The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.

A rare disorder of phenylalanine metabolism, an inborn error of amino acid metabolism, characterized by the development of microcephaly, growth retardation, congenital heart disease, facial dysmorphism and intellectual disability in nonphenylketonuric offspring of mothers with excess phenylalanine (Phe) concentrations.

The incidence of maternal phenylketonuria (PKU) in Europe is estimated to be 1/10,000. Increased survival and improved health among females with treated PKU, thanks to neonatal screening, has increased the number of potential pregnancies with a risk of elevated maternal Phe.

Hyperphenylalaninemia is classified by serum phenylalanine concentrations of more than 1,200 micromol/L (classic PKU; see this term) or less than 600 micromol/L (hyperphenylalaninemia; see this term), between 600 and 1.200 micromol/L as mild PKU. Maternal phenylketonuria syndrome in offspring has been shown to result in intrauterine and postnatal growth retardation with associated low birth weight, microcephaly, and intellectual disability. Congenital heart malformation is also found and may include double-chambered right ventricle, tetralogy of Fallot, and ventricular septal defects (see these terms). In severe cases, facial dysmorphism may also occur with various features reported including receding forehead, fused eyes, strabismus, dysplastic ear helices, high palate ,underdeveloped philtrum, anteverted nostrils, broad flat nasal bridge, deviated nasal septum, micrognathia, and ptosis. Optimal maternal Phe concentrations should be strictly maintained throughout pregnancy to reduce the risk of these abnormalities. This can be achieved by minimal Phe intake, along with tyrosine-enriched supplements. Studies have also shown that dietary treatment to control Phe concentrations can prevent the disorder if started before conception.

Abnormally high maternal Phe concentrations underlie the clinical effects found in children with this disorder. PKU and hyperphenylalaninemia are caused by mutations in the PAH gene (12q22-q24.2).

Phenylketonuria is transmitted in an autosomal recessive manner. Affected children will therefore mostly be heterozygous carriers or non-carriers of the defect.

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