PAH – Classic Phenylketonuria

Classic phenylketonuria (PKU) is an autosomal recessive metabolic disorder manifesting with hyperphenylalaninemia, intellectual disability, and reduced hepatic PAH activity (HP:0005982). It is definitively associated with biallelic pathogenic variants in PAH (HGNC:8582) leading to loss of enzymatic function and toxic phenylalanine accumulation.

Genetic evidence: AR inheritance is supported by a consanguineous Iranian pedigree carrying a novel homozygous c.335dupA (p.Asp112GlufsTer2) variant in exon 3 (PMID:28706611). Segregation studies identified two distinct nonsense mutations at codon 272 and 273 segregating in families from France and Belgium (PMID:1671881).

Case series: The Texas newborn screening cohort reported 18 classic PKU probands with 36 distinct PAH alterations—including 25 missense, 6 splice-site, 3 deletions, and 2 nonsense variants—with c.1222C>T (p.Arg408Trp) predominating at 19% of alleles (PMID:11385716). Southern Italy analyses in 51 patients uncovered 32 disease-causing mutations, confirming splicing defects (c.707-2delA) and missense lesions (p.Gln301Pro) underpinning severe PKU (PMID:19292873). A cohort of 94 Turkish patients (47 variants; ~68% missense) further underscores regional allelic heterogeneity (PMID:35355500).

Variant spectrum: Over 100 PAH pathogenic alleles have been described, spanning missense (p.Arg408Trp), nonsense (p.Gly272Ter), splice-site (c.1066-11G>A), frameshift (p.Asn167Ser), and small-deletion mutations, with founder events (R408W–VNTR-8 in Ireland; R243Q in China).

Functional evidence: In vitro expression and structural studies of >60 PAH missense variants reveal residual enzyme activities correlating with clinical severity and demonstrate protein misfolding, aggregation, and accelerated degradation as a unifying mechanism of haploinsufficiency (PMID:9450897). Chemical chaperone rescue and biophysical assays highlight potential therapeutic modulation.

No studies refute the AR PAH–classic PKU link. The robust concordance of genetic and functional findings confirms PAH as definitively linked to classic PKU, underpinning molecular diagnosis, genotype-based management, and newborn screening strategies.

Key Take-home: Biallelic PAH loss-of-function variants cause classic PKU, with genotype predicting residual PAH activity and clinical phenotype.

References

• Avicenna journal of medical biotechnology • 2017 • A Novel Variant in the PAH Gene Causing Phenylketonuria in an Iranian Pedigree. PMID:28706611
• Journal of medical genetics • 1991 • Two distinct mutations at a single BamHI site in phenylketonuria. PMID:1671881
• Human mutation • 2001 • Molecular analysis of phenylketonuria (PKU) in newborns from Texas. PMID:11385716
• The FEBS journal • 2009 • Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy. PMID:19292873
• Journal of pediatric endocrinology & metabolism • 2022 • Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Turkey. PMID:35355500
• Human mutation • 1998 • In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. PMID:9450897

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