The packet lists PAH as the associated gene, with a ClinGen gene-disease validity classification of DEFINITIVE; the gene is located on chromosome 12. The inheritance pattern in the packet is autosomal recessive, and GeneReviews likewise describes PAH deficiency as inherited in an autosomal recessive manner. The packet does not supply a molecular mechanism field.

GeneReviews states that the parents of an affected child are presumed to be heterozygous for a PAH pathogenic variant and that heterozygous carriers are asymptomatic. When both parents are known to be heterozygous, it gives each sibling of an affected individual a 25% chance at conception of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither familial variant. It also notes significant intrafamilial variability, so the phenotype in one affected individual might not predict the phenotype in an affected sibling.

GeneReviews describes genotype-phenotype correlations as imperfect, although genotype can be predictive of sapropterin dihydrochloride responsiveness.

Newborn screening. The packet records PKU as screened, with a RUSP category of CORE: HHS recommends the condition for inclusion in state newborn-screening panels; actual state panels vary. GeneReviews describes screening as primarily based on dried blood spots collected between 24 and 72 hours after birth, with phenylalanine and tyrosine concentrations quantified by tandem mass spectrometry. Most US laboratories set their own cutoff levels, and newborns with elevated phenylalanine undergo additional testing, including plasma or serum amino acid analysis and urine or blood pterin analysis.

Symptomatic presentation. GeneReviews describes diagnosis also arising in individuals with late-diagnosed or untreated infantile-onset disease. Clinical findings it lists include epilepsy, intellectual disability and neurobehavioral or psychiatric manifestations, movement disorders and other neurologic findings, musty body odor, eczema, and decreased skin and hair pigmentation. Brain imaging findings include white matter abnormalities, occasional cerebral or cerebellar atrophy, and restricted diffusion.

Establishing the diagnosis. According to GeneReviews, the diagnosis is established in neonates following an out-of-range screening result with biochemical testing (plasma amino acid analysis) and molecular genetic testing.

GeneReviews states that there is no cure for PAH deficiency and that gene therapy trials are under way. It describes the mainstay of treatment for individuals with untreated blood phenylalanine concentrations meeting the 360 umol/L threshold it cites as lifelong treatment with an age-appropriate phenylalanine-restricted diet, comprising dietary protein restriction and phenylalanine-free protein supplementation with medical foods (amino acid or glycomacropeptide based). For infants with out-of-range screening results, it describes referral to a metabolic specialty center with a metabolic physician or biochemical geneticist and a metabolic dietitian, with a low-phenylalanine diet ideally begun within the first week of life.

Pharmacologic options. GeneReviews states that, in certain individuals, FDA-approved pharmacologic therapies may include sapropterin dihydrochloride, sepiapterin, and enzyme substitution therapy (pegvaliase). The packet's orphan drug records list Kuvan (sapropterin; BioMarin Pharmaceutical) and Sephience (sepiapterin; PTC Therapeutics) with APPROVED status for hyperphenylalaninemia. GeneReviews describes sapropterin as a synthetic form of naturally occurring BH4, reports that 25% to 50% of persons with PAH deficiency are sapropterin responsive, and describes sepiapterin as an alternate biopterin converted to BH4 with greater responsiveness in many persons. Pegvaliase is described as a PEGylated recombinant phenylalanine ammonia lyase approved in the United States for adults with uncontrolled blood phenylalanine concentrations (a 600 umol/L threshold is cited) on existing management. GeneReviews states that the decision to offer pharmacologic therapy rests on many factors and that a metabolic specialist develops a plan for each individual.

Other designations. The packet lists orphan drug designations for several gene therapy and engineered-bacteria products; these are designations rather than approvals, and two Homology Medicines vector records carry WITHDRAWN status.

The packet does not certify a natural history field or life expectancy data for PKU. GeneReviews states that most individuals with PAH deficiency will have normal development if blood phenylalanine concentrations are appropriately controlled, while developmental, neuropsychological, and psychosocial concerns merit attention across the life span. It reports that a review of 55 studies and a meta-analysis of 14 studies noted significantly higher IQs in individuals who maintained blood phenylalanine concentrations within the 360 umol/L threshold throughout life. GeneReviews also notes that treatment of late-diagnosed or untreated disease sometimes improves neurobehavioral and motor disturbances but does not reduce neurocognitive impairment, and that evidence is emerging that lowering phenylalanine in adults with persistently elevated levels can improve neuropsychological function and related MRI changes.

The packet records 45 clinical trials for phenylketonuria, all counted as active. Records listed include a Phase 3 study of sepiapterin (NCT06302348; PTC Therapeutics; recruiting), an AAV gene therapy study in adult classic PKU (NCT06332807, PHEdom; Phase 1; NGGT INC.; recruiting), a Phase 2 study of MZE782 (NCT07694440; Maze Therapeutics; recruiting), and a Phase 1 study of AG-181 (NCT07241234; Agios Pharmaceuticals; recruiting). Dietary and measurement studies are also listed. Registry records describe studies, not outcomes.

GeneReviews describes therapies under investigation as including gene therapy, mRNA therapy, a phenylalanine uptake receptor blocker, and diet and dietary supplement studies. The National Society for Phenylketonuria (UK) is listed as a patient organization, and the National Organization for Rare Disorders is listed as sponsoring PKU medical assistance and emergency relief programs that are accepting enrollment.