Implicit response-irrelevant number information triggers the SNARC effect : Evidence using a neural overlap paradigm

Peer reviewedPostprin

Improving outcome measures in late onset Pompe disease: Modified Rasch-Built Pompe-Specific Activity scale

Background and purpose The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries. Methods Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis. Results Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct. Conclusions After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries

Confirmation that abnormal desmin accumulation and migration are due to a desmin gene mutation in a familial cardiomyopathy and distal myopathy.

status: publishe

Widening the spectrum of filamin-C myopathy: Predominantly proximal myopathy due to the p.A193T mutation in the actin-binding domain of FLNC

We report three patients with a predominantly proximal myopathy due to p.A193T mutation in the actin-binding domain of FLNC, which has so far only been associated with a distal myopathy. They presented with a late onset myopathy characterized by predominant limb-girdle and proximal weakness. We describe the clinical, electrophysiological, pathological, muscle imaging and genetic features. One of our patients did not have typical histological features for a myofibrillar myopathy in muscle biopsy. This observation is important for the recognition of the full clinical spectrum of filamin-C-related myopathies. Muscle imaging has an important role in distinguishing the different filamin-C myopathy types

Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4

Abstract Background Nusinersen recently became available as the first treatment for Spinal Muscular Atrophy (SMA) and data on its effectiveness and safety in adult SMA patients are still scarce. Methods We evaluated the effectiveness and safety of nusinersen treatment during 14 months in 16 adult patients with SMA types 3 and 4 in a prospective study, and retrospectively detailed the natural history of 48 adult SMA patients types 2, 3 and 4. Results Hand grip strength (p = 0.03), hand motor function (p = 0.04) as assessed by a sub-score of the Revised Upper Limb Module (RULM) and the Medical Research Council (MRC) sum score (p = 0.04) improved significantly at month 14. Importantly, the MRC sum score had declined significantly (p &lt; 0.01) prior to start of treatment in these patients. A minimal clinically important difference (MCID) in the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM scores was achieved in 31% and 50% of the patients, respectively, but the mean changes from baseline failed to reach significance. Forced Vital Capacity (FVC) transiently increased at month 6 (p = 0.01), whereas the Peak Expiratory Flow (PEF) did not. The Activity Limitations scale declined significantly prior to start of treatment (p &lt; 0.01) and showed an improvement with nusinersen which was not significant. The safety evaluation did not reveal serious adverse events and no signs of nephrotoxicity or antisense oligonucleotide (ASO)-mediated inflammation. Conclusions We conclude that hand grip strength and hand motor function, as well as MRC sum scores improved significantly in nusinersen-treated adult patients with SMA types 3 and&nbsp;4.</p

Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance.

Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material

Expanded phenotypic spectrum of the m.8344A&gt;G &quot;MERRF&quot; mutation: Data from the German mitoNET registry.

The m.8344A&gt;G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A&gt;G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5&nbsp;years &plusmn;10.9 (6-48&nbsp;years) with adult onset in 75&nbsp;% of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63&nbsp;% of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72&nbsp;%). Other common features in our cohort were migraine (52&nbsp;%), psychiatric disorders (54&nbsp;%), respiratory dysfunction (45&nbsp;%), gastrointestinal symptoms (38&nbsp;%), dysarthria (36&nbsp;%), and dysphagia (35&nbsp;%). Brain MRI revealed cerebral and/or cerebellar atrophy in 43&nbsp;% of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A&gt;G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes

Individual values and motivational complexities in ethical clothing consumption: A means-end approach

With the expansion of ethical consumption, there is an increased need to understand the variety of consumer motives for consumer engagement in such behaviour. For the rapidly growing area of ethical clothing, this study explores consumers' desired consumption outcomes and personal values that drive ethical product preferences. Analysis of data obtained through a semi-qualitative laddering approach (n = 98 ethical clothing consumers) reveals five dominant perceptual patterns relating not only to environmental and altruist ethical concerns, but also more individual motives of value for money, personal image, and well-being. Further analysis shows that consumers have to compromise and balance between their conflicting end-goals. The study augments previous findings in ethical clothing research, as researchers can better understand how specific attributes of products relate to the emotional and symbolic aspects and link back to consumer values. Though limited in scope by its exploratory character, the study contributes towards a deeper understanding of ethical consumer behaviour. Implications for theory practice and further research are discussed

Comprehensive analysis of the mutation spectrum in 301 German ALS families.

Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe