Phenylketonuria

A 3-month-old infant presents with progressive developmental delay, seizures, and a distinctive mousy odour to the urine. Newborn screening was not performed. The inheritance pattern shown in the pedigree is marked as **A** (autosomal recessive, both parents carriers). Which of the following best explains the biochemical defect underlying this clinical presentation?

A 3-week-old female infant is referred to metabolic genetics after newborn screening reveals markedly elevated phenylalanine (1,840 micromol/L) with a low tyrosine level and elevated Phe:Tyr ratio. The parents are first cousins from a consanguineous community. Mutation analysis identifies homozygosity for a severe PAH gene mutation on chromosome 12q23.2 (p.R408W). A four-generation pedigree shows affected individuals in multiple branches, both sexes affected, transmission from unaffected parents, and clustering in consanguineous branches marked by double horizontal lines. The inheritance pattern marked **A** in the diagram is most consistent with this family presentation. Which of the following best describes the genetic mechanism underlying this inheritance pattern?