Publications by authors named "Flemming Güttler"

17 Publications

  • Page 1 of 1

Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study.

Mol Genet Metab 2019 12 14;128(4):415-421. Epub 2019 Sep 14.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address:

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase gene (PAH). The correlation between genotype and phenotype can be complex and sometimes variable but often very useful for categorizing and predicting dietary tolerance and potential outcome. We reviewed medical records for 367 patients diagnosed with PKU or persistent mild hyperphenylalaninemia (MHP) between 1950 and 2015 who had PAH genotyping. In 351 we had the full PAH genotype as well as phenotypic characteristics such as phenylalanine (Phe) concentrations (at newborn screening, confirmation, and highest known), and dietary Phe tolerance. On 716 mutant chromosomes, including 14 in genotypes with only one identified variant, we identified 114 different pathogenic variants. The most frequent, p.R408W, was present in 15.4% of the alleles; other frequent variants were c.1315 + 1G > A (6.1%), p.I65T (5.7%), and p.R261Q (5.7%). Three variants, c.142 T > G (p.L48 V), c.615G > C (p.E205D), and c.1342_1345delCTCC, were novel. We used the phenotypic parameters of variants paired with null alleles (functional hemizygotes) to assign the variants as classic PKU, moderate PKU, mild PKU, MHP-gray zone, or MHP. We also included the phenotype association(s) for all of the full genotypes. In 103 patients, we also could assign sapropterin dihydrochloride responsiveness, which is a synthetic form of the tetrahydrobiopterin (BH) PAH cofactor. This compilation from a single metabolic center provides further information on PAH variants in the United States and the correlations between genotype and phenotype.
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http://dx.doi.org/10.1016/j.ymgme.2019.09.004DOI Listing
December 2019

Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation.

J Inherit Metab Dis 2010 Feb;33(1):9-16

Center for PKU, The Kennedy Center, Glostrup, Denmark.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation due to defects in the enzyme phenylalanine hydroxylase (PAH). Phe accumulation can lead to cognitive impairment. Some individuals with PKU respond to tetrahydrobiopterin (BH4) treatment, the natural cofactor of PAH, by a reduction in blood Phe concentrations.We tested 12 patients with PKU, 8-29 years of age, all carrying the common Y414C mutation in the PAH gene. Three were homozygous and nine were compound heterozygous, with the second mutation being a putative null mutation. During the study period, genuine protein was increased to approximately 1 g/kg. The patients were treated with 20, 10, and 5 mg BH4/kg/day for 1 week on each dose, starting with 20 mg/kg. A positive response was defined as a decline in blood Phe>30%. Blood Phe was measured four times a week. Nonresponding children were excluded from the study. Eleven of 12 patients had a positive response with 20 mg/kg, 5/10 responded on 10 mg/kg, and 1/9 on 5 mg/kg. Two were late responders, with a response on 20 mg/kg after >48 h. We could confirm the previously reported inconsistent responsiveness of Y414C in the nine heterozygous patients, whereas the three homozygous patients had early median Phe declines of 73%, 51%, and 27%, respectively, on the three different doses. The varying responses despite uniform trial conditions and genotypes may be due to individual differences in BH4 absorption or metabolism. No side effects were observed.
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http://dx.doi.org/10.1007/s10545-009-9002-0DOI Listing
February 2010

Mutations in the regulatory domain of phenylalanine hydroxylase and response to tetrahydrobiopterin.

Genet Test 2007 ;11(2):174-8

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.

Tetrahydrobiopterin (BH4) is a co-factor that enhances the activity of other enzymes, and this co-factor level is found to be affected in phenylketonuria (PKU), an amino acid metabolism disorder. The present study was aimed at understanding the effect of BH4 on mutations in the regulatory domain of phenylalanine hydroxylase (PAH). Among 14 patients, 5 patients were classical PKU, 3 were atypical PKU, and 6 were mild PKU. All of these patients had at least one mutation in the regulatory domain. Patients were given 10 mg/kg BH4, and the response of blood phenylalanine (Phe) levels was monitored following treatment. The level of blood Phe decreased after BH4 treatment in all of the patients. These studies suggest that mutations in the regulatory domain also responded to BH4 even if the patient had classical PKU.
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http://dx.doi.org/10.1089/gte.2006.0520DOI Listing
September 2007

Response of phenylketonuria to tetrahydrobiopterin.

J Nutr 2007 06;137(6 Suppl 1):1564S-1567S; discussion 1573S-1575S

Department of Health and Human Performance, University of Houston, Houston, TX 77204, USA.

A favorable response, indicated by decline of blood phenylalanine (Phe) in patients with phenylketonuria (PKU), to orally administered 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH4) has been reported in many countries following the first publication in 1999. In this review, we describe the experience in the United States with PKU patients and their response to BH4. A significant response to BH4 is arbitrarily considered as a decrease of 30% or greater of blood Phe concentration 24 h after administration of BH4. In our studies, 18 of 37 patients with PKU (49%) responded to oral BH4 by >30% decrease in blood Phe concentration. Four PKU patients responded with a decrease of blood Phe concentration between 17.3 and 26.3%. It is suggested that patients with sufficient response to BH4 are candidates who will benefit from BH4 as it becomes available for PKU management. In a separate trial, 20 patients with PKU were screened with ascending doses of BH4: 10, 20, and 40 mg/kg. A favorable response was found in 10 subjects (50%) after 10 mg/kg BH4 and 14 subjects (70%) after 20 mg/kg BH4. There was no additional advantage to 40 mg/kg BH4. A 1-wk trial with 10 and 20 mg/kg BH4 in the same 20 patients showed blood Phe concentrations lowest after 7 d of BH4. The BH4-responsive patients were genotyped and most were compound heterozygotes with 1 mild mutation on 1 allele, responsible for the increase of the residual activity of Phe hydroxylase when BH4 was added. Individuals with the same genotype exhibit different responses upon administration of BH4, attributed to epigenetic factors, such as the metabolic makeup of the individual. Patients with PKU, regardless of their genotype or classification, need to be screened for response to BH4. The majority of patients are identified by 10 mg/kg BH4.
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http://dx.doi.org/10.1093/jn/137.6.1564SDOI Listing
June 2007

Low proportion of whole exon deletions causing phenylketonuria in Denmark and Germany.

Hum Mutat 2007 Feb;28(2):207

Kennedy Institute-National Eye Clinic, Glostrup, Denmark.

Phenylketonuria (PKU) is an autosomal recessive genetic disorder caused by mutations of the gene encoding phenylalanine hydroxylase (PAH). More than 500 different PAH mutations have been identified and about 90% of these are single base mutations. Although the identification rate of the PAH mutations is generally very high, some variants remain unidentified. A fraction of these mutations are the result of genomic deletions or duplications, which are not recognized with standard PCR-based methods. Here we present the results of exon deletion or duplication analysis in a total of 34 families, in which two mutations had not been identified using conventional diagnostic screening techniques. Using multiplex ligation-dependent probe amplification (MLPA), we found a deletion covering exon 1 and exon 2 (c.1-?_168+?del) in one patient, a deletion of exon 3 (c.169-?_352+?del) in four patients, and a deletion of exon 5 (c.442-?_509+?del) in two patients. A deletion was thus detected in about 20% (7/34) of the families tested. Out of a combined cohort of 570 independent PKU patients from Denmark and Germany, exon deletions were identified in a total of four patients. The estimated allelic frequency of exon deletions in PKU patients in these two populations is therefore below 0.5%.
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http://dx.doi.org/10.1002/humu.9481DOI Listing
February 2007

Tetrahydrobiopterin and maternal PKU.

Mol Genet Metab 2005 Dec;86 Suppl 1:S139-41

Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

A 29-year-old woman with PKU is presented, who was successfully treated with phenylalanine restriction as well as oral BH4 during this pregnancy, with a normal outcome. Her PAH mutation was R408W/F39L. Remarkably, the blood phenylalanine control was easily accomplished during this pregnancy. The lack of nausea and vomiting during the first trimester suggests that the occurrence of CHD in babies born to women with PKU may be reduced with BH4.
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http://dx.doi.org/10.1016/j.ymgme.2005.09.004DOI Listing
December 2005

Behavioural effects of phenylalanine-free amino acid tablet supplementation in intellectually disabled adults with untreated phenylketonuria.

Acta Paediatr 2005 Sep;94(9):1218-22

Department of Paediatrics, Nutrition and Metabolism Unit, Hacettepe University, Ankara, Turkey.

Aim: To evaluate the effects of phenylalanine (Phe)-free essential amino acid (AA) tablets enriched in tyrosine and tryptophan on the performance of intellectually disabled adult patients with untreated phenylketonuria (PKU).

Methods: Phe-free AA tablets and placebo tablets were administered to 19 untreated PKU subjects on a normal diet for 6 mo in a prospective double-blinded crossover study. The adaptive behaviour of the patients was tested prior to the study and at 6 and 12 mo after the start, using a simplified version of the Vineland Adaptive Behaviour Scale. For each sub-domain, the patients were rated either "0" (for poor performance) or "1" (for good performance). Neurological signs and symptoms and specific behavioural characteristics were recorded monthly by caretakers. Every 6 mo, neurological examination of the patients was performed, and the caretakers were interviewed. The statistical significance of the results was tested by means of the Fisher's exact and Wilcoxon tests.

Results: The most significant changes were an improved concentration and the development of a meaningful smile, which were observed in 44% and 43% of the patients on AA tablet treatment, respectively, but not patients on placebo. Other important but less significant changes included increased awareness of external stimuli (63%) and less self-injury (43%), and 40% were smiling and laughing occasionally. The mean overall rating increased from an initial value of 6.3 to 10.1 in patients when on AA tablet treatment (p=0.002), and to 7.0 in patients when on placebo (p=0.068). The difference between active AA treatment and placebo was statistically significant (p=0.027).

Conclusions: This pilot study suggests that Phe-free AA tablets enriched in tyrosine and tryptophan may improve the quality of life in some intellectually disabled adults with untreated PKU.
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http://dx.doi.org/10.1111/j.1651-2227.2005.tb02078.xDOI Listing
September 2005

Inter-individual variation in brain phenylalanine concentration in patients with PKU is not caused by genetic variation in the 4F2hc/LAT1 complex.

Mol Genet Metab 2005 Dec 19;86 Suppl 1:S119-23. Epub 2005 Sep 19.

Kennedy Institute, Glostrup, Denmark.

It remains a question why some patients with phenylketonuria (PKU) have high IQ and low brain phenylalanine (Phe) concentrations in spite of high blood Phe levels. One possible explanation for the low brain Phe concentrations in these patients would be a reduced transport of Phe across the blood-brain barrier. The 4F2hc/LAT1 complex has been suggested to be the most important molecular component responsible for this transport. To test the hypothesis that structural variant(s) in the genes encoding 4F2hc and LAT1 might result in a complex with reduced affinity for Phe, we have screened the two genes for sequence variants in a group of 13 PKU patients with a low ratio of brain to blood Phe concentrations. Several common sequence variants were identified, but none of these is predicted to affect the resulting protein product. Our data suggest that individual vulnerability to Phe in patients with PKU is not due to structural variants in the 4F2hc/LAT1 complex.
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http://dx.doi.org/10.1016/j.ymgme.2005.07.031DOI Listing
December 2005

Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency.

Prenat Diagn 2005 Aug;25(8):671-5

The John F. Kennedy Institute, Glostrup, Denmark.

Objectives: Tyrosine hydroxylase (TH) is a key enzyme in the biosynthesis of dopamine, epinephrine and norepinephrine. The primary diagnosis of TH deficiency is based on the measurement of neurotransmitter metabolites and pterins in the cerebrospinal fluid, and the final diagnosis is made by detection of mutations in the TH gene. The clinical expression varies with presentations as infantile parkinsonism, L-dopa responsive spastic paraplegia, or as a progressive severe encephalopathy. Treatment with L-dopa is not always sufficient and a number of patients with poor or no response to L-dopa have recently been described.

Methods: TH is not expressed in amniotic fluid cells or in chorionic villus, so prenatal diagnosis by measurement of the enzyme activity is not possible. The only possibility of a prenatal diagnosis is by analyzing the TH gene for mutations.

Results: Here we describe a case of severe TH deficiency, identification of two novel mutations (p.R328W and p.T399M) and most importantly, the first prenatal diagnosis of this disease.

Conclusions: The availability of prenatal diagnosis offers the parents new options. They may use the result as preparation for the birth of a child with TH deficiency, or they may decide termination of an affected pregnancy.
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http://dx.doi.org/10.1002/pd.1193DOI Listing
August 2005

Levodopa-responsive infantile parkinsonism due to a novel mutation in the tyrosine hydroxylase gene and exacerbation by viral infections.

Mov Disord 2005 Jun;20(6):764-7

Department of Pediatrics, Division of Neuropediatrics, University of Göttingen, 37099 Göttingen, Germany.

Autosomal recessive forms of infantile dystonia due to mutations in the tyrosine hydroxylase (TH) gene have been described recently. The main clinical manifestations are Segawa's disease, or infantile hypokinetic rigid Parkinsonism. Here, we report on a patient with hyperrigidity, psychomotor developmental delay, and dystonic posturing of the hands, symptoms that appeared after a viral infection at the age of 14 months. Low homovanillic acid/5-hydroxyindolacetic acid (HVA/5HIAA) ratio in cerebrospinal fluid suggested a TH deficiency. Molecular analysis revealed a novel (H246Y) and a known (D498G) compound heterozygote mutation in the TH gene. The patient showed a remarkable response to treatment with levodopa. The new mutation and the association of viral infections with the onset and worsening of symptoms are discussed.
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http://dx.doi.org/10.1002/mds.20416DOI Listing
June 2005

Biopterin responsive phenylalanine hydroxylase deficiency.

Genet Med 2004 Jan-Feb;6(1):27-32

Department of Pediatrics and Microbiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.

Purpose: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. There have been more than 400 mutations identified in the PAH gene leading to variable degrees of deficiency in PAH activity, and consequently a wide spectrum of clinical severity. A pilot study was undertaken to examine the response to 6-R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in patients with atypical and classical PKU.

Methods: PAH gene mutation analysis was performed using denaturing gradient gel electrophoresis and gene sequencing. Patients with classical, atypical, or mild PKU were orally given BH4 10 mg/kg. Blood phenylalanine and tyrosine levels were determined using tandem MS/MS at 0 hours, 4 hours, 8 hours, and 24 hours intervals.

Results: Thirty-six patients were given a single oral dose of 10 mg/kg of BH4. Twenty one patients (58.33%) responded with a decrease in blood phenylalanine level. Of the patients that responded, 12 were classical, 7 atypical, and 2 mild. The mean decline in blood phenylalanine at 24 hours was > 30% of baseline. There were 15 patients who did not respond to the BH4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH4 binding domains. Five patients responding to BH4 had mutations not previously identified.

Conclusion: The data presented suggest higher than anticipated number of PKU mutations respond to BH4, and such mutations are on all the domains of PAH.
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http://dx.doi.org/10.1097/01.gim.0000108840.17922.a7DOI Listing
July 2004

Pregnancy experiences in the woman with mild hyperphenylalaninemia.

Pediatrics 2003 Dec;112(6 Pt 2):1548-52

Division of Genetics, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

Objective: A major issue in maternal phenylketonuria (MPKU) has been whether maternal non-PKU mild hyperphenylalaninemia (MHP) is teratogenic. Such untreated pregnancies and their outcomes are presented on this report.

Methods: Enrolled pregnancies in which the untreated prepregnancy assigned phenylalanine level (APL) was no more than 600 micro mol/L were included in the Maternal PKU Collaborative Study and were followed according to protocol.

Results: Forty-eight enrolled women with non-PKU MHP had mean APL 408 +/- 114 micromol/L. They had a total of 58 pregnancies that resulted in live births. Fifty were untreated. Maternal phenylalanine (Phe) levels in the untreated pregnancies decreased during pregnancy for average Phe exposure of 270 +/- 84 micromol/L, virtually identical to the level of 269 +/- 136 micromol/L in the 8 treated pregnancies. Birth measurements in the 50 offspring from untreated pregnancies were within normal limits with z scores of -0.25 for weight, 0.28 for length, and -0.63 for head circumference, although birth head circumference was negatively correlated with maternal APL (r = -0.30). Only 1 offspring had congenital heart disease. Offspring IQ was 102 +/- 15 compared with 96 +/- 14 in the mothers with untreated pregnancies and with 109 +/- 21 in control offspring.

Conclusion: Maternal non-PKU MHP no more than 600 micromol/L does not require dietary therapy. The naturally lower Phe level during pregnancy seems to protect against teratogenesis.
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December 2003

Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome.

Pediatrics 2003 Dec;112(6 Pt 2):1530-3

Department of Inherited Metabolic Disease and Molecular Genetics, The John F. Kennedy Institute, Glostrup, Denmark.

Objective: The aim of the present study was to examine to what extent maternal and offspring phenylalanine hydroxylase (PAH) genotypes in conjunction with maternal IQ and dietary control during pregnancy are related to cognitive development in offspring of women with phenylketonuria (PKU).

Methods: PAH gene mutations were determined in 196 maternal PKU subjects and their offspring. The women were grouped according to PAH genotype, which predicts the metabolic phenotype (severe PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). IQ was determined in both the mothers (Wechsler Adult Intelligence Scale-Revised at >18 years) and their children (Wechsler Intelligence Scale for Children-Revised at > or = 6-7 years of age).

Results: According to PAH genotypes, 62% of the women exhibited severe PKU, 19% exhibited mild PKU, and 19% exhibited MHP. Maternal IQ increased, and the assigned phenylalanine (Phe) levels decreased with decreasing severity of PAH genotype. In offspring of mild maternal PKU, multiple regression analysis showed offspring IQ to be significantly related to maternal IQ but not to Phe exposure during pregnancy, which was <750 micromol/L in all cases of mild PKU. In offspring of mothers with severe PKU and average Phe exposure during pregnancy of 360 to 750 micromol/L, multiple regression analysis revealed both maternal IQ and Phe exposure to be significant predictors of offspring IQ. When average Phe exposure was <360 micromol/L, cognitive development was normal (mean IQ: 105), whereas an average Phe exposure of >750 micromol/L severely depressed offspring IQ (mean IQ: 56) in this group regardless of maternal IQ. It could not be documented that the offspring PAH genotype affects cognitive development.

Conclusion: Female individuals with severe PKU should be offered a diet for a lifetime. If good metabolic control is established, then women with PKU will have children with IQ scores that are not influenced by their disease.
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December 2003

The Maternal Phenylketonuria International Study: 1984-2002.

Pediatrics 2003 Dec;112(6 Pt 2):1523-9

Childrens Hospital of Los Angeles and the University of Southern California School of Medicine, Los Angeles, California 90027, USA.

Objective: The purpose of this report is to review the obstetric medical, psychological, and nutritional aspects and outcome of the women and offspring enrolled in the Maternal Phenylketonuria Study, which was established to assess the efficacy of a phenylalanine (Phe)-restricted diet in preventing the morbidity associated with this disorder.

Methods: A total of 382 women with hyperphenylalaninemia (HPA) were enrolled in the study and completed 572 pregnancies. Outcome measures were analyzed with chi2, Fisher exact text, analysis of variance, t test, Wilcoxon nonparametric test, and multiple logistic regression. Outcome measures were stratified according to maternal HPA classification and the time when dietary control was achieved.

Results: Optimal birth outcomes occurred when maternal blood Phe levels between 120 and 360 micromol/L were achieved by 8 to 10 weeks of gestation and maintained throughout pregnancy (trimester averages of 600 micromol/L). Mothers with mild HPA achieved similar birth outcomes as mothers who were in control preconceptually and those in control by 8 to 10 weeks of pregnancy.

Conclusions: Before conception, counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with HPA. The achievement of pre- and periconceptional dietary control with a Phe-restricted diet significantly decreased morbidity in the offspring of women with HPA.
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December 2003

Dopa-responsive dystonia and Tourette syndrome in a large Danish family.

Arch Neurol 2003 Apr;60(4):618-22

Department of Biochemistry, John F. Kennedy Institute, Glostrup, Denmark.

Background: Guanosine triphosphate cyclohydrolase I (GTPCH) catalyzes the first step in the synthesis of tetrahydrobiopterin (BH4). Autosomal dominantly inherited defects in the GTPCH gene (GCH1) cause a form of dystonia that is responsive to treatment with levodopa (dopa-responsive dystonia [DRD]).

Objective: To investigate molecular and clinical aspects of DRD in a large Danish family.

Methods: For analysis of the GCH1 gene, a mutation-scanning method based on denaturing gradient gel electrophoresis (DGGE) was used. A novel mutation, X251R, was identified in the GCH1 gene of 2 distantly related Danish patients with DRD, one of whom also had Tourette syndrome (TS). Thirty-five additional family members were investigated for this mutation, and 16 of them underwent clinical neurological examination.

Results: A total of 18 patients were heterozygous for the X251R allele, 16 of whom had neurological complaints spanning from very mild parkinsonism to severe invalidism due to dystonia. Of 13 symptomatic heterozygotes who had been neurologically examined, 10 had signs of dystonia or parkinsonism. Sixteen of the heterozygotes were treated with levodopa, and 13 reported a treatment benefit. Three of the symptomatic heterozygotes had signs of TS.

Conclusions: This study confirms the large variability in DRD symptoms and emphasizes the usefulness of molecular analysis for diagnosis and treatment of DRD. The presence of TS is suggested to be coincidental, though the development of TS-like symptoms due to mutations in GCH1 cannot be excluded.
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http://dx.doi.org/10.1001/archneur.60.4.618DOI Listing
April 2003

Comparison of epidermal keratinocytes and dermal fibroblasts as potential target cells for somatic gene therapy of phenylketonuria.

Mol Genet Metab 2002 Aug;76(4):313-8

Department of Human Genetics, University of Aarhus, Denmark.

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) and increased levels of phenylalanine. PAH requires the cofactor BH(4) to function and the rate-limiting step in the synthesis of BH(4) is GTP cyclohydrolase I (GTP-CH). The skin is a potential target tissue for PKU gene therapy. We have previously shown that overexpression of PAH and GTP-CH in primary human keratinocytes leads to high levels of phenylalanine clearance without BH(4) supplementation [Gene Ther. 7 (2000) 1971]. Here, we investigate the capacity of fibroblasts, another cell type from the skin, to metabolize phenylalanine. After retroviral gene transfer of PAH and GTP-CH both normal and PKU patient fibroblasts were able to metabolize phenylalanine, however, in lower amounts compared to genetically modified keratinocytes. Further comparative analyses between keratinocytes and fibroblasts revealed a higher copy number of transgenes in keratinocytes and also a higher metabolic capacity.
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http://dx.doi.org/10.1016/s1096-7192(02)00101-4DOI Listing
August 2002

Mental illness in mild PKU responds to biopterin.

Mol Genet Metab 2002 Mar;75(3):284-6

Childrens Hospital of Los Angeles, USC School of Medicine, Los Angeles, California, USA.

A 25-year-old woman with mild hyperphenylalaninemia developed disabling depression and panic attacks. The mutations on the phenylalanine hydroxylase gene indicated that she might be responsive to tetrahydrobiopterin therapy. Mutation analyses were performed by the John F. Kennedy Institute in Glostrup, Denmark. The response to tetrahydrobiopterin therapy was impressive at an oral dose of 50 mg twice a day. A 25-year-old woman with mild hyperphenylalaninemia due to a PAH mutation of IVS12nt1g-->a/E390G has been treated for 1 year with BH4 therapy. A maintenance dosage of only 100 mg/day has resulted in significant improvement of depression and panic attacks, with discontinuation of psychotropic medication.
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http://dx.doi.org/10.1006/mgme.2001.3289DOI Listing
March 2002