| 1. |
- Pagnamenta, A. T., et al.
(författare)
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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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| 2. |
- Wiessner, M., et al.
(författare)
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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
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Tidskriftsartikel (refereegranskat)abstract
- Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).
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| 3. |
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| 4. |
- Auer-Grumbach, Michaela, et al.
(författare)
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Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
- 2016
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 99:3, s. 607-623
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Tidskriftsartikel (refereegranskat)abstract
- Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade beta-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.
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| 5. |
- Ebrahimi-Fakhari, Darius, et al.
(författare)
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
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Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Tidskriftsartikel (refereegranskat)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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| 6. |
- Beetz, Andrea, et al.
(författare)
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The Effect of a Real Dog, Toy Dog and Friendly Person on Insecurely Attached Children During a Stressful Task : An Exploratory Study
- 2011
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Ingår i: Anthrozoos. - : Taylor & Francis. - 0892-7936 .- 1753-0377. ; 24:4, s. 349-368
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of stress by an attachment figure is a key feature of attachment relationships. Previous research suggests that in some cases animal companionship may be regarded as an attachment relationship. This may be particularly important for persons with an insecure or disorganized attachment pattern who may find it more difficult than securely attached individuals to accept social support from humans. In our study, we investigated whether 31 boys (aged 7-12 years) with insecure/disorganized attachment would profit more from the presence of a dog (n = 11) than of a friendly human (n = 11) or a toy dog (n = 9) as support during a socially stressful situation (Trier Social Stress Test for Children, TSST-C). Stress levels were assessed via salivary cortisol recorded five times before, during, and after the TSST-C. The behavior of the children was coded from video recordings. Self-reported stress levels did not significantly differ between the groups before and after the TSST-C. Salivary cortisol, however, was significantly lower in the real dog condition than in the other two conditions (Kruskal-Wallis H test on area under the curve increase (AUCi): chi(2) = 15.17, df = 2, p = 0.001). Also, the more the children stroked the dog, the less pronounced was their stress reaction (r(s) = -0.818, p = 0.002). Our data suggest an important role of physical contact in the stress reducing effect. We conclude that the children investigated profited more from interacting with a friendly dog than with either a human or a toy dog in a stressful situation. We discuss the relevance of our findings for animal-assisted interventions.
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| 7. |
- Marconi, L., et al.
(författare)
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The SHERPA project : Smart collaboration between humans and ground-aerial robots for improving rescuing activities in alpine environments
- 2012
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Ingår i: Proc. of the IEEE Int. Workshop on Safety, Security and Rescue Robotics (SSRR). - : IEEE. - 9781479901647 - 9781479901630 - 9781479901654 ; , s. 1-4
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Konferensbidrag (refereegranskat)abstract
- The goal of the paper is to present the foreseen research activity of the European project “SHERPA” whose activities will start officially on February 1th 2013. The goal of SHERPA is to develop a mixed ground and aerial robotic platform to support search and rescue activities in a real-world hostile environment, like the alpine scenario that is specifically targeted in the project. Looking into the technological platform and the alpine rescuing scenario, we plan to address a number of research topics about cognition and control. What makes the project potentially very rich from a scientific viewpoint is the heterogeneity and the capabilities to be owned by the different actors of the SHERPA system: the human rescuer is the “busy genius”, working in team with the ground vehicle, as the “intelligent donkey”, and with the aerial platforms, i.e. the “trained wasps” and “patrolling hawks”. Indeed, the research activity focuses on how the “busy genius” and the “SHERPA animals” interact and collaborate with each other, with their own features and capabilities, toward the achievement of a common goal.
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| 8. |
- Zoltan-Csaba, Marton, et al.
(författare)
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Part-Based Geometric Categorization and Object Reconstruction in Cluttered Table-Top Scenes
- 2014
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Ingår i: Journal of Intelligent and Robotic Systems. - : Springer. - 0921-0296 .- 1573-0409. ; 76:1, s. 35-56
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents an approach for 3D geometry-based object categorization in cluttered table-top scenes. In our method, objects are decomposed into different geometric parts whose spatial arrangement is represented by a graph. The matching and searching of graphs representing the objects is sped up by using a hash table which contains possible spatial configurations of the different parts that constitute the objects. Additive feature descriptors are used to label partially or completely visible object parts. In this work we categorize objects into five geometric shapes: sphere, box, flat, cylindrical, and disk/plate, as these shapes represent the majority of objects found on tables in typical households. Moreover, we reconstruct complete 3D models that include the invisible back-sides of objects as well, in order to facilitate manipulation by domestic service robots. Finally, we present an extensive set of experiments on point clouds of objects using an RGBD camera, and our results highlight the improvements over previous methods.
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