De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder

De mens centraal reactie op artikel Translational medicine op z'n kop: praktijkkennis vertalen naar onderzoek

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Remarkable intra-cerebral lesions on MRI in a patient with Noonan syndrome

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Malignant migrating partial seizures in a 4-month-old boy.

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[Sudden blindness: consider Leber's hereditary optic neuropathy]

Item does not contain fulltextIn 3 young male patients, aged 10, 19 and 21 years respectively, sequential, severe, painless bilateral visual loss occurred. Ophthalmological examination revealed no other abnormalities and this delayed the diagnosis Leber's hereditary optic neuropathy (LHON). LHON is a mitochondrial genetic disease characterised by bilateral acute or subacute painless loss of central vision. LHON causes blindness, predominantly in young adult males but less frequently in women and children as well. Occasionally, LHON is associated with other neurological and cardiac changes. The first patient recovered his vision within 2 years, but the other 2 remained blind. All 3 patients had a m.11778G > A mutation in the mitochondrial DNA (mtDNA). Over 95% of LHON cases are primarily the result of one of three mitochondrial DNA point mutations. In addition, analysis of patients grouped according to mtDNA mutation has demonstrated differences in both the clinical features of visual failure and in recurrence risks for relatives that are associated with each of the pathogenic mtDNA mutations. Depending on the type of mutation, recovery of vision occurs in 4-58% of the patients. Whilst pathogenic mtDNA mutations are required for the development of LHON, other factors must be responsible for the variable penetrance and male predominance. Familiarity with the clinical spectrum of LHON is necessary for early diagnosis. There is no proven treatment

Acute toxicity profile of craniospinal irradiation with intensity-modulated radiation therapy in children with medulloblastoma: A prospective analysis

BACKGROUND: To report on the acute toxicity in children with medulloblastoma undergoing intensity-modulated radiation therapy (IMRT) with daily intrafractionally modulated junctions. METHODS: Newly diagnosed patients, aged 3-21, with standard-risk (SR) or high-risk (HR) medulloblastoma were eligible. A dose of 23.4 or 36.0Gy in daily fractions of 1.8Gy was prescribed to the craniospinal axis, followed by a boost to the primary tumor bed (54 or 55.8Gy) and metastases (39.6-55.8Gy), when indicated. Weekly, an intravenous bolus of vincristine was combined for patients with SR medulloblastoma and patients participating in the COG-ACNS-0332 study. Common toxicity criteria (CTC, version 2.0) focusing on skin, alopecia, voice changes, conjunctivitis, anorexia, dysphagia, gastro-intestinal symptoms, headache, fatigue and hematological changes were scored weekly during radiotherapy. RESULTS: From 2010 to 2014, data from 15 consecutive patients (SR, n = 7; HR, n = 8) were collected. Within 72 h from onset of treatment, vomiting (66 %) and headache (46 %) occurred. During week 3 of treatment, a peak incidence in constipation (33 %) and abdominal pain/cramping (40 %) was observed, but only in the subgroup of patients (n = 9) receiving vincristine (constipation: 56 vs 0 %, P = .04; pain/cramping: 67 vs 0 %, P = .03). At week 6, 73 % of the patients developed faint erythema of the cranial skin with dry desquamation (40 %) or moist desquamation confined to the skin folds of the auricle (33 %). No reaction of the skin overlying the spinal target volume was observed. CONCLUSIONS: Headache at onset and gastro-intestinal toxicity, especially in patients receiving weekly vincristine, were the major complaints of patients with medulloblastoma undergoing craniospinal irradiation with IMRT

Parental quality of life in complex paediatric neurologic disorders of unknown aetiology

Complex paediatric neurology (CPN) patients generally present with non-specific symptoms, such as developmental delay, impaired movement and epilepsy. The diagnostic trajectory in these disorders is usually complicated and long-lasting, and may be burdensome to the patients and their parents. Additionally, as caring for a chronically ill child can be stressful and demanding, parents of these patients may experience impaired health-related quality of life (HRQoL). This study aims to assess parental HRQoL and factors related to it in CPN. Physical and mental HRQoL of 120 parents was measured and compared to the general population using the SF-12 questionnaire. Parents also completed this questionnaire for the measurement of patient HRQoL. Additional questionnaires were used to measure parental uncertainty (Visual Analogue Scale) and worry phenomena (Penn State Worry Questionnaire), and to obtain socio-demographic data. A linear mixed model with random effect was used to investigate which of these variables were associated with parental HRQoL. As compared to the general population, HRQoL of these parents appeared diminished. Fathers showed both lowered physical (51.76, p < 0.05) and mental (49.41, p < 0.01) HRQoL, whereas mothers only showed diminished mental (46.46, p < 0.01) HRQoL. Patient HRQoL and parental worry phenomena were significantly correlated with overall and mental parental HRQoL. The reduction in parental mental HRQoL is alarming, also because children strongly rely on their parents and parental mental health is known to influence children's health. Awareness of these problems among clinicians, and supportive care if needed are important to prevent exacerbation of the problems

Telangiectasias: Small lesions referring to serious disorders

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The diagnostic pathway in complex paediatric neurology: A cost analysis

Item does not contain fulltextBACKGROUND: The diagnostic trajectory of complex paediatric neurology may be long, burdensome, and expensive while its diagnostic yield is frequently modest. Improvement in this trajectory is desirable and might be achieved by innovations such as whole exome sequencing. In order to explore the consequences of implementing them, it is important to map the current pathway. To that end, this study assessed the healthcare resource use and associated costs in this diagnostic trajectory in the Netherlands. METHODS: Fifty patients presenting with complex paediatric neurological disorders of a suspected genetic origin were included between September 2011 and March 2012. Data on their healthcare resource utilization were collected from the hospital medical charts. Unit prices were obtained from the Dutch Healthcare Authority, the Dutch Healthcare Insurance Board, and the financial administration of the hospital. Bootstrap simulations were performed to determine mean quantities and costs. RESULTS: The mean duration of the diagnostic trajectory was 40 months. A diagnosis was established in 6% of the patients. On average, patients made 16 physician visits, underwent four imaging and two neurophysiologic tests, and had eight genetic and 16 other tests. Mean bootstrapped costs per patient amounted to euro12,475, of which 43% was for genetic tests (euro5,321) and 25% for hospital visits (euro3,112). CONCLUSION: Currently, the diagnostic trajectories of paediatric patients who have complex neurological disease with a strong suspected genetic component are lengthy, resource-intensive, and low-yield. The data from this study provide a backdrop against which the introduction of novel techniques such as whole exome sequencing should be evaluated

Novel hypomyelinating leukoencephalopathy affecting early myelinating structures.

Item does not contain fulltextOBJECTIVE: To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities. DESIGN: In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. SUBJECTS: The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations. RESULTS: Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintense-hypointense-hyperintense stripes in 3 patients. The T1-weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. CONCLUSIONS: The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelination.1 januari 201