| 1. |
- Wiessner, M., et al.
(författare)
-
Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
-
Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
-
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).
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Derrien, M., et al.
(författare)
-
Fasting breath H-2 and gut microbiota metabolic potential are associated with the response to a fermented milk product in irritable bowel syndrome
- 2019
-
Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:4
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives Aim of this study was to assess the effect of a fermented milk product containing Bifidobacterium lactis CNCM I-2494 (FMP) on gastrointestinal (GI) symptoms and exhaled H-2 and CH4 during a nutrient and lactulose challenge in patients with irritable bowel syndrome (IBS). We included 125 patients with IBS (Rome III). Fasted subjects were served a 400ml liquid test meal containing 25g lactulose. The intensity of eight GI symptoms and the amount of exhaled H-2 and CH4 were assessed before and during 4h after meal intake. The challenge was repeated after 14 days consumption of FMP or a control product in a double-blind, randomized, parallel design. The metabolic potential of fecal microbiota was profiled using 16S MiSeq analysis of samples obtained before and after the intervention. 106 patients with IBS were randomized. No difference between FMP or control groups was found on GI symptoms or breath H-2 and CH4 in the whole cohort. A post-hoc analysis in patients stratified according to their fasting H-2 levels showed that in high H-2 producers (fasting H-2 level >= 10ppm, n = 35), FMP consumption reduced fasting H-2 levels (p = 0.003) and H-2 production during the challenge (p = 0.002) and tended to decrease GI discomfort (p = 0.05) vs. control product. The Prevotella /Bacteroides metabolic potential at baseline was higher in high H-2 producers (p<0.05) vs. low H-2 producers and FMP consumption reduced this ratio (p<0.05) vs. control product. The response to a fermented milk product containing Bifidobacterium lactis CNCM I-2494 (FMP) in patients with IBS seems to be associated with the metabolic potential of the gut microbiota.
|
|
