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Nenad Blau - One of the best experts on this subject based on the ideXlab platform.
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Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria.
Genetics in Medicine, 2018Co-Authors: Sven F. Garbade, Friedrich K. Trefz, Georg F Hoffmann, Nan Shen, Nastassja Himmelreich, Dorothea Haas, Peter Burgard, Nenad BlauAbstract:The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU. A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0–2.7 for classic PKU, 2.8–6.6 for mild PKU and 6.7–10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P
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long term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria
Molecular Genetics and Metabolism, 2005Co-Authors: Julia B. Hennermann, Nenad Blau, Christoph Buhrer, Barbara Vetter, Eberhard MönchAbstract:Hyperphenylalaninemia caused by phenylalanine hydroxylase (PAH) deficiency requires lifelong rigorous diet starting in early infancy to prevent severe neurodevelopmental handicap. In a considerable number of children with mild Hyperphenylalaninemia, long-term tetrahydrobiopterin (BH4) treatment significantly improves phenylalanine (phe) tolerance, but it has never been investigated in classic phenylketonuria (PKU). We performed a BH4-loading test in 40 consecutive infants with phe serum concentrations exceeding 240 microM, who had been detected by newborn screening programs. Eighteen out of 40 infants were found to be BH4 responsive. Five of them, responding to the neonatal BH4-loading test, showed a phe tolerance of less than 20 mg/kg/day and a phe pretreatment level of >1000 microM. They were treated with BH4 (20 mg/kg/day) over a period of 24 months. All five children had a sustained response to BH4, allowing substantial easing of dietary restrictions. Before BH4 treatment daily phe tolerance was 18-19 mg/kg, increasing to 30-80 mg/kg on BH4 treatment and decreasing again to 12-17 mg/kg after termination of BH4 treatment. Mutation analysis revealed compound heterozygosity for a putative null and a variant PAH mutation in four patients and homozygosity for a variant PAH mutation in one patient. We conclude that BH4 sensitivity is not restricted to mild Hyperphenylalaninemia and that long-term BH4 treatment may also improve phenylalanine tolerance in a considerable number of children with a more severe PKU phenotype.
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6 pyruvoyl tetrahydropterin synthase deficiency with mild Hyperphenylalaninemia
Annals of Neurology, 2005Co-Authors: Michelle Demos, Keith Hyland, Nenad Blau, Paula J. Waters, Hilary Vallance, Yolanda Lillquist, Nawal Makhseed, Mary B. ConnollyAbstract:Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with Hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild Hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for Hyperphenylalaninemia. Ann Neurol 2005;58:164–167
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6‐Pyruvoyl‐tetrahydropterin synthase deficiency with mild Hyperphenylalaninemia
Annals of neurology, 2005Co-Authors: Michelle Demos, Keith Hyland, Nenad Blau, Paula J. Waters, Hilary Vallance, Yolanda Lillquist, Nawal Makhseed, Mary B. ConnollyAbstract:Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with Hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild Hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for Hyperphenylalaninemia. Ann Neurol 2005;58:164–167
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Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia
American journal of human genetics, 2001Co-Authors: Luisa Bonafé, Beat Thony, Johann Penzien, Barbara Czarnecki, Nenad BlauAbstract:Classic tetrahydrobiopterin (BH4) deficiencies are characterized by Hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without Hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH4. Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC→CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397–1401delAGAAC) resulting in abolished SPR-gene expression and an A→G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of Hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH4 biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH4 in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH4 and to neurotransmitter deficiencies without Hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.
Johannes J. Duvekot - One of the best experts on this subject based on the ideXlab platform.
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Maternal phenylketonuria and Hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and
2012Co-Authors: Babette W. Prick, Wim C. J. Hop, Johannes J. DuvekotAbstract:Background: Untreated maternal phenylketonuria or Hyperphenylalaninemia may result in nonphenylketonuric offspring with neonatal sequelae, especially intellectual disability, microcephaly, and congenital heart disease (CHD). Dietary treatment to control phenylalanine concentrations can prevent these sequelae. Objective: We aimed to present an overview of reported pregnancy complications and neonatal sequelae of maternal phenylketonuria or Hyperphenylalaninemia in untreated and treated pregnancies. Design: A MEDLINE and EMBASE search was conducted for case reports and case series that assessed maternal phenylketonuria or Hyperphenylalaninemia during pregnancy. Pregnancy complications (spontaneous abortion, intrauterine-fetal-death, and preterm delivery) and neonatal sequelae [small for gestational age (SGA), microcephaly, CHD, intellectual or developmental disabilities (IDDs), and facial dysmorphism (FD)] were analyzed. Fifteen unpublished pregnancies from our clinic were added. Results: We retrieved 196 pregnancies, of which 126 pregnancies were untreated and 70 pregnancies were treated. The occurrence of pregnancy complications was not significantly different between untreated and treated pregnancies. Except for SGA, all neonatal sequelae were more frequent in untreated pregnancies. Moreover, the occurrence of SGA, microcephaly, and IDDs was significantly related to the mean phenylalanine concentration in each trimester, whereas the occurrence of FD was related only to the first trimester. Conclusions: We present the largest cohort of untreated pregnant women with phenylketonuria or Hyperphenylalaninemia since 1980. The results follow the general pattern reported by other researchers. We underline that the treatment of pregnant women with phenylketonuria or Hyperphenylalaninemia is of great importance to prevent neonatal sequelae. We strongly recommend starting treatment before conception because we showed the deleterious effect of an increased mean first-trimester phenylalanine concentration on FD. Am J Clin Nutr 2012;95:374‐82.
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Maternal phenylketonuria and Hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies
The American journal of clinical nutrition, 2011Co-Authors: Babette W. Prick, Wim C. J. Hop, Johannes J. DuvekotAbstract:Background: Untreated maternal phenylketonuria or Hyperphenylalaninemia may result in nonphenylketonuric offspring with neonatal sequelae, especially intellectual disability, microcephaly, and congenital heart disease (CHD). Dietary treatment to control phenylalanine concentrations can prevent these sequelae. Objective: We aimed to present an overview of reported pregnancy complications and neonatal sequelae of maternal phenylketonuria or Hyperphenylalaninemia in untreated and treated pregnancies. Design: A MEDLINE and EMBASE search was conducted for case reports and case series that assessed maternal phenylketonuria or Hyperphenylalaninemia during pregnancy. Pregnancy complications (spontaneous abortion, intrauterine-fetal-death, and preterm delivery) and neonatal sequelae [small for gestational age (SGA), microcephaly, CHD, intellectual or developmental disabilities (IDDs), and facial dysmorphism (FD)] were analyzed. Fifteen unpublished pregnancies from our clinic were added. Results: We retrieved 196 pregnancies, of which 126 pregnancies were untreated and 70 pregnancies were treated. The occurrence of pregnancy complications was not significantly different between untreated and treated pregnancies. Except for SGA, all neonatal sequelae were more frequent in untreated pregnancies. Moreover, the occurrence of SGA, microcephaly, and IDDs was significantly related to the mean phenylalanine concentration in each trimester, whereas the occurrence of FD was related only to the first trimester. Conclusions: We present the largest cohort of untreated pregnant women with phenylketonuria or Hyperphenylalaninemia since 1980. The results follow the general pattern reported by other researchers. We underline that the treatment of pregnant women with phenylketonuria or Hyperphenylalaninemia is of great importance to prevent neonatal sequelae. We strongly recommend starting treatment before conception because we showed the deleterious effect of an increased mean first-trimester phenylalanine concentration on FD.
Beat Thony - One of the best experts on this subject based on the ideXlab platform.
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the mechanism of bh4 responsive Hyperphenylalaninemia as it occurs in the enu1 2 genetic mouse model
Human Mutation, 2012Co-Authors: Christineh N Sarkissian, Ming Ying, Tanja Scherer, Beat Thony, Aurora MartinezAbstract:The Pah(enu1/enu2) (ENU1/2) mouse is a heteroallelic orthologous model displaying blood phenylalanine (Phe) concentrations characteristic of mild Hyperphenylalaninemia. ENU1/2 mice also have reduced liver phenylalanine hydroxylase (PAH) protein content (∼20% normal) and activity (∼2.5% normal). The mutant PAH protein is highly ubiquitinated, which is likely associated with its increased misfolding and instability. The administration of a single subcutaneous injection of l-Phe (1.1 mg l-Phe/g body weight) leads to an approximately twofold to threefold increase of blood Phe and phenylalanine/tyrosine (Phe/Tyr) ratio, and a 1.6-fold increase of both nonubiquitinated PAH protein content and PAH activity. It also results in elevated concentrations of liver 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), potentially through the influence of Phe on GTP cyclohydrolase I and its feedback regulatory protein. The increased BH(4) content seems to stabilize PAH. Supplementing ENU1/2 mice with BH(4) (50 mg/kg/day for 10 days) reduces the blood Phe/Tyr ratio within the mild hyperphenylalaninemic range; however, PAH content and activity were not elevated. It therefore appears that BH(4) supplementation of ENU1/2 mice increases Phe hydroxylation levels through a kinetic rather than a chaperone stabilizing effect. By boosting blood Phe concentrations, and by BH(4) supplementation, we have revealed novel insights into the processing and regulation of the ENU1/2-mutant PAH.
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Mutations in the Sepiapterin Reductase Gene Cause a Novel Tetrahydrobiopterin-Dependent Monoamine-Neurotransmitter Deficiency without Hyperphenylalaninemia
American journal of human genetics, 2001Co-Authors: Luisa Bonafé, Beat Thony, Johann Penzien, Barbara Czarnecki, Nenad BlauAbstract:Classic tetrahydrobiopterin (BH4) deficiencies are characterized by Hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without Hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH4. Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC→CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397–1401delAGAAC) resulting in abolished SPR-gene expression and an A→G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of Hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH4 biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH4 in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH4 and to neurotransmitter deficiencies without Hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.
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isolated central form of tetrahydrobiopterin deficiency associated with hemizygosity on chromosome 11q and a mutant allele of ptps
Human Mutation, 2000Co-Authors: Nenad Blau, Tanja Schereroppliger, Alessandra Baumer, Mariluce Riegel, Ana Matasovic, Albert Schinzel, Jaak Jaeken, Beat ThonyAbstract:6-Pyruvoyl-tetrahydropterin synthase (PTS or PTPS) is involved in tetrahydrobiopterin (BH4) biosynthesis, the cofactor for various enzymes including the aromatic amino acid hydroxylases. Inherited PTPS deficiency is a heterogeneous disease with different phenotypes leading to BH4 depletion. The severe form of PTPS deficiency causes Hyperphenylalaninemia and monoamine neurotransmitter deficiency, whereas the mild form gives rise to Hyperphenylalaninemia only. From 228 patients with PTPS deficiency at least 32 different mutant alleles have been identified on its corresponding gene, located on chromosome 11q22.3-q23.3. Here we describe a new allele from a child with PTPS deficiency who exhibited a mild but transient form of Hyperphenylalaninemia, yet was deficient in CSF monoamines. The patient was found to carry, on her genomic DNA and cDNA, a homozygous A>G transition, leading to PTPS codon alteration Tyr99 to Cys (Y99C). The mother and several members of the maternal family were carriers of the Y99C allele, also verified by the reduced PTPS enzyme activity in erythrocytes. By cytogenetic, molecular, and FISH analyses, a de novo deletion spanning from 11q14 to 11q23.3 on the patient's paternal chromosome was mapped, establishing hemizygosity of the Y99C allele. The PTPS mutation observed in this patient generates a novel phenotype with an apparently isolated central form of BH4 deficiency. Hum Mutat 16:54–60, 2000. © 2000 Wiley-Liss, Inc.
Cary O Harding - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic liver repopulation for phenylketonuria
Journal of Inherited Metabolic Disease, 2010Co-Authors: Cary O Harding, K. M. GibsonAbstract:Problems with long-term dietary compliance in phenylketonuria (PKU) necessitate the development of alternative treatment approaches. Therapeutic liver repopulation with phenylalanine hydroxylase (PAH)-expressing cells following hepatocyte or haematopoietic stem cell transplantation has been investigated as a possible novel treatment approach for PKU. Successful therapeutic liver repopulation requires both a stimulus for liver regeneration at the time of cell transplantation and a selective growth advantage for the PAH+ donor cells. Unfortunately, wild-type PAH+ hepatocytes do not enjoy any growth advantage over PAH− cells. Successful correction of Hyperphenylalaninemia following therapeutic liver repopulation has been accomplished only in an animal model that yields a selective advantage for the donor cells. Haematopoietic stem cell (HSC)-mediated therapeutic liver repopulation has not been reported in any hyperphenylalaninemic system, and the success of HSC-mediated liver repopulation for PKU may be limited by the slow kinetics of this approach. If therapeutic liver repopulation is to be employed successfully in humans with PKU, an effective method of providing a selective growth advantage for the donor cells must be developed. If this can be achieved, liver repopulation with 10–20% wild-type hepatocytes will likely completely normalize Phe clearance in individuals with PKU.
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219 persistent correction of Hyperphenylalaninemia following liver directed raav2 8 mediated gene therapy for murine phenylketonuria pku
Molecular Therapy, 2006Co-Authors: Cary O Harding, Melanie B Gillingham, Elizabeth Daghighi, Andrew Bird, Dwight D KoeberlAbstract:Top of pageAbstract We recently reported the complete correction of Hyperphenylalaninemia in Pahenu2 mice, a model of human phenylketonuria (PKU), following portal vein injection of a rAAV2/ 8 vector expressing the mouse phenylalanine hydroxylase (PAH) cDNA under the control of a strong liver specific (LSP) promoter. Our goal now is to evaluate the persistence of this effect following a single vector injection. Three hyperphenylalaninemic Pahenu2 mice (two female, one male) each received 5 X 1011 vector genomes (vg) of mouse PAH-expressing rAAV2/8 via portal vein injection. An additional two animals (one male, one female) received saline via portal vein injection only. Serum phenylalanine (PHE) levels decreased significantly by two weeks post injection in rAAV2/8 treated mice (mean preinjection serum PHE |[plusmn]| SE = 2074 |[plusmn]| 157 |[mu]|M vs. 150 |[plusmn]| 49.9 |[mu]|M two weeks post injection, p = 0.001; normal =157 |[plusmn]| 32 |[mu]|M), while serum PHE levels remain unchanged in saline treated controls. This effect has persisted out to 32 weeks post injection although serum PHE has increased modestly over time in the two rAAV2/8-treated female mice. The mean serum PHE level in rAAV2/8-treated mice 32 weeks after treatment was 630 |[mu]|M, still a significant decrease from preinjection levels. Body weight and physical appearance of the animals have remained normal followingrAAV2/8 treatment except or the expected increase in coat pigmentation following correction of lood PHE levels. Liver-directed, rAAV2/8 vector-mediated gene therapy has successfully corrected Hyperphenylalaninemia in Pahenu2, but the stability of expression and the incidence of long-term adverse effects must continue to be evaluated.
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873. Low Level Hepatocyte Repopulation Corrects Hyperphenylalaninemia in Murine Phenylketonuria
Molecular Therapy, 2004Co-Authors: Cary O Harding, Kelly Hamman, Heather Clark, Eugenio Montini, Muhsen Al-dhalimy, Markus Grompe, Milton J. FinegoldAbstract:Objective: Determine the minimal number of phenylalanine hydroxylase (PAH) positive hepatocytes and minimal level of PAH activity required to correct Hyperphenylalaninemia in Pahenu2 mice, a model of human phenylketonuria (PKU).
Keith Hyland - One of the best experts on this subject based on the ideXlab platform.
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6 pyruvoyl tetrahydropterin synthase deficiency with mild Hyperphenylalaninemia
Annals of Neurology, 2005Co-Authors: Michelle Demos, Keith Hyland, Nenad Blau, Paula J. Waters, Hilary Vallance, Yolanda Lillquist, Nawal Makhseed, Mary B. ConnollyAbstract:Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with Hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild Hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for Hyperphenylalaninemia. Ann Neurol 2005;58:164–167
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6‐Pyruvoyl‐tetrahydropterin synthase deficiency with mild Hyperphenylalaninemia
Annals of neurology, 2005Co-Authors: Michelle Demos, Keith Hyland, Nenad Blau, Paula J. Waters, Hilary Vallance, Yolanda Lillquist, Nawal Makhseed, Mary B. ConnollyAbstract:Severe 6-pyruvoyl-tetrahydrobiopterin synthase deficiency is a tetrahydrobiopterin deficiency disorder that presents in infancy with developmental delay, seizures, and abnormal movements associated with Hyperphenylalaninemia usually detectable by neonatal phenylketonuria screening programs. We describe an 8-year-old girl with delay, seizures, and dystonia with mild Hyperphenylalaninemia detected in late childhood. The diagnosis of 6-pyruvoyl-tetrahydrobiopterin synthase deficiency was made by analysis of pterins in urine, pterins and neurotransmitters in cerebrospinal fluid, and enzyme assay. The patient improved clinically taking oral tetrahydrobiopterin, levodopa/carbidopa, and 5-hydroxytryptophan. This treatable condition may not always be detected by routine population screening for Hyperphenylalaninemia. Ann Neurol 2005;58:164–167
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presentation diagnosis and treatment of the disorders of monoamine neurotransmitter metabolism
Seminars in Perinatology, 1999Co-Authors: Keith HylandAbstract:For many years, all of the described cases of monoamine neurotransmitter deficiency were associated with hyperphenylalaminemia that was generally detected at neonatal screening. It is now clear that inherited deficiency of monoamines often occurs in the absence of Hyperphenylalaninemia and that the normal battery of screening tests used to investigate individuals with suspected metabolic disease will not detect these cases. Diagnosis in this situation must rely heavily on clinical suspicion. This article, therefore, describes the presentation and clinical symptoms that results from defective monoamine neurotransmission; outlines therapeutic approaches; and explains how cerebrospinal fluid profiles of monoamine metabolites, their precursors, and the cofactor required for monoamine synthesis can be used to pinpoint the exact site of the metabolic lesion.