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- Dreha-Kulaczewski, Steffi, et al.
(författare)
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Folate receptor α deficiency : Myelin‐sensitive MRI as a reliable biomarker to monitor the efficacy and long‐term outcome of a new therapeutic approach
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Ingår i: Journal of Inherited Metabolic Disease. - 0141-8955. ; , s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral folate transport deficiency, caused by a genetic defect in folate recep-torα, is a devastating neurometabolic disorder that, if untreated, leads to epi-leptic encephalopathy, psychomotor decline and hypomyelination. Currently,there are limited data on effective dosage and duration of treatment, thoughearly diagnosis and therapy with folinic acid appears critical. The aim of thislong-term study was to identify new therapeutic approaches and novel bio-markers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, bio-chemical, structural and quantitative MRI parameters of seven patients withgenetically confirmed folate receptorαdeficiency were acquired over 13 years.Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetiza-tion transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patientsstarted oral treatment immediately following diagnosis or in an interval of upto 2.5 years. Escalation to intravenous and intrathecal administration was per-formed in the absence of effects. Five patients improved, one with a presymp-tomatic start of therapy remained symptom-free, and one with inconsistenttreatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parame-ters normalized immediately after therapy initiation, myelin-sensitive MTI andDTI measures correlated with gradual clinical improvement and ongoing mye-lination under therapy. Early initiation of treatment at sufficient doses, consid-ering early intrathecal applications, is critical for favorable outcome. Themajority of patients showed clinical improvements that correlated best withMTI parameters, allowing individualized monitoring of myelination recovery.Presymptomatic therapy seems to ensure normal development and warrantsnewborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelinationdisorders in general.
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- Sofou, Kalliopi, et al.
(författare)
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Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.
- 2021
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Ingår i: EMBO molecular medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis-like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient-derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re-expression of VPS16. Patient-derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re-expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis-like diseases that result from mutations in HOPS/CORVET subunits.
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- Wagner, Leona, et al.
(författare)
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Proteolytic degradation of neuropeptide Y (NPY) from head to toe: Identification of novel NPY-cleaving peptidases and potential drug interactions in CNS and Periphery.
- 2015
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 135:5, s. 1019-1037
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Tidskriftsartikel (refereegranskat)abstract
- The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor-selectivity by dipeptidyl-peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P (AmpP), secreted meprin-A (Mep-A) and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S and tissue kallikrein could also be identified. Expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme (ACE) could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive ACE inhibitors, while it ablates suspected hypertensive side-effects of only antidiabetic DP4-inhibitors application. This article is protected by copyright. All rights reserved.
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