Dominant VPS16 Pathogenic Variants: Not Only Isolated Dystonia.

Background: VPS16 pathogenic variants have been recently associated with inherited dystonia. Most patients affected by dominant VPS16-related disease display early-onset isolated dystonia with prominent oromandibular, bulbar, cervical, and upper limb involvement, followed by slowly progressive generalization.

Cases: We describe six newly reported dystonic patients carrying VPS16 mutations displaying unusual phenotypic features in addition to dystonia, such as myoclonus, choreoathetosis, pharyngospasm and freezing of gait.

Fatigue and depression predict health-related quality of life in patients with pediatric-onset multiple sclerosis.

Background: Fatigue, depression and loss in health-related quality of life (HRQoL) have been reported to occur in a substantial amount of patients with pediatric-onset MS (POMS). This study aims to evaluate depression, fatigue and HRQoL and its relationship in a cohort of patients with POMS and matched healthy controls (HCs).

Methods: In a multicenter cross-sectional study, Beck Depression Inventory II, Depressionstest für Kinder, the Pediatric Quality of Life Inventory (PedsQL™) 4.

Clinical and magnetic resonance imaging features of children, adolescents, and adults with a clinically isolated syndrome.

Background: The diagnosis of multiple sclerosis (MS) both in children and adults is based on clinical and magnetic resonance imaging (MRI) features according to the McDonald criteria. Little is known about differences in the presentation between pre-pubertal children, adolescents, and adult patients at disease onset.

Objective: To compare (1) the clinical, cerebrospinal fluid (CSF), and MRI characteristics, and (2) the diagnostic performance of the 2010 McDonald criteria between pre-pubertal, adolescent, and adult patients with a clinically isolated syndrome (CIS).

Natalizumab therapy for highly active pediatric multiple sclerosis.

Importance: Given the high frequency of failure of first-line therapies, there is an urgent need for second-line treatment strategies for pediatric patients with multiple sclerosis (MS).

Objective: To report the use of natalizumab in pediatric MS. Natalizumab, a humanized monoclonal antibody targeting α4 integrin, is effective against active relapsing-remitting MS in adults.

Neuropsychological aspects of childhood multiple sclerosis: an overview.

While cognitive impairment, major depression, and fatigue have been well documented in adult patients with multiple sclerosis (MS), there is still little information regarding MS-associated cognitive disabilities in infants and adolescents who represent 3 to 5% of all MS cases. Recent studies show that cognitive decline related to MS profoundly interferes with academic success and psychosocial adjustment. Neuropsychological dysfunction affects quality of life more significantly than mere Expanded Disability Status Scale is able to reflect.

Axonemal localization of the dynein component DNAH5 is not altered in secondary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic disorder characterized by recurrent airway infections and situs inversus in half of affected individuals. Diagnosis currently relies on demonstration of abnormal ciliary ultrastructure or altered ciliary beat. Alterations encountered in secondary ciliary dyskinesia (SCD) caused by inflammation often complicate the diagnostic workup.

Primary ciliary dyskinesia: clinical presentation, diagnosis and genetics.

Primary ciliary dyskinesia (PCD) is a phenotypically and genetically heterogeneous disorder with an autosomal-recessive inheritance pattern. Only rarely other modes of inheritance such as X-linked transmission are observed. The disease phenotype is caused by defects of respiratory cilia, sperm tails and the cilia of the embryonic node.

A cysteinyl leukotriene 2 receptor variant is associated with atopy in the population of Tristan da Cunha.

The clinical heterogeneity of asthma suggests that the contribution of genetic variability in candidate gene loci to well-defined phenotypes, such as atopy, may be examined to identify appropriate genetic risk factors for asthma. The gene encoding the cysteinyl leukotriene 2 (CysLT2) receptor has been implicated in atopy since it is localized to a region of chromosome 13q14 that has been linked to atopy in several populations and the cysteinyl leukotrienes are known to activate eosinophils and mast cells in atopy. Accordingly, we analysed the contribution of CysLT2 receptor gene variation to atopy in the inhabitants of Tristan da Cunha, a population characterized by both a founder effect and a 47% prevalence of atopy.

Monocyte chemoattractant protein-4 core promoter genetic variants: influence on YY-1 affinity and plasma levels.

Monocyte chemoattractant protein-4 (MCP-4) is a CC chemokine implicated in the recruitment of eosinophils, monocytes, and T-lymphocytes in diseases of mucosal inflammation, including asthma. We tested the hypothesis that there is a genetic basis for differences in MCP-4 expression among individuals by evaluating the effects of core promoter variants on MCP-4 expression. We identified two single-nucleotide T-to-C polymorphisms in the MCP-4 core promoter that occur 896 and 887 base pairs preceding the transcription initiation site.

Association of a missense mutation in the NOS3 gene with exhaled nitric oxide levels.

There is evidence that genetic factors affect nitric oxide formation and that sequence variants in the nitric oxide synthase genes contribute to the observed variance of nitric oxide levels in exhaled air (fraction of expired nitric oxide, FENO) in subjects with asthma. We identified a strong association between a known functional NOS3 missense sequence variant in the endothelial nitric oxide gene (G894T) and FENO level in a cohort of subjects with asthma. Age- and sex-adjusted FENO levels were lowest in asthmatic subjects with the TT genotype (geometric mean FENO [95% CI] = 7.

A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma.

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400-800 microg/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period.

Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide.

Genetic factors may contribute to the variability of exhaled nitric oxide in healthy individuals. We studied exhaled nitric oxide and genetic variants in both neuronal and endothelial nitric oxide synthases in 105 healthy nonsmoking and smoking subjects. Genomic DNA was screened for a repeat polymorphism in intron 20 of the neuronal nitric oxide synthase gene and for the 894G/T mutation of the endothelial nitric oxide synthase gene.

Endothelial nitric oxide synthase variants in cystic fibrosis lung disease.

Variants in the genes encoding for the nitric oxide synthases may act as disease modifier loci in cystic fibrosis, affecting both an individual's nitric oxide level and pulmonary function. In this study, the 894G/T variant in exon 7 of the endothelial nitric oxide synthase gene was related to exhaled nitric oxide and pulmonary function in 70 cystic fibrosis patients who were aged 14.8 +/- 6.

IFN regulatory factor-1 regulates IFN-gamma-dependent cathepsin S expression.

Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-gamma.

Cloning and functional analysis of the mouse 5-lipoxygenase promoter.

5-lipoxygenase (ALOX5), an enzyme essential for the formation of all leukotrienes, is highly regulated at multiple levels, including gene transcription. The human ALOX5 promoter sequence has been cloned and is well characterized. Several important cis-acting elements have been identified including a G+C-rich sequence approximately 145-179 base pairs (bp) upstream from the ATG start codon.

Circadian variation of exhaled nitric oxide and urinary eosinophil protein X in asthmatic and healthy children.

Asthmatic symptoms and the frequency of admissions to hospital because of acute asthma tend to increase in the early morning hours, and it is therefore possible that airway inflammation increases during the night. To elucidate the hypothetical circadian variation of airway inflammation, we measured concentrations of exhaled nitric oxide (FeNo), urinary eosinophil protein X excretion (EPX), and forced expiratory volume in the first second (FEV1) in 20 asthmatic and 6 nonatopic nonasthmatic children every 3 h during a 21-h period. Compared with control subjects, asthmatic subjects had higher FeNo (median, 22.