Phenylketonuria

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Summary

Phenylketonuria (PKU) is an inborn metabolic disorder and is caused by different mutations in the enzyme phenylalanine hydroxylase (PAH), which is responsible for the alteration of phenylalanine to tyrosine. Untreated PKU can lead to psychotic disorders and the postnatal development of the brain can be harmed.

Phenotype

PKU results in enrichment of phenylalanine and decrease of tyrosine, whereby other features of the phenylalanine metabolism pathway are affected like the production of melanin. Thus symptoms like fair skin, light hair and blue or sometimes even red eyes can occur. Additionally there can be mousy odour, eczema, epilepsy and perceptible posture changes. In some cases the concerned persons show psychotic disorders, ADHD (attention-deficit hyperactivity disorder), aggressions, autistic features, hyperactivity and self-mutilation.

There are two different PKU variants defined:

• Classical Phenylketonuria is described here (entweder gar keine Umwandlung von PHE zu TYR oder nur teilweise nicht...)
• Atypical (mild) Phenylketonuria is ... (differences??)

Cross-References: http://omim.org/entry/261600 --> OMIM --> pubmed health …

Treatment

After birth every child is tested with a newborn-screening, where some disorders are analysed. If a higher concentration of phenylalanine or a bad ratio of phenylalanine and tyrosine is found, PKU is diagnosed and the patient can be treated as followed:

• Special low phenylalanine diet for the whole life (routine treatment; constrains in meat, fish, eggs, nuts, legumes and milk products and careful usage in starchy food)
• Tyrosine enriched food or medicaments
• Intake of the enzyme PAL (phenylalanine ammonia lyase), which converts phenylalanine to a harmless metabolite
• Tetrahydrobiopterin (only for mild PKU!!!)

Cross-References: OMIM WIKIPEDIA ...

Biochemical disease mechanism

• The symptoms of PKU are caused by the complete or partial defected catalysing of phenylalanine to tyrosine.
• As it occurs at the beginning of the phenylalanine metabolism pathway other metabolic diseases are associated like albinism or cretinism (WIKI-Link!).
• PKU was named after the phenylketone (phenylpyruvate) in which phenylalanine is converted.
• Protein phenylalanine hydroxylase:
  • is expressed in liver,
  • has a sequence length of 452 aa,
  • is encoded by the gene PAH (see Genomic information) on chromosome 12.

Cross-References: pathway: phenylalanin metabolism http://www.genome.jp/kegg-bin/show_pathway?scale=0.67&query=&map=ko00360&scale=0.82&auto_image=&show_description=hide&multi_query=

Mutations and Genomic information

Genomic information

PKU is an autosomal recessive disorder which can be caused by 400 different known mutations on the PAH gene. This gene lies on the human chromosome 12 and consists of 13 exons. Most common are missense mutations, but also nonsense and silent mutations can be found. Normally the enzyme phenylalanine hydroxylase ...

Reference sequence

Which sequence does not cause the disease and is most often found in the population. Create a page for the reference sequence.

Cross-References: http://www.uniprot.org/uniprot/P00439 The Uniprot entry for PAH P00439 gives the protein sequence used as reference in this practical: