PAH – Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the phenylalanine hydroxylase gene (PAH). Loss of PAH function leads to accumulation of phenylalanine in blood and brain, resulting in neurotoxicity and intellectual disability if untreated. The gene–disease relationship between PAH and PKU has been established over decades across diverse populations.

Clinical Validity

The association is classified as Definitive, supported by observations in 149 unrelated probands with autosomal recessive PKU ([PMID:8659548]), extensive segregation in over 88 families ([PMID:8444221]), and concordant functional loss-of-function data across multiple expression systems.

Genetic Evidence

PKU follows autosomal recessive inheritance with affected individuals harboring compound heterozygous or homozygous PAH variants. Segregation analysis in 88 additional affected relatives demonstrates consistent co-segregation of biallelic PAH variants with disease ([PMID:8444221]). More than 300 unique variants—missense, nonsense, splice-site, frameshift, and large deletions—have been reported in AR PKU cohorts ([PMID:8659548]). A recurrent nonsense mutation, c.331C>T (p.Arg111Ter), is observed in multiple ethnicities and reliably predicts classical PKU ([PMID:1975096]).

Functional / Experimental Evidence

In vitro expression and kinetic studies of mutant PAH proteins demonstrate that nonsense and frameshift mutations ablate enzyme activity, while missense mutations often impair folding, oligomerization, or cofactor affinity ([PMID:8829656]; [PMID:10767175]). Chemical chaperones like glycerol and cofactor supplementation (BH₄) can partially rescue residual activity in kinetic variant forms, supporting a loss-of-function mechanism amenable to targeted therapy ([PMID:11386853]; [PMID:10767175]).

Conflicting Evidence

No studies have refuted the causal role of PAH variants in PKU; genotype–phenotype correlations are generally predictive, though some missense variants show variable expressivity requiring careful functional characterization.

Conclusion

Genetic testing for PAH variants combined with phenylalanine quantification enables early diagnosis, informs dietary and cofactor-responsive therapy, and guides reproductive counseling. Key takeaway: Autosomal recessive PAH mutations are the definitive cause of PKU, and comprehensive molecular analysis is critical for precision management.

References

• American Journal of Human Genetics • 1996 • Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. PMID:8659548
• European Journal of Pediatrics • 1993 • Relation between genotype and phenotype in Swedish phenylketonuria and hyperphenylalaninemia patients. PMID:8444221
• Prenatal Diagnosis • 1990 • Prenatal detection of an Arg----Ter mutation at codon 111 of the PAH gene using DNA amplification. PMID:1975096
• Human Mutation • 1996 • PKU mutation G46S is associated with increased aggregation and degradation of the phenylalanine hydroxylase enzyme. PMID:8829656
• Molecular Genetics and Metabolism • 2000 • The V388M mutation results in a kinetic variant form of phenylalanine hydroxylase. PMID:10767175

Evidence Based Scoring (AI generated)