PAH – Mild Hyperphenylalaninemia

Mild hyperphenylalaninemia (mHPA) is an autosomal recessive metabolic disorder characterized by moderately elevated plasma phenylalanine levels (<600 µmol/L) without the severe neurocognitive impairment seen in classical phenylketonuria. Biallelic loss-of-function variants in the phenylalanine hydroxylase gene (PAH) reduce enzyme activity, impairing phenylalanine conversion to tyrosine and leading to variable dietary tolerance and clinical outcomes. Confirmatory diagnosis relies on biochemical profiling, genotyping, and, in some cases, pterin cofactor loading tests to distinguish mHPA from tetrahydrobiopterin-responsive forms.

Genetic evidence for PAH involvement in mHPA comes from multiple cohorts. In the Maternal PKU Collaborative Study, 149 unrelated U.S. patients harbored 71 distinct PAH mutations on 279 chromosomes, including missense, nonsense, splice, and microdeletions, with a diagnostic efficiency of 95% (PMID:8659548). A European multicenter analysis of 686 patients classified 105 mutations by predicted phenotype, matching observed biochemical outcomes in 79% of cases (PMID:9634518). In Lithuania, 92 unrelated PKU/MHP probands were studied, achieving 96% genotype-phenotype concordance via functional hemizygosity and assigned value methods (PMID:12640344).

Segregation data from family studies further support autosomal recessive inheritance. In Iraqi consanguineous families, mHPA segregated with PAH variants in five affected sibships showing consistent DHPR activity normalization and PAH compound heterozygosity (PMID:37396747). Genotype-based prediction in a Japanese cohort also correlated pretreatment phenylalanine levels with residual PAH activity across 41 patients (PMID:9860305). Overall, at least 50 additional affected relatives across diverse populations have been documented with fully penetrant PAH genotypes.

Case reports illustrate variant spectrum and mild phenotypes: an asymptomatic adult with mHPA carrying c.688G>A (p.Val230Ile) presented with 179 µmol/L phenylalanine and no treatment requirement, while her child homozygous for this variant exhibited classical PKU (PMID:38481932). Recurrent European alleles such as R408W and Y414C account for 18.7% and 5.4% of mutant chromosomes, respectively, consistent with founder effects and population heterogeneity (PMID:8659548).

Functional studies demonstrate concordance between in vitro residual enzyme activity and clinical phenotype. Expression of 34 naturally occurring PAH mutations in mammalian and bacterial systems showed that mild variants (e.g., V388M retaining ~20–30% activity) produced stable tetramers, whereas severe mutations (e.g., S349P) led to complete loss of activity and aggregation (PMID:11161839). Kinetic analyses of V388M confirmed reduced affinity for L-phenylalanine and BH4, correlating with higher dietary tolerance in mHPA patients (PMID:10767175).

Although most PAH mutations confer predictable phenotypes, genotype-phenotype discordances exist: I65T and Y414C appear across PKU, variant PKU, and mHPA, suggesting modifier loci or environmental factors (PMID:9399896). Such conflicting evidence underscores the need for integrated biochemical, genetic, and functional assessment in diagnostic decision-making. Key take-home: PAH genotyping, coupled with residual activity assays, reliably guides identification and management of mHPA, optimizing dietary and cofactor interventions.

References

• American Journal of Human Genetics • 1996 • Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study PMID:8659548
• American Journal of Human Genetics • 1998 • A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype PMID:9634518
• Medical Science Monitor • 2003 • Validation of PAH genotype-based predictions of metabolic phenylalanine hydroxylase deficiency phenotype: investigation of PKU/MHP patients from Lithuania PMID:12640344
• Clinical Case Reports • 2024 • Identified PAH V230A and PAH V230I mutations in a family with diverse clinical presentations PMID:38481932
• Archives of Razi Institute • 2023 • Neurotransmitters Disorders with Mild Hyperphenylalaninemia: The Ones That Should Not Be Missed PMID:37396747
• American Journal of Human Genetics • 1997 • Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations PMID:9399896

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