High prolactin levels in dihydropteridine reductase deficiency: A sign of therapy failure or additional pathology?
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ABSTRACT:
SUBMITTER: Vitturi N
PROVIDER: S-EPMC8411106 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dihydropteridine reductase (DHPR) deficiency is a genetic disorder of tetrahydrobiopterin (BH4) regeneration and may present with hyperphenylalaninemia, microcephaly, hypotonia, mental retardation, and convulsions. BH4 is an essential cofactor for the hydroxylation of aromatic amino acids and a deficiency of BH4 results in decreased synthesis of dopamine and serotonin. We present a 27-month-old female patient with DHPR deficiency who was treated with L-dopa/carbidopa (2 mg/kg, four times per day), 5-hydroxytryptophan (2 mg/kg, four times per day), folinic acid (10 mg/day), and BH4 supplementation (20 mg/kg, twice a day). Although remarkable clinical improvement with normal plasma phenylalanine (Phe) levels and increased phenylalanine tolerance was noted 1 month after the treatment, CSF neurotransmitter metabolites did not improve. BH4 supplementation was increased to 40 mg/kg/day and the CSF study was repeated 1 month later. There was no significant change of CSF neurotransmitters, BH4 or BH2 levels but plasma Phe level was within normal range. Surprisingly, she had developmental improvement noted at 1-month and 3-month visits following an augmented neurotransmitter and BH4 treatment. She was able to pull herself to the standing position and sit down on her own. She was also noted to be more alert and responsive following treatment. Her expressive language did not improve, although her receptive language was markedly improved. The above treatment improved patient's clinical findings, normalized blood Phe levels, and increased Phe tolerance in the diet, but neither 20 nor 40 mg/kg/day BH4 supplementation corrected neurotransmitter or BH4 levels or increased BH2 level in CSF. Further studies are needed to find the optimal management plan for patients with DHPR deficiency.
| S-EPMC3755580 | biostudies-literature
Project description:Tetrahydrobiopterin (BH4) is a cofactor that participates in the biogenesis reactions of a variety of biomolecules, including l-tyrosine, l-3,4-dihydroxyphenylalanine, 5-hydroxytryptophan, nitric oxide, and glycerol. Dihydropteridine reductase (DHPR, EC 1.5.1.34) is an enzyme involved in the BH4 regeneration. DHPR deficiency (DHPRD) is an autosomal recessive disorder, leading to severe and progressive neurological manifestations, which cannot be exclusively controlled by l-phenylalanine (l-Phe) restricted diet. In fact, the supplementation of neurotransmitter precursors is more decisive in the disease management, and the administration of sapropterin dihydrochloride may also provide positive effects. From the best of our knowledge, there is limited information regarding DHPRD in the past 5 years in the literature. Here, we describe the medical journey of the first patient to have DHPRD confirmed by molecular diagnostic methods in Brazil. The patient presented with two pathogenic variants of the quinoid dihydropteridine reductase (QDPR) gene-which codes for the DHPR protein, one containing the in trans missense mutation c.515C>T (pPro172Leu) in exon 5 and the other containing the same type of mutation in the exon 7 (c.635T>C [p.Phe212Ser]). The authors discuss their experience with sapropterin dihydrochloride for the treatment of DHPRD in this case report.
| S-EPMC8411105 | biostudies-literature
Project description:BACKGROUND:Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH4 ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters. METHODS:We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing. RESULTS:Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database. CONCLUSION:Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing.
| S-EPMC7196484 | biostudies-literature
Project description:Radioimmunoassay, immunoprecipitation, affinity chromatography and two-dimensional gel electrophoresis were used to test cultured cells from three families with dihydropteridine reductase deficiency for a catalytically incompetent product of the mutant gene. No mutant enzyme was detected in one dihydropteridine reductase-deficient homozygote or in her parents. A second homozygote and both her parents had easily detectable concentrations of inactive mutant enzyme. In a third family one parent fitted into each of these categories.
| S-EPMC1163317 | biostudies-other
Project description:Dihydropteridine reductase from Dictyostelium discoideum (dicDHPR) can produce D-threo-BH(4) [6R-(1'R,2'R)-5,6,7,8-tetrahydrobiopterin], a stereoisomer of L-erythro-BH(4), in the last step of tetrahydrobiopterin (BH(4)) recycling. In this reaction, DHPR uses NADH as a cofactor to reduce quinonoid dihydrobiopterin back to BH(4). To date, the enzyme has been purified to homogeneity from many sources. In this report, the dicDHPR-NAD complex has been crystallized using the hanging-drop vapour-diffusion method with PEG 3350 as a precipitant. Rectangular-shaped crystals were obtained. Crystals grew to maximum dimensions of 0.4 x 0.6 x 0.1 mm. The crystal belonged to space group P2(1), with unit-cell parameters a = 49.81, b = 129.90, c = 78.76 A, beta = 100.00 degrees , and contained four molecules in the asymmetric unit, forming two closely interacting dicDHPR-NAD dimers. Diffraction data were collected to 2.16 A resolution using synchrotron radiation. The crystal structure has been determined using the molecular-replacement method.
| S-EPMC2581689 | biostudies-literature
Project description:Dihydropteridine reductase has been purified 900-fold from rat liver. Dopamine inhibited the enzyme up to 50% at a concentration of 0.11mm. In the presence of dopamine the enzyme gave non-hyperbolic v-against-[S] plots. This enzyme may have a role in control of dopamine biosynthesis.
| S-EPMC1162951 | biostudies-other
Project description:Isolated prolactin (PRL) deficiency is a rare entity of unknown etiology manifesting as failure of puerperal lactogenesis.The aim of the study was to determine the cause of isolated PRL deficiency in an affected woman.We examined genetic and autoimmune causes of isolated PRL deficiency at academic medical centers.The patient was a 39-year-old woman with puerperal alactogenesis after two deliveries and undetectable PRL. The other pituitary axes, serum calcium levels, and cranial magnetic resonance imaging were normal.Recombinant human PRL (r-hPRL) was administered to the patient.We measured the sequencing of candidate genes and immunofluorescence analysis of autoantibodies directed against pituitary endocrine cells.There were no rare sequence variants in the genes encoding for PRL, putative PRL-releasing peptide, putative PRL-releasing peptide receptor, or in other genes important for lactotroph lineage development (POU1F1, PROP1, LHX3, LHX4, HESX1, OTX2, and LSD1). The patient serum, on the contrary, contained autoantibodies that specifically recognized a subset of PRL-secreting cells but not PRL itself or any other pituitary cells or hormones. The mother was able to lactate fully after 17 days of treatment with r-hPRL 60 ?g/kg every 12 hours, but alactogenesis resumed after treatment was completed.These studies report a new autoimmune etiology for women with isolated PRL deficiency and puerperal alactogenesis.
| S-EPMC3790613 | biostudies-literature
Project description:BackgroundPyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition.MethodsRetrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables.ResultsPatients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (-1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal.ValuesAll patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms.DiscussionPatients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.
| S-EPMC7749858 | biostudies-literature
Project description:The oxidation of 4,5-diaminopyrimidin-6(1H)-one, 5,6,7,8-tetrahydropteridin-4(3H)-one, its 6-methyl and cis-6,7-dimethyl derivatives, and 6-methyl- and cis-6-7-dimethyl-5,6,7,8-tetrahydropterins, by horseradish peroxidase/H2O2 is enzymic and follows Michaelis-Menten kinetics, and its Km and kcat. values were determined. This oxidation of 5,6,7,8-tetrahydropterins produces quinonoid dihydropterins of established structure, and they are known to be specific substrates for dihydropteridine reductase. By analogy the peroxidase/H2O2 oxidation of the 5,6,7,8-tetrahydropteridin-4(3H)-ones should produce similar quinonoid dihydro species. The quinonoid species derived from 5,6,7,8-tetrahydropteridin-4(3H)-one and its 6-methyl and cis-6,7-dimethyl derivatives are shown to be viable substrates for human brain dihydropteridine reductase, and apparent Km and Vmax. values are reported.
| S-EPMC1146570 | biostudies-other
Project description:Dihydropteridine reductase (EC 1.6.99.7) was purified from human liver obtained at autopsy by a three-step chromatographic procedure with the use of (1) a naphthoquinone affinity adsorbent, (2) DEAE-Sephadex and (3) CM-Sephadex. The enzyme was typically purified 1000-fold with a yield of 25%. It gave a single band on non-denaturing and sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, and showed one spot on two-dimensional gel electrophoresis. The molecular weight of the enzyme was determined to be 50000 by sedimentation-equilibrium analysis and 47500 by gel filtration. On sodium dodecyl sulphate/polyacrylamide-gel electrophoresis, a single subunit with mol.wt. 26000 was observed. A complex of dihydropteridine reductase with NADH was observed on gel electrophoresis. The isoelectric point of the enzyme was estimated to be pH 7.0. Amino acid analysis showed a residue composition similar to that seen for the sheep and bovine liver enzymes. The enzyme showed anomalous migration in polyacrylamide-gel electrophoresis. A Ferguson plot indicated that this behaviour is due to a low net charge/size ratio of the enzyme under the electrophoretic conditions used. The kinetic properties of the enzyme with tetrahydrobiopterin, 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine, NADH and NADPH are compared, and the effects of pH, temperature and a number of different compounds on catalytic activity are presented.
| S-EPMC1163052 | biostudies-other