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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.
Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Patients are now being diagnosed earlier because of the initiation of programs in which all hyperphenyalaninemic infants are being investigated for the possibility of defective metabolism of biopterin. However, it has been documented that it is possible to miss a patient with abnormal synthesis of BH4 because early phenylalanine levels may be normal. Therefore, evaluation for a disorder in this pathway should be undertaken in infants with unexplained neurologic disease. Five disorders are considered in this chapter: deficiencies of GTP cyclohydrolase I (GTPCH), recessive as well as dominant forms, 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), dihydropteridine reductase (DHPR), and pterin-4a-carbinolamine dehydratase (PCD) (Figure 16.3). The clinical manifestations of all of them are quite similar, but the carbinolamine hydratase is relatively benign. In addition, variant forms of PTPS and DHPR deficiency exist in which the neurologic signs are either minor or absent. Elevated phenylalanine should initiate investigation in most of these disorders. Sepiapterin reductase, the dominant form of GTPCH I deficiency, and some children with recessively inherited GTPCH deficiency are exceptions in which biopterin is deficient only in the brain [6, 7]. The next step in elucidating a diagnosis is measurement of pterin metabolites in urine or in dry blood spots, and DHPR activity in blood spots. Enzyme activity may be assessed in erythrocytes or cultured fibroblasts. Diagnosis may also be secured by determination of mutations of the relevant gene. Improved prognosis with early therapy makes prompt diagnosis and the timely initiation of therapy important.
The role of biomarkers in stage III non-small cell lung cancer
Published in Expert Review of Respiratory Medicine, 2023
Rafael Rosell, María González-Cao, Masaoki Ito, Mariacarmela Santarpia, Andrés Aguilar, Jordi Codony-Servat
Reactive oxygen species (ROS) production is harmful for polyunsaturated fatty acids (PUFAs) and lipid membranes. Following peroxidation, PUFAs disrupt cellular permeability and membrane function, inducing ferroptosis. In addition to the three previously mentioned resistance mechanisms against ferroptosis (GPX4, FSP1 and DHODH), tetrahydrobiopterin (BH4) has revealed an essential mechanism to compensate from GPX4 inhibition, suggesting that the inhibition of the SLC17A11-GPX4 axis can cause resistance through overexpression of BPH4. Loss of long-chain ACSL4 (Figure 2), which catalyzes the integration of PUFA into membrane phospholipids, improved cell survival when GPX4 is inhibited [59]. It was discovered that under GPX4 inhibition there is an upregulation of enzymes involved in the BH4 pathway, such as GTP cyclohydroxylase−1 (GCH1), 6-pyruvoyltetrahydropterin synthase (PTS) and sepiapterin reductase (SPR). Furthermore, it was identified that dihydrofolate reductase (DHFR) catalyzes the regeneration of BH4 and its inhibition by methotrexate is synergistic with GPX4 blockade [59]. Of utmost relevance, is the fact that sulfasalazine has demonstrated to inhibit sepiapterin reductase (SPR) [60]. Therefore, since sulfasalazine inhibits SLC17A11 (Figures 3, 2), it can presumably be inferred that the use of sulfasalazine could neutralize the counterbalanced rebound effect of BH4 upregulation. Notwithstanding, the action of methotrexate as a potential complementary drug should be kept in mind.
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
6-Pyruvoyl-tetrahydropterin synthase (PTS) is a key enzyme in BH4 synthesis. It is involved in the second step of de novo biosynthesis of BH4, which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases [1]. PTS deficiency is the primary cause of BH4 deficiency, which is divided into severe and mild types [3]. Patients with the severe type usually show decreased levels of L-dopa and serotonin in cerebrospinal fluid and abnormal development of nervous system [4]. They often require the combination therapy of BH4, L-dopa, and serotonin, and prognosis varies. In contrast, the mild type is characterized by normal physical and nervous system development [5]. In some cases, only BH4 supplementation or even no treatment is required to maintain a normal level of phenylalanine.