How practical are recommendations for dietary control in phenylketonuria?

Walter, J H; White, Fiona J.; Hall, S K; MacDonald, Anita; Rylance, G; Boneh, Avihu; Francis, Dorothy E. M.; Shortland, Graham; Schmidt, Michael; Vail, Andy

doi:10.1016/s0140-6736(02)09334-0

Cited by 270 publications

(229 citation statements)

References 3 publications

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“…There was no statistically significant difference between the groups, with 20% of the results in the control group and 25% of those in the supplemented group having phenylalanine concentrations of more than 360µmol/l. This compares favourably with published data (Walter et al 2002). Figure 1 shows that DHA levels in erythrocyte membrane phospholipids in the supplemented group stabilized 20 weeks after entry, having declined much less precipitously from levels at entry than the control group.…”

Section: Biochemical Outcomessupporting

confidence: 88%

A randomized trial of long-chain polyunsaturated fatty acid supplementation in infants with phenylketonuria

Agostoni

Harvie

McCulloch

et al. 2006

Developmental Medicine &Amp; Child Neurology

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Forty‐two infants (20 males, 22 females) with classical phenylketonuria (PKU) entered a prospective, double‐blind, randomized study to investigate the effects on biochemical and physiological outcomes of a phenylalanine‐free infant formula containing a fat blend supplemented with the long‐chain polyunsaturated fatty acids (LC‐PUFA), docosahexaenoic acid (DHA, C22:6n‐3), and arachidonic acid (AA, C20:4n‐6). Between entry and 20 weeks (entry and 1y) of age, median DHA levels in erythrocyte membrane phospholipids decreased by 15% (22%) in the LC‐PUFA supplemented group (n=21) and by 61% (64%) in the control group (p<0.001; n=18). A dietary supply of LC‐PUFA in infants with PKU prevents the decline in DHA levels associated with a diet supplying minimal sources of LC‐PUFA. DHA status in turn, independent of diet, may influence the maturation of the visual system in infants with PKU.

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Section: Biochemical Outcomessupporting

confidence: 88%

A randomized trial of long-chain polyunsaturated fatty acid supplementation in infants with phenylketonuria

Agostoni

Harvie

McCulloch

et al. 2006

Developmental Medicine &Amp; Child Neurology

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“…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 …”

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

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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...

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“…13 Researchers often rely on surrogate end points, including biomarkers that they perceive as meaningful, particularly if these end points have been correlated with clinical outcomes; however, surrogate end points are less convincing for both policy decision makers and patients. 14 Patient access to interventions, particularly expensive orphan drugs, often requires approval by multiple clinical and policy decision makers.…”

Section: Outcomes: Defining Effectivenessmentioning

confidence: 99%

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

Potter

Khangura

Tingley

et al. 2016

Genetics in Medicine

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How practical are recommendations for dietary control in phenylketonuria?

Cited by 270 publications

References 3 publications

A randomized trial of long-chain polyunsaturated fatty acid supplementation in infants with phenylketonuria

A randomized trial of long-chain polyunsaturated fatty acid supplementation in infants with phenylketonuria

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

Translating rare-disease therapies into improved care for patients and families: what are the right outcomes, designs, and engagement approaches in health-systems research?

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