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Genotype-phenotype correlation In PKU

Szeged, December 12, 2011. Genotype-phenotype correlation In PKU. Introduction. HPA – BH4-responsive – classic atypical (BH4-dependent) Severity depends partially on the mutation of PAH enzyme

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Genotype-phenotype correlation In PKU

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  1. Szeged, December 12, 2011. Genotype-phenotype correlation In PKU

  2. Introduction • HPA – BH4-responsive – classic atypical (BH4-dependent) • Severity depends partially on the mutation of PAH enzyme • Genotype correlates with the metabolic phenotype in most of the cases – homozygous, severe null mutations • … or „mild” mutations • Most of the patients are compound heterozygous (or – in Hungary - R408W homozygous) • There are significant genotype-phenotype inconsistencies between identical PAH mutation bearing patients • So the PKU/HPA phenotype manifestation is more complex than it could be predictable based on the Mendelian inheritance of the mutated alleles

  3. PAH enzyme N-terminal regulatory domain: AA 1–142 Catalytic domain: AA 143–410 C-terminal domain: AA 411–452 → tetramerization

  4. PAH gene mutations www.pahdb.mcgill.ca • 12q22-q24.1, 13 exon • 564 mutation

  5. PAH gene mutations

  6. BH4-responsive PAH mutations • ~70 known mutation • Mostly point-mutation (never splice, insertion or deletion) • Mostly in the catalytic domain, but not in the cofactor-binding site

  7. BH4-responsive PAH mutations

  8. Our cases: null mutations • Since 2006 we could not have the patients' DNA sequenced • 52 patients' DNA sequence and mutations are known • Classic PKU: null mutations

  9. Non-null mutations Trefz et al. J Inherit Metab Dis (2009) 32:22–26

  10. Same genotype – different BH4-responsiveness Y414C (mild)/R408W (null) → moderate PKU? BH4 loading with 20 mg/kg bw in 3 patients, all genotype Y414C/R408W. Lindner M et al, Mol Genet Metab 2001; 73:104-106.

  11. HPA cases

  12. Interesting cases

  13. Tesztelt BH4-reszponzív esetek

  14. Genotype-phenotype in PKU Pathogenic mutation phenotype 1 phenotype 2 phenotype 3 • Genetically determined factors: other intragenic differences, polymorphisms modifying genes: aminoacid transport, competition, metabolism, excretion Non-genetically determined factors

  15. Conclusion • Confirming the genotype may help in the judgement and predicition of the severity of the disease • There are significant genotype-phenotype inconsistencies between similar PAH mutation bearing patients: mainly the regulatory domain mutations lead to unpredictable phenotype, in the cases of compound heterozygosy • BH4-loading test result may vary in a patient - intracellular environment, metabolic status influence the mutated enzyme activity • The standard(ized) Phe+BH4 loading test is the gold standard for planning the treatment!

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