PAH – Maternal Phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder caused by biallelic loss-of-function variants in the PAH gene, leading to deficient phenylalanine hydroxylase activity and elevated maternal phenylalanine levels during pregnancy. Maternal PKU (MPKU) syndrome manifests as fetal embryopathy with microcephaly, congenital heart defects, growth restriction, intellectual disability and seizures when maternal PKU is untreated during gestation. Despite universal newborn screening, undiagnosed MPKU persists, as illustrated by a 33-year-old woman whose PKU was only recognized after a pregnancy complicated by MPKU embryopathy (PMID:19557660).

Inheritance of MPKU follows an autosomal recessive pattern; both parents of affected women carry one PAH pathogenic allele, and affected mothers are homozygous or compound heterozygous for deleterious PAH variants. To date, over 365 PKU patients harboring 73 distinct PAH mutations have been described across 161 genotypes, confirming robust disease causality (PMID:9399896).

The mutational spectrum includes missense, nonsense, splice-site, frameshift and large deletion alleles. A representative pathogenic variant is c.1045T>C (p.Ser349Pro), which abolishes catalytic activity and impairs protein stability in both bacterial and mammalian expression systems (PMID:7860062).

Functional studies demonstrate that PAH deficiency results from haploinsufficiency and misfolding of mutant enzymes. In vitro expression assays, protein aggregation analyses, and structural modeling consistently correlate residual PAH activity with clinical severity, enabling genotype–phenotype predictions and informing dietary management.

Together, genetic and experimental data establish a definitive association between PAH and MPKU embryopathy. Early identification of PAH deficiency in women of childbearing age enables strict phenylalanine dietary control before and during pregnancy, preventing fetal teratogenic effects.

Key Take-home: PAH gene testing in women with hyperphenylalaninemia is critical for MPKU prevention and guides preconception and prenatal care.

References

• The journal of maternal-fetal & neonatal medicine • 2009 • Undiagnosed maternal phenylketonuria: own clinical experience and literature review. PMID:19557660
• American journal of human genetics • 1997 • Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. PMID:9399896
• Human genetics • 1995 • A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in north African Jews with phenylketonuria. PMID:7860062

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