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- 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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- Chenot, E., et al.
(författare)
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Diagenetic and detrital influences on clay mineralogy and carbon isotope geochemistry of Campanian-Maastrichtian sediments in the Tremp-Graus Basin (southern Pyrenees, Spain) : [Influencias diagenéticas y detríticas en la mineralogía de las arcillas y en la geoquímica de los isótopos de carbono de los sedimentos del Campaniano-Maastrichtiano de la cuenca de Tremp-Graus (sur de los Pirineos, España)]
- 2022
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Ingår i: Journal of Iberian Geology. - : Springer Science and Business Media LLC. - 1698-6180 .- 1886-7995. ; 48:1, s. 29-43
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Tidskriftsartikel (refereegranskat)abstract
- A 1000 m-thick sequence of Upper Cretaceous sediments outcropping in the Isabena Valley (Tremp-Graus Basin, Spain) has been studied to explore the evolution of environmental conditions that prevailed in this basin. A biostratigraphic study based on calcareous nannofossils was carried out to better constraint the age of the deposits, supplemented by carbon isotope stratigraphy on bulk carbonates. Clay mineral assemblages were identified by X-Ray diffraction combined with organic matter (OM) characterisation by Rock–Eval pyrolysis. The Late Campanian Event and Campanian Maastrichtian Boundary Event are clearly identified from the new δ13Ccarb dataset. The clay assemblage is composed of a complex mixture of chlorite, illite, kaolinite and mixed-layers including illite–smectite and chlorite–smectite. A progressive illitisation of smectite is recorded from the top to the base of the section due to the increasing burial depth. This evolution is consistent with increasing Tmax values of OM evolving from 425 (immature OM) to 449 °C (mature OM) from the top to the base of the section. Thus, detrital minerals are preserved only in the upper part of the section. The clay sedimentation is dominated by smectites likely originating from the Ebro massif, while increasing proportions of kaolinite are recorded from the uppermost Campanian and during the Maastrichtian. This evolution of the clay mineral assemblage is interpreted as a result from a change of source from south to northeast, with contributions from kaolinite-rich weathering profiles (including bauxites) to the northeast of the study area, reflecting a more hydrolysing climate.
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- Gadalla, Shahinaz M, et al.
(författare)
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Outcomes of allogeneic hematopoietic cell transplant in patients with dyskeratosis congenita.
- 2013
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Ingår i: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. - : Elsevier BV. - 1523-6536. ; 19:8, s. 1238-1243
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Tidskriftsartikel (refereegranskat)abstract
- We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita transplanted between 1981 and 2009. The median age at transplantation was 13 years (range 2 - 35). Approximately 50% of transplants were from related donors. Bone marrow was the predominant source of stem cells (n=24/34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II-IV acute GVHD and the 3-year probability of chronic GVHD were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation due to graft failure (n=6) or other transplant-related complications; 9 of these patients had been transplanted from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years from transplantation, 4 of these were attributed to pulmonary failure. Transplant-regimen intensity and transplants from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing non-radiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.
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