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- Chelban, V., et al.
(författare)
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PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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| 2. |
- Koutsis, G, et al.
(författare)
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Effects of an endurance training programme on the passive and noradrenaline-activated compliances of rat aorta
- 1995
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Ingår i: European Journal of Applied Physiology and Occupational Physiology. - New York, USA : Springer-Verlag New York. - 0301-5548 .- 1432-1025. ; 71:2-3, s. 173-9
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Tidskriftsartikel (refereegranskat)abstract
- The effects of a 12-week endurance training programme (treadmill) upon the passive and the noradrenaline-activated properties of the aorta were studied in 15 trained and 24 sedentary rats. Aortic compliance was studied by measuring the length-tension curves of rings of the descending aorta without (passive properties) and with noradrenaline (noradrenaline activated) in a bubbling Krebs bath kept at a temperature of 37 degrees. The training effect on aortic volume compliance was studied by transforming the tension-length curves into a cross-sectional area-pressure curve according to Laplace's law. The noradrenaline responsiveness was studied by the dose-effect curve. The mechanical data were correlated with the results of a histomorphometric study which measured the aortic wall thickness and the percentages and amounts of elastic, connective and muscle components. Passive aortic compliance and volume compliance were higher in endurance-trained rats whose tunica media presented a lower percentage of collagen and a larger amount of elastic tissue. The dose-effect curve showed that the maximal aortic response to noradrenaline was stronger in trained rats but that the half maximal effective dose was not different. As a consequence, the length-tension curves of the noradrenaline fully activated aorta were similar in trained and sedentary rats except at the highest tensions where collagen is the main factor determining aortic stiffness. The increased noradrenaline response in trained rats was probably the result of the hypertrophy of the smooth muscle cells as maximal active strain (Newtons per square metre) was similar in trained and sedentary rats.
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