Mapping the Severity of Phenylalanine Hydroxylase Deficiency

ABSTRACT

Since the 1960s, phenylalanine hydroxylase (PAH) deficiency can be detected via newborn screening, allowing early start of treatment to prevent severe intellectual disability. Precise determination of PAH deficiency severity continues to be hampered by several factors. Nevertheless, as therapeutic options broaden, precise determination of PAH deficiency severity becomes critical to inform individualized treatment selection. Although various methods (hepatic PAH activity, pretreatment phenylalanine (Phe) levels, Phe loading test, Phe tolerance, in vitro expression analysis, tracer studies, prediction models) have been used to assess and/or classify PAH deficiency, all of them still report inconsistencies in the correlation between genotype and biochemical phenotype. Establishing the genotype–phenotype correlation for different genotypes is complicated by the enormous genetic heterogeneity within the PAH gene. Furthermore, variability in the terminology applied to different phenotype strata further complicates interpretation. Here, we aim to summarize the methods that have been described in the literature to assess the classification of PAH deficiency and propose terminology to describe phenotype levels as a crucial step to overcome these issues.