examination results, disease location, surgical procedure, and complications. RESULTS: The patients were 2 and 14 years old and exhibited disease located in the upper thoracic region (T2-T3 and T1-T2). Both patients displayed severe neurological deficits (Frankel B and C). The kyphotic angles were 82.2° and 43.2°. The patients were stabilized by applying fusion using transpedicular screws via a posterior approach. They also underwent anti-tuberculosis treatment for approximately 1 year. One year later, neither patient exhibited any neurological deficit, and their kyphotic angles were measured as 11° and 1°, respectively. CONCLUSIONS: The recommended treatment approach for unstable cases of Pott's disease located in the upper thoracic region who exhibit neurological deficit and severe kyphotic angling or the development of kyphosis on the thoracic vertebrae is surgical. Decompression, stabilization, and fusion and kyphotic correction can be safely performed via a posterior approach. One of the present cases is the youngest patient described in the literature to undergo transpedicular surgery as a result of Pott's disease. Our other case is the first described in the literature who developed ptosis as a result of tuberculosis and underwent a procedure via posterior transpedicular screw.

Treatment of Lyme neuroborreliosis with plasmapheresis.

Lyme disease is a rare tick-borne multisystemic infection caused by Borrelia burgdorferi. Different neurological conditions were reported in the disease. In this article, we present a 15-year-old patient hospitalized with ataxia who was diagnosed with Lyme neuroborreliosis. Intravenous immunoglobulin and ceftriaxone treatment was applied to the patient for 4 weeks. However, ataxia did not recover, upper and lower muscle weakness developed, and deep tendon reflexes diminished during follow-up. The patient was diagnosed with Guillain-Barre syndrome arising from B. burgdorferi. Second dose of intravenous immunoglobulin treatment was started for 5 days but the patient didn't recover. Therefore administration of plasmapheresis was decided. All symptoms relieved following the plasmapheresis. The effect of plasmapheresis in pediatric neuroborreliosis has not been documented before. This study highlights that plasmapheresis could be a useful alternative for pediatric neuroborreliosis cases. J. Clin. Apheresis 31:476-478, 2016. © 2015 Wiley Periodicals, Inc.

Pediatric Lyme Neuroborreliosis: Different clinical presentations of the same agent; Single center experience.

OBJECTIVES: Lyme disease is a vector-associated infectious disease, caused by the agent, spirochete Borrelia burgdorferi. Neurologic findings are observed in approximately 12% of the cases and termed Lyme neuroborreliosis (LNB). Lyme neuroborreliosis may manifest with different clinical neurologic manifestations. METHODS: The study was conducted at tertiary training and research hospital. From January 2014 to September 2015, a total of 75 patients diagnosed with encephalitis, ataxia, Guillain Barre Syndrome (GBS), facial paralysis, acute disseminated encephalomyelitis (ADEM), pseudotumorcerebri were evaluated for inclusion to the study. Among these patients whom investigations of B. burgdorferi antibody IgM and/or IgG ELISA and Western Blot (WB) were detected to be positive, were assessed. Epidemiologic data, tick bite histories, duration of symptoms, clinical findings, radiologic findings, treatment durations and prognosis were investigated. RESULTS: Totally 7 patients had been treated with the diagnosis of Lyme neuroborreliosis. The mean age was 9.14±4.91 years; duration of symptoms before admission was 8.0±4.50 days; and the duration of antibiotic use was 2.85±0.89 weeks. All patients had received ceftriaxone and intravenous immunoglobulin (IVIG); 3 patients had received plasmapheresis (42.9%) and one patient had received pulse corticosteroid therapy. While the patient with the diagnosis of encephalomyeloneuritis and atypical GBS had partially improved, the other patients were completely cured. CONCLUSION: In this article, we report pediatric LNB patients, B. burgdorferi should also be considered in patients with atypical or severe neurologic involvement or a history of tick bite; it is known that the prognosis is good with appropriate and early treatment.

Cerebral salt wasting in pediatric critical care; not just a neurosurgical disorder anymore.

OBJECTIVE: Cerebral salt-wasting syndrome (CSWS) is a hypovolemic hyponatremia caused by natriuresis and diuresis, of which the exact pathogenesis is unknown. Although CSWS has been more commonly described to be associated with neurosurgical disorders, increasing numbers of patients are diagnosed and new etiological factors are being identified as the awareness of it increases. METHODS: The files of the patients who had been hospitalized and treated with the diagnosis of CSWS at the pediatric critical care unit during the last three years were retrospectively reviewed. RESULTS: Totally 9 patients had been treated with the diagnosis of CSWS. The causes of CSWS were identified as tuberculosis meningitis in two patients, status epilepticus in two patients, ketamine infusion in one patient, medulloblastoma in one patient, sepsis in one patient, brain oedema following child abuse in one patient, and cerebral infarct in one patient. All of the patients had received isotonic saline and hypertonic saline while 77.7% of them had received fludrocortisone. The mean time to correction of hyponatremia was 20.37±14.73 days. One patient had died. CONCLUSION: Cerebral salt-wasting syndrome is increasingly described in the etiology of hyponatremia that is commonly seen in children hospitalized especially at critical care units. Serum sodium, urinary sodium and polyuria should be primarily considered in the diagnosis, and supportive laboratory tests such as uric acid and brain natriuretic peptide (BNP) should not be stipulated. At hospitals providing inpatient care services, clinical and laboratory characteristics of CSWS should be known in detail especially at pediatric critical care units.

Cerebral salt wasting in tuberculous meningitis: Two cases and review of the literature. Case Report.

Cerebral salt wasting syndrome (CSWS) is characterized by severe natriuresis and volume depletion in the presence of cerebral pathology. In literature, there are few reports about tuberculous meningitis and cerebral CSWS. In this article, we report two tuberculous meningitis cases with CSWS and present a review of the literature on this topic. Cerebral salt wasting diagnosis was based on hyponatraemia associated with high urinary sodium excretion and inappropriately high urine output in the presence of dehydration. Treatment was made with sodium-fluid replacement plus fludrocortisone therapy in both cases. In agreement with the literature we argue that cerebral salt wasting syndrome might be more common than the syndromes of inappropriate antidiuretic hormone secretion (SIADH) in cerebral disorders. Differentiating the cerebral salt wasting syndrome from the SIADH is very important because unrecognized cerebral salt wasting syndrome can lead to inadequate management and result in unnecessary hyponatremia-related morbidity. The electrolyte and hydration status of patients should be monitored closely in patients with tuberculous meningitis.

Placento-Cranial Adhesions in Amniotic Band Syndrome and the Role of Surgery in Their Management: An Unusual Case Presentation and Systematic Literature Review.

Amniotic band syndrome is a group of sporadic congenital anomalies that involve the limbs, craniofacial regions and trunk, ranging from simple digital band constriction to complex craniofacial and central nervous system abnormalities. Placento-cranial adhesions in amniotic band syndrome are extremely rare, and severe conditions are associated with high morbidity and mortality rates. In this study, we pooled placento-cranial adhesion case reports that were published in the medical literature and added an unpublished case from our institution. The purpose of this article was to review and discuss the clinical features and outcomes of placento-cranial adhesions in amniotic band syndrome.

Oromandibular Dystonia Related to Sertraline Treatment in a Child.

In children, similar to adults, the agents that cause movement disorders are most commonly dopaminergic and antidopaminergic drugs. However, it is also known that selective serotonin reuptake inhibitors (SSRIs), which are frequently prescribed in child psychiatry practice, may rarely lead to tremor, akathisia, dystonia, dyskinesia, and parkinsonism. In this study, we report a rare side effect of SSRIs, namely oromandibular dystonia related to sertraline, in a pediatric patient who was diagnosed with posttraumatic stress disorder.

Genetic dilemma: eNOS gene intron 4a/b VNTR polymorphism in sepsis and its clinical features in Turkish children.

The role of endothelial nitric oxide synthase gene intron 4 a/b (eNOS4a/b) variable number of tandem repeats (VNTR) polymorphism in various diseases was investigated. We investigated whether this polymorphism is associated with susceptibility to sepsis and its clinical features such as acute respiratory distress syndrome (ARDS), multiorgan dysfunction syndrome (MODS) and shock. eNOS4a/b VNTR polymorphism was determined by the polymerase chain reaction in 100 children with sepsis and in 134 healthy controls. The genotype distribution of eNOS4 was not different between the patients and controls (p=0.44). There was no statistically significant association between genotypes/allele frequency and outcomes like mortality, MODS, ARDS, and shock (p>0.05). This is the first study that evaluates the effect of eNOS4a/b polymorphism in sepsis. We were unable to show a relationship between eNOS gene intron 4 a/b VNTR polymorphism and MODS, ARDS, mortality and shock. Larger studies that do research on the interaction of such genes are needed to clarify the association between eNOS4a/b polymorphism and sepsis.

Appraisal of the "pediatric ARDS: consensus recommendations from the pediatric acute lung injury consensus conference" with the AGREE II instrument

Background/aim: The ″Pediatric Acute Lung Injury Consensus Conference″ (PALICC) was convened in order to develop a taxonomy to define pediatric acute respiratory distress syndrome (ARDS). The Appraisal of Guidelines for Research and Evaluation (AGREE) assesses the quality of guidelines. The aim of this study is to evaluate the new pediatric ARDS guideline using the AGREE II instrument. To the best of our knowledge, this is the first assessment of the new pediatric ARDS clinical practice guideline in the English literature. Materials and methods: Four appraisers assessed the new pediatric ARDS guideline with the AGREE II instrument. At the end of the evaluation each appraiser rated the overall quality of the guidelines. Results: Results of the assessment were editorial independence 100%, clarity of presentation 94%, scope and purpose 89%, stakeholder involvement 78%, rigor of development 78%, and applicability 78%. Conclusion: The new pediatric ARDS guideline received good scores especially with respect to editorial independence and clarity of presentation. Our overall AGREE II review of the PALICC guideline indicates that it has been created using high quality methodology and should be recommended for use and implementation as currently published.

Retrospective analysis of children with myelin oligodendrocyte glycoprotein antibody-related disorders.

BACKGROUND: Knowledge has been expanding on myelin oligodendrocyte glycoprotein (MOG) antibody-associated central nervous system disorders. We delineate the clinical and paraclinical findings and outcome of our pediatric patients with MOG antibody seropositive disease. METHODS: We retrospectively analyzed the clinical presentation, cerebrospinal fluid findings, magnetic resonance imaging (MRI) studies, course and outcome of children seropositive for anti-MOG IgG. RESULTS: Total 20 children with neurological symptoms and serum anti-MOG IgG were identified from six centers in Turkey. Median age at onset was 9 years (mean 8.8 ±â€¯5.0 years, range: 1.5-16.5 years). Final diagnoses were acute disseminated encephalomyelitis (ADEM) (n = 5), ADEM + optic neuritis (n = 4), neuromyelitis optica spectrum disorder (NMOSD) (n = 3), myelitis (n = 2), relapsing optic neuritis (n = 2), multiphasic DEM (n = 3), and unclassified relapsing demyelinating disease (n = 1). Seven/20 (35%) children experienced a single episode while 13/20 (65%) had a least one relapse during follow-up. On MRI, subcortical white matter, brainstem, and corpus callosum were preferentially involved regions. Full recovery was observed in 15/20 (75%) children. CONCLUSION: MOG autoimmunity in children has a wide clinical spectrum, tendency to relapse, and a favourable outcome compared with other relapsing demyelinating diseases.

Diagnostic dilemma in an adolescent boy: hemophagocytic syndrome in association with kala azar.

Leishmaniasis is caused by infection with the hemoparasite Leishmania. The disease is a major public health problem in at least 88 countries, including Turkey. Prolonged fever with anorexia and loss of appetite are the major presenting features of visceral leishmaniasis. It is rarely defined as an etiological cause of hemophagocytic syndrome. The clinical course triggered by leishmania infection and hemophagocytosis may coincide, and this may lead to considerable diagnostic difficulty, especially in young children. In this report, we describe an adolescent boy with visceral leishmaniasis as a rare cause of the hemophagocytic syndrome. This is the first reported association between hemophagocytosis and visceral leishmaniasis in an adolescent.

Platelet Indices in the Diagnosis of Ventriculoperitoneal Shunt Infection in Children.

AIM: Ventriculoperitoneal shunt infection (VPSI) is one of the main causes of mortality and morbidity in hydrocephalus. Platelet indices, mean platelet volume (MPV) and platelet distribution width (PDW) have been evaluated for some infectious diseases. In this study we aimed to investigate whether MPV and PDW values are decisive for the diagnosis of VPSI in children. MATERIAL AND METHODS: Charts of VPSI from 2012 to 2015 were reviewed retrospectively. Twenty-five ventriculoperitoneal shunt infected patients and 25 healthy children as the control group were included in the study. Platelet indices were recorded. RESULTS: A total of 25 VPSI patients and 25 healthy children were enrolled in the study. Significant differences were detected between the MPV and PDW values in the two groups (p < 0.001). ROC curve analysis suggested a cut off point for MPV as below 9.2 fl (smaller values indicate patients) for the diagnosis of VPSI, with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 80%, 92%, 91% and 82%, respectively. For PDW, the cut-off point was 12.25 (larger values indicate pathology) for diagnosis of VPSI, with sensitivity, specificity, PPV and NPV of 68%, 80%, 77% and 71%, respectively. CONCLUSION: Our results suggest that MPV and PDW can be used for the diagnosis of VPSI in children with an accuracy of at least 75%. Moreover, MPV"s specificity is higher than the other platelet parameters and leucocyte count.

Concurrency of Guillain-Barre syndrome and acute transverse myelitis: a case report and review of literature.

Guillain-Barré syndrome and acute transverse myelitis manifest as demyelinating diseases of the peripheral and central nervous system. Concurrency of these two disorders is rarely documented in literature. A 4-year-old girl presenting with cough, fever, and an impaired walking ability was admitted to hospital. She had no previous complaints in her medical history. A physical examination revealed lack of muscle strength of the lower extremities and deep tendon reflexes. MRI could not be carried out due to technical problems; therefore, both Guillain-Barré syndrome and acute transverse myelitis were considered for the diagnosis. Intravenous immunoglobulin treatment was started as first line therapy. Because this treatment did not relieve the patient's symptoms, spinal MRI was carried out on the fourth day of admission and demyelinating areas were identified. Based on the new findings, the patient was diagnosed with acute transverse myelitis, and high dose intravenous methylprednisolone therapy was started. Electromyography findings were consistent with acute polyneuropathy affecting both motor and sensory fibers. Therefore, the patient was diagnosed with concurrency of Guillain-Barré syndrome and acute transverse myelitis. Interestingly, while concurrency of these 2 disorders is rare, this association has been demonstrated in various recent publications. Progress in diagnostic tests (magnetic resonance imaging and electrophysiological examination studies) has enabled clinicians to establish the right diagnosis. The possibility of concurrent Guillain-Barré syndrome and acute transverse myelitis should be considered if recovery takes longer than anticipated.

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin.

BACKGROUND: Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS: Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION: In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING: This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

Epstein-Barr virus encephalitis with substantia nigra involvement.

Infectious mononucleosis due to Epstein-Barr virus (EBV) is a usually benign systemic viral illness common in children. Many studies described nervous system manifestations of infectious mononucleosis with a wide spectrum of neurologic deficits. Neurologic complications of EBV are seen in both acute and reactivate infection. Herein, we describe a patient diagnosed by acute EBV encephalitis with substantia nigra involvement and excellent clinical recovery.

A rare cause of status epilepticus; alpha lipoic acid intoxication, case report and review of the literature.

INTRODUCTION: Alpha lipoic acid is a powerful antioxidant widely used for the supplementary treatment of diabetic neuropathy. Intoxication with alpha lipoic acid is very rare. There is no reported dose of safety in children. CASE REPORT: A 14-month-old previously healthy girl was referred to our hospital with the diagnosis of drug intoxication. She was admitted to the emergency department with lethargy and continuing involuntary movements for several hours after she had ingested an unknown amount of alpha lipoic acid. On admission she was lethargic and had myoclonic seizures involving all extremities. She had no fever and laboratory examinations were normal except for mild metabolic acidosis. The seizures were unresponsive to bolus midazolam, phenytoin infusion and levetiracetam infusion. She was taken to the pediatric intensive care unit with the diagnosis of status epilepticus. After failure of the treatment with midazolam infusion she was intubated and thiopental sodium infusion was started. Her myoclonic seizures were controlled with thiopental sodium infusion. After 48 h intubation and mechanical ventilation thiopental sodium was gradually reduced and then stopped. Following the withdraw of thiopental sodium, she was seizure free on her discharge on the 8th day. CONCLUSION: Alpha lipoic acid and derivatives cause side effects in children like refractory convulsions. They are frequently rendered as vitamins by diabetic patients and are left at places where children can easily access them. Therefore, when faced with refractory convulsions in children who have had no disease before, intoxication by medicaments with alpha lipoic acid should be taken into consideration.

An Adolescent Case of Osteopetrosis with Portal Hypertension as well as Mandibula Osteomyelitis.

Osteopetrosis is a clinical syndrome characterized by the failure of osteoclasts to resorb bone. Excessive bone density can interfere with vital tissues and structures, causing serious problems of the body. Hematopoietic insufficiency, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment may develop in a patient with osteopetrosis. Herein, we present an adolescent girl diagnosed with non-infantile type of osteopetrosis with rare complications of the disease like mandibular osteomyelitis and portal hypertension (PHT) without liver cirrhosis. To our knowledge, this is the first pediatric case with osteopetrosis related PHT.

Cerebral salt wasting in status epilepticus: two cases and review of the literature.

BACKGROUND: Cerebral salt wasting is a hypovolemic hyponatremia state, caused by natriuresis and diuresis. The most important element of treatment is to replace the volume and sodium loss and improve the current clinic. PATIENTS: We present two children who were treated in the intensive care unit who subsequently developed cerebral salt wasting. Diagnosis was based on hyponatremia associated with high urinary sodium excretion and inappropriately high urine output in the presence of dehydration. As part of the treatment, one patient was given fluid and sodium replacement, measures that were insufficient in the other patient, who also required fludrocortisone treatment. CONCLUSION: The status epilepticus may be involved in the etiology of cerebral salt wasting. In both patients, cerebral salt wasting was detected in the posttreatment follow-up evaluations. Cerebral salt wasting is particularly likely to occur in individuals with status epilepticus, and the electrolyte and hydration status of these patients should be monitored closely, even after the convulsions are taken under control.

Cooccurrence of Darier's Disease and Epilepsy: A Pediatric Case Report and Review of the Literature.

Darier's disease is a skin disorder characterized by multiple eruptions of hyperkeratosis or crusted papules at seborrheic areas with histologic acantholysis and dyskeratosis. It is caused by mutations in a single gene, being ATP2A2 and that is expressed in the skin and brain. The cooccurrence of various neurologic and psychiatric diseases with Darier's disease has been reported frequently in literature. They include mood disorders, epilepsy, encephalopathy, and schizophrenia. In this study, we report a pediatric case with the cooccurrence of Darier's disease and epilepsy. We also revised current English literature on this topic.