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Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
The incidence of PKU is approximately 1:10,000–1:15,000 newborns and is more common among Northern Europeans. Infants with NBS results consistent with PKU are referred to a metabolic clinic for confirmatory testing using plasma amino acids. PKU is diagnosed if PHE concentration is persistently above 120 µmol/L and TYR is low or low normal, in an individual with an otherwise normal amino acid profile. BH4 deficiency is ruled out by measuring urine pterins and blood dihydropteridine reductase activity in all individuals with elevated PHE and PHE:TYR ratio.
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Differential diagnosis: Other DRD syndromes: Sepiapterin deficiency, tyrosine hydroxylase deficiency, dihydropteridine reductase deficiency, 6-pyruvoyltetrahydropterin synthase deficiency, DNACJ12 mutations, PRKN mutations.7Dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan may help differentiate from other forms of dystonia–parkinsonism with nigrostriatal degeneration.Diagnosis: Genetic test for GCH1 mutations (if available).CSF neurotransmitter profile: low levels of HVA, 5-HIAA, BH4, and neopterin.Dramatic and sustained response to small doses of levodopa.All patients with early-onset dystonia (<21 years) should have a trial of levodopa.
Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
Melanin is produced from L-tyrosine by tyrosinase (TYR) [27]. The 5,6,7,8-tetrahydrobiopterin (6-BH4) is an essential cofactor for the synthesis of L-tyrosine from L-phenylalanine by phenylalanine hydroxylase (PAH) and for the hydroxylation of L-tyrosine to L-DOPA by tyrosine hydroxylase (TH) [27]. Schallreuter et al. reported that vitiligo patients had an increase in GTP-cyclohydrolase I (GTP-CH-I) activity, which led to an excessive synthesis of 6-BH4 [27]. Moreover, the influence of H2O2 on dihydropteridine reductase (DHPR), the last enzyme in the 6-BH4-recycling process, which is deactivated when H2O2 levels are greater than 30 μM, has been demonstrated [28]. In addition, higher levels of 6-BH4 are associated with an overproduction of norepinephrine, which directly stimulates the upregulation of both monoamine oxidase-A (MAO-A) and catechol-O-methyltransferase metabolic pathways in these patients [28]. Another consequence of the augmented levels of 6-BH4 and increased MAO-A activity in the epidermis of vitiligo patients is the accumulation of toxic levels of H2O2. Furthermore, it has been reported that DHPR activity is significantly decreased in patients with vitiligo [28].
Clinical, biochemical and molecular spectrum of mild 6-pyruvoyl-tetrahydropterin synthase deficiency and a case report
Published in Fetal and Pediatric Pathology, 2021
Boyan Song, Zhijun Ma, Wei Liu, Lihong Lu, Yongjian Jian, Lu Yu, Zhihui Wan, Xiaofei Yue, Yuanyuan Kong
The patient is a female infant, delivered vaginally after 40 weeks of pregnancy, with a birth weight of 3430 g and a body length of 51 cm. The neonatal screening showed that the patient’s blood phenylalanine level was 221.6 µmol/L (reference range: 30–117 µmol/L). At day 21 after birth, she was admitted to our hospital. The phenylalanine level in blood was 859.6 µmol/L. No manifestations, such as skin whitening and yellowing, poor appetite, sucking weakness, dysphagia, decreased responsiveness, weakness, somnolence or convulsions were detected. No specific odor was found in urine. Moreover, jaundice, rash, and bleeding spots were not observed on the skin. No unusual facies and no yellow hair were observed. The anterior fontanel was flat and soft, and the tension was not high. Because getting results of urine pterin spectrum analysis and dihydropteridine reductase (DHPR) analysis for further diagnosis need several days, a low phenylalanine diet was administered.
An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies
Published in Expert Review of Neurotherapeutics, 2020
Mahmoud Reza Ashrafi, Man Amanat, Masoud Garshasbi, Reyhaneh Kameli, Yalda Nilipour, Morteza Heidari, Zahra Rezaei, Ali Reza Tavasoli
Contrast enhancement that is visible in post contrast T1W sequence (e.g. X-ALD, AxD type I, and mitochondrial disorders) [103] enlarged perivascular spaces (e.g. hypomelanosis of Ito, Mucopolysaccharidosis, Lowe syndrome, chromosomal abnormalities, PTEN mutation, and Sener syndrome) [119–122]. dystrophic calcification (e.g. AGS, RNASET2 deficient leukoencephalopathy, LCC, coates plus, ALSP, cockayne syndrome, dihydropteridine reductase deficiency, and mitochondrial disorders) [111,123,124] and megalencephaly (e.g. MLC, AxD, Canavan, and L-2-hydroxy glutaric aciduria) [109,125] are other reported special characteristics in brain MRI of individuals with leukodystrophies (Figure 4).Brain MRI has limitations and can be inconclusive in some cases. Distinguishing between genetic and acquired white matter abnormalities can be very difficult using MRI; especially in adults. Characterizing the microstructural properties of brain white matter can be a promising method for better diagnosis of leukodystrophies and assessing their prognosis. Diffusion tensor imaging (DTI) has become one of the most popular MRI techniques in brain research, which is based on the motion of water molecules [126]. This technique can provide a quantitative measurement of abnormal white matter in individuals with inherited white matter disorders [127–129]. DTI can be more sensitive than T1W, T2W, and FLAIR sequences for detecting white matter disorders and may be used for monitoring of treatment [127]. Apparent diffusion coefficient, magnetic resonance spectroscopy, and magnetization transfer imaging are other techniques used in specific types of leukodystrophies [12]. Further studies are needed to evaluate the potential of these new imaging techniques in different aspects of leukodystrophies.
Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice
Published in Gut Microbes, 2020
Klytaimnistra Kiouptsi, Giulia Pontarollo, Hristo Todorov, Johannes Braun, Sven Jäckel, Thomas Koeck, Franziska Bayer, Cornelia Karwot, Angelica Karpi, Susanne Gerber, Yvonne Jansen, Philipp Wild, Wolfram Ruf, Andreas Daiber, Emiel Van Der Vorst, Christian Weber, Yvonne Döring, Christoph Reinhardt
A set of markers were concordantly altered under HFD and normal diet. Interleukin 23 receptor (IL23r) was decreased whereas epithelial cell markers, such as epithelial cell adhesion molecule (EPCAM), and the incretin glucagon-like peptide-1 (Glp-1, Gcg) with vascular protective functions were increased in the absence of microbiota irrespectively of the diet and the genotype. In contrast, microbiota had also differential effects when comparing WT mice on a normal diet with Ldlr−/- mice on an HFD. Specifically, under HFD inflammation markers, e.g. tumor necrosis factor (Tnf), interleukin 1 alpha (IL1a), glial cell derived neurotrophic factor family receptor alpha 1 (Gfra1), and C-X-C motif chemokine ligand 9 (Cxcl9), as well as follistatin (Fst) levels, were reduced in GF Ldlr-/- mice relative to their CONV-R counterparts. In addition, proteins known to be expressed in the gastrointestinal track, i.e. integrin subunit beta 6 (Itgb6) and v-set and immunoglobulin domain containing 2 (Vsig2) were increased, possibly related to changes in gut permeability. GF HFD Ldlr−/- mice also had higher markers associated with metabolic processes, e.g. carbonic anhydrase 13 (Ca13), quinoid dihydropteridine reductase (Qdpr), mitogen-activated protien kinase 6 (Map2k6), Axin1, which in part may be related to differences in the formulation of the diet independent of lipid content. Interestingly, the downregulation of interleukin 17a/f (IL17a/f) in response to loss of the gut microbiota in GF WT mice was no longer seen in GF HFD-fed Ldlr−/- mice. While macrophage densities were not changed in late atherosclerotic lesions, these proteome changes indicate that GF conditions nevertheless alter immune cell activation or polarization in atherosclerotic mice.