Preliminary report on the effects of diet discontinuation in PKU

Koch, Richard; Azen, Colleen; Friedman, E. G.; Williamson, Malcolm L.

doi:10.1016/s0022-3476(82)80503-9

Cited by 60 publications

(24 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There have been an increased number of reports of intellectual decline, and white matter changes, in patients who stopped the dietary restriction of Phe. 8,14 Neuropsychological and neuroimaging improvement have been reported when low Phe diet was resumed. At the same period of time, the problem of maternal PKU was looming, and the practice of diet discontinuation was questioned.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Biopterin responsive phenylalanine hydroxylase deficiency

Matalon

Koch

Michals‐Matalon

et al. 2004

Genetics in Medicine

Self Cite

View full text Add to dashboard Cite

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 (BH 4 ) 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 BH 4 . 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 Ͼ 30% of baseline.There were 15 patients who did not respond to the BH 4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH 4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH 4 binding domains. Five patients responding to BH 4 had mutations not previously identified. Conclusion: The data presented suggest higher than anticipated number of PKU mutations respond to BH 4 , and such mutations are on all the domains of PAH. Genet Med 2004:6(1):27-32.

show abstract

Section: Discussionmentioning

confidence: 99%

“…It has been difficult to comply with this treatment. [7][8][9][10][11][12][13][14][15][16][17] In order to maintain optimal mental functioning in patients with PKU, a search for better methods of treatment has been on going. These methods include enzyme therapy, competition with transport of Phe to the brain, and potentially gene therapy.…”

mentioning

confidence: 99%

Biopterin responsive phenylalanine hydroxylase deficiency

Matalon

Koch

Michals‐Matalon

et al. 2004

Genetics in Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since then, unfavorable effects of diet discontinuation in early-treated patients have been described. [2][3][4][5] Such reports have prompted a change in the policies of PKU clinics regarding diet discontinuation;6'7 the majority of clinics now recommend indefinite continuation of diet. 7 Some clinics have tried reinstitution of the phenylalanine-restricted diet.…”

Section: Introductionmentioning

confidence: 99%

Reinstitution of diet therapy in PKU patients from twenty-two US clinics.

Schuett¹,

Brown²,

Michals³

1985

Am J Public Health

View full text Add to dashboard Cite

In a nationwide survey we found 72 PKU (phenylketonuria) patients who had terminated diet but later returned to diet. Sixty-one patients resumed diet due to clinical problems. Age at initial diet discontinuation ranged from three to 20 years. The most prevalent problems reported were poor school performance, and mood and/or behavior changes. Following diet reinstitution, only positive changes were noted for 42 patients, no changes for 19 patients, and 11 had one or more negative changes. Improvements

show abstract

“…Although relatively successful, dietary therapy is a heavy burden on patients and their families and leads to poor compliance, particularly in adolescents and young adults (7,8). Poor com-pliance or discontinuation of dietary therapy can result in various neurologic and behavioral problems, such as loss of intellectual function, tremor, and hyperactivity (9). In addition, increased blood phenylalanine through noncompliance to diet during pregnancy has an effect on offspring, leading to birth defects (10).…”

mentioning

confidence: 99%

Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer

Park

Kang

et al. 2004

Pediatr Res

View full text Add to dashboard Cite

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). The accumulation of phenylalanine leads to severe mental and psychomotor retardation, and hypopigmentation of skin and hair. Low-phenylalanine diet therapy can prevent irreversible damage if instituted from birth. However, poor compliance with the strict lifelong dietary therapy leads to various neurologic and behavioral problems. To develop a safe and promising gene therapy method for PKU, we investigated whether a recombinant adeno-associated virus could be used as a PAH gene transfer vector to reduce the excessive phenylalanine level in the PKU mouse model. A recombinant adeno-associated virus vector encoding the human PAH gene (rAAV-hPAH), driven by EF1-␣ promoter, was infused into PAH-deficient mice, Pah enu2 , via the hepatic portal vein. Two weeks after injection, the plasma phenylalanine level dramatically decreased to 360 M in male PKU mice, accompanied by the coat color changing to black. The mean plasma phenylalanine level of untreated PKU mice was 1800 M. The PAH enzyme activities of treated mice increased to 10 -17% of wild-type mice. No signs of liver toxicity were observed after gene transfer. The biochemical and phenotypic corrections were sustained for up to 25 wk (25-wk detection period). In contrast, the treatment was less effective in female PKU mice. These results indicate that recombinant adenoassociated virus vector-mediated gene therapy can be a useful therapeutic candidate for patients with PKU. Further studies are needed to clarify the differences in PKU pathogenesis in males and females, and to explore alternative administration routes besides hepatic portal vein injection. Abbreviations PKU, phenylketonuria PAH, phenylalanine hydroxylase AAV, adeno-associated virus rAAV-hPAH, recombinant adeno-associated virus vector encoding human phenylalanine hydroxylase cDNA BH 4 , tetrahydrobiopterin RT-PCR, reverse-transcriptase polymerase chain reaction TLC, thin layer chromatography PKU (MIM 261600) is an autosomal recessive metabolic disorder caused by a number of mutations, primarily singlebase substitutions, in the PAH gene, located on chromosome 12q22-24.1 (1, 2). This disorder is characterized by the disruption of phenylalanine metabolism due to the lack of phenylalanine hydroxylase activity. PAH (L-phenylalanine-4-monooxygenase, EC 1.14.16.1), predominantly expressed in liver, catalyzes the conversion of the essential amino acid phenylalanine into tyrosine using BH 4 as a cofactor (3, 4). The loss of this enzymatic activity results in the accumulation of phenylalanine and its abnormal derivatives in the blood and other tissues. Excessive blood phenylalanine concentration causes severe mental and psychomotor retardation from toxicity to the CNS, although the exact mechanism is not well known, and other clinical symptoms such as hypopigmentation of skin, hair, and eyes, growth failure, and "mousy" odor (5, 6).These symptoms can be prevented by a strict, lifelong die...

show abstract

Preliminary report on the effects of diet discontinuation in PKU

Cited by 60 publications

References 19 publications

Biopterin responsive phenylalanine hydroxylase deficiency

Biopterin responsive phenylalanine hydroxylase deficiency

Reinstitution of diet therapy in PKU patients from twenty-two US clinics.

Long-Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse Model by Adeno-Associated Virus Vector-Mediated Gene Transfer

Contact Info

Product

Resources

About