| 1. |
- Burstedt, Marie, et al.
(författare)
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Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations
- 2013
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 91:5, s. 437-444
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate phenotypes caused by different RLBP1 mutations in autosomal recessive retinitis pigmentosa of Bothnia type. Methods: Compound heterozygotes for mutations in the RLBP1 gene [c.677T>A]+[c.700C>T] (p.M226K+p.R234W), n=10, aged 7-84years, and homozygotes c.677T>A (p.M226K), n=2, aged 63 and 73years, were studied using visual acuity (VA), low-contrast VA, visual fields (VFs) and optical coherence tomography (OCT). Retrospective VA and VFs, standardized dark adaptation and full-field electroretinograms (ERGs) were analysed and prolonged dark adaptometry and ERG (at 24hr) were performed. Results: Progressive decline of VA and VF areas was age-dependent. Retinal degenerative maculopathy, peripheral degenerative changes and retinitis punctata albescens (RPA) were present. Early retinal thinning in the central foveal, foveal (O 1mm), and inner ring (O 3mm) in the macular region, with homogenous, high-reflectance RPA changes, was visualized in and adjacent to the retinal pigment epithelium/choriocapillaris using OCT. Reduced dark adaptation and affected ERGs were present in all ages. Prolonged dark adaptation and ERG (at 24hr), an increase in final threshold, and ERG rod and mixed rod/cone responses were found. Conclusions: The two RLBP1 genotypes presented a phenotypical and electrophysiological expression of progressive retinal disease similar to that previously described in homozygotes for the c.700C>T (p.R234W) RLBP1 mutation. The uniform phenotypical expression of RLBP1 mutations is relevant information for the disease and of importance in planning future treatment strategies.
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| 2. |
- Kvarnung, Malin, et al.
(författare)
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Genomic screening in rare disorders : new mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability
- 2018
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Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 94:6, s. 528-537
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.
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| 3. |
- Birznieks, Ingvars, et al.
(författare)
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Mechanisms for force adjustments to unpredictable frictional changes at individual digits during two-fingered manipulation.
- 1998
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Ingår i: Journal of Neurophysiology. - 0022-3077 .- 1522-1598. ; 80:4, s. 1989-2002
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies on adaptation of fingertip forces to local friction at individual digit-object interfaces largely focused on static phases of manipulative tasks in which humans could rely on anticipatory control based on the friction in previous trials. Here we instead analyze mechanisms underlying this adaptation after unpredictable changes in local friction between consecutive trials. With the tips of the right index and middle fingers or the right and left index fingers, subjects restrained a manipulandum whose horizontal contact surfaces were located side by side. At unpredictable moments a tangential force was applied to the contact surfaces in the distal direction at 16 N/s to a plateau at 4 N. The subjects were free to use any combination of normal and tangential forces at the two fingers, but the sum of the tangential forces had to counterbalance the imposed load. The contact surface of the right index finger was fine-grained sandpaper, whereas that of the cooperating finger was changed between sandpaper and the more slippery rayon. The load increase automatically triggered normal force responses at both fingers. When a finger contacted rayon, subjects allowed slips to occur at this finger during the load force increase instead of elevating the normal force. These slips accounted for a partitioning of the load force between the digits that resulted in an adequate adjustment of the normal:tangential force ratios to the local friction at each digit. This mechanism required a fine control of the normal forces. Although the normal force at the more slippery surface had to be comparatively low to allow slippage, the normal forces applied by the nonslipping digit at the same time had to be high enough to prevent loss of the manipulandum. The frictional changes influenced the normal forces applied before the load ramp as well as the size of the triggered normal force responses similarly at both fingers, that is, with rayon at one contact surface the normal forces increased at both fingers. Thus to independently adapt fingertip forces to the local friction the normal forces were controlled at an interdigital level by using sensory information from both engaged digits. Furthermore, subjects used both short- and long-term anticipatory mechanisms in a manner consistent with the notion that the central nervous system (CNS) entertains internal models of relevant object and task properties during manipulation.
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| 4. |
- Burstedt, Magnus K, et al.
(författare)
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Control of forces applied by individual fingers engaged in restraint of an active object.
- 1997
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Ingår i: Journal of Neurophysiology. - 0022-3077 .- 1522-1598. ; 78:1, s. 117-128
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the coordination of fingertip forces in subjects who used the tips of two fingers to restrain an instrumented manipulandum with horizontally oriented grip surfaces. The grip surfaces were subjected to tangential pulling forces in the distal direction in relation to the fingers. The subjects used either the right index and middle fingers (unimanual grasp) or both index fingers (bimanual grasp) to restrain the manipulandum. To change the frictional condition at the digit-object interfaces, either both grip surfaces were covered with sandpaper or one was covered with sandpaper and the other with rayon. The forces applied normally and tangentially to the grip surfaces were measured separately at each plate along with the position of the plates. Subjects could have performed the present task successfully with many different force distributions between the digits. However, they partitioned the load in a manner that reflected the frictional condition at the local digit-object interfaces. When both digits contacted sandpaper, they typically partitioned the load symmetrically, but when one digit made contact with rayon and the other with sandpaper, the digit contacting the less slippery material (sandpaper) took up a larger part of the load. The normal forces were also influenced by the frictional condition, but they reflected the average friction at the two contact sites rather than the local friction. That is, when friction was low at one of the digit-object interfaces, only the applied normal forces increased at both digits. Thus sensory information related to the local frictional condition at the respective digit-object interfaces controlled the normal force at both digits. The normal:tangential force ratio at each digit appeared to be a controlled variable. It was adjusted independently at each digit to the minimum ratio required to prevent frictional slippage, keeping an adequate safety margin against slippage. This was accomplished by the scaling of the normal forces to the average friction and by partitioning of the load according to frictional differences between the digit-object interfaces. In conclusion, by adjusting the normal:tangential force ratios to the local frictional condition, subjects avoided excessive normal forces at the individual digit-object interfaces, and by partitioning the load according the frictional difference, subjects avoided high normal forces. Thus the local frictional condition at the separate digit-object interfaces is one factor that can strongly influence the distribution of forces across digits engaged in a manipulative act.
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| 5. |
- Burstedt, Magnus K, et al.
(författare)
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Coordination of fingertip forces during human manipulation can emerge from independent neural networks controlling each engaged digit.
- 1997
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Ingår i: Experimental Brain Research. - : Springer Science and Business Media LLC. - 0014-4819 .- 1432-1106. ; 117:1, s. 67-79
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the coordination of fingertip forces in subjects who lifted an object (i) using the index finger and thumb of their right hand, (ii) using their left and right index fingers, and (iii) cooperatively with another subject using the right index finger. The forces applied normal and tangential to the two parallel grip surfaces of the test object and the vertical movement of the object were recorded. The friction between the object and the digits was varied independently at each surface between blocks of trials by changing the materials covering the grip surfaces. The object's weight and surface materials were held constant across consecutive trials. The performance was remarkably similar whether the task was shared by two subjects or carried out unimanually or bimanually by a single subject. The local friction was the main factor determining the normal:tangential force ratio employed at each digit-object interface. Irrespective of grasp configuration, the subjects adapted the force ratios to the local frictional conditions such that they maintained adequate safety margins against slips at each of the engaged digits during the various phases of the lifting task. Importantly, the observed force adjustments were not obligatory mechanical consequences of the task. In all three grasp configurations an incidental slip at one of the digits elicited a normal force increase at both engaged digits such that the normal:tangential force ratio was restored at the non-slipping digit and increased at the slipping digit. The initial development of the fingertip forces prior to object lift-off revealed that the subjects employed digit-specific anticipatory mechanisms using weight and frictional experiences in the previous trial. Because grasp stability was accomplished in a similar manner whether the task was carried out by one subject or cooperatively by two subjects, it was concluded that anticipatory adjustments of the fingertip forces can emerge from the action of anatomically independent neural networks controlling each engaged digit. In contrast, important aspects of the temporal coordination of the digits was organized by a "higher level" sensory-based control that influenced both digits. In lifts by single subjects this control was mast probably based on tactile and visual input and on communication between neural control mechanisms associated with each digit. In the two-subject grasp configuration this synchronization information was based on auditory and visual cues.
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| 6. |
- Gkourogianni, Alexandra, et al.
(författare)
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Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
- 2020
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell Publishing Inc.. - 0803-5253 .- 1651-2227. ; 109:10, s. 2067-2074
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
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| 7. |
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| 8. |
- Stray-Pedersen, Asbjorg, et al.
(författare)
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Primary immunodeficiency diseases : Genomic approaches delineate heterogeneous Mendelian disorders
- 2017
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Ingår i: Journal of Allergy and Clinical Immunology. - : MOSBY-ELSEVIER. - 0091-6749 .- 1097-6825. ; 139:1, s. 232-245
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Tidskriftsartikel (refereegranskat)abstract
- Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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