Maternal phenylketonuria (ORPHA:2209)
A rare disorder of phenylalanine (Phe) 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 non-phenylketonuric offspring of mothers with excess blood Phe concentrations.
Epidemiology
The incidence of maternal phenylketonuria (PKU) in Europe is not known. 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 blood Phe.
Clinical description
Hyperphenylalaninemia is classified by blood Phe concentrations of more than 1,200 micromol/L (classic PKU) or less than 600 micromol/L (mild hyperphenylalaninemia), between 600 and 1,200 micromol/L as mild PKU. Maternal phenylketonuria syndrome has been shown to result in intrauterine and postnatal growth retardation with associated low birth weight, microcephaly, and intellectual disability in the offspring. Congenital heart malformation is also found and may include double-chambered right ventricle, tetralogy of Fallot, and ventricular septal defects. In severe cases, facial dysmorphism may also occur with various features reported including receding forehead, ptosis or fused eyes, strabismus, dysplastic ear helices, high palate, underdeveloped philtrum, anteverted nostrils, broad flat nasal bridge, deviated nasal septum, and micrognathia. Optimal maternal blood Phe concentrations should be strictly maintained throughout pregnancy to reduce the risk of these abnormalities. This can be achieved by minimal dietary Phe intake, along with tyrosine-enriched supplements. Studies have also shown that dietary treatment to control blood Phe concentrations can prevent the disorder if started before conception.
Etiology
Abnormally high maternal blood 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).
Diagnostic methods
The diagnosis is based on clinical observation, blood Phe analysis and genetic test to evaluate the presence of the PAH variant.
Genetic counseling
Phenylketonuria is transmitted in an autosomal recessive manner. Children of affected parents will therefore mostly (75%) be heterozygous carriers or non-carriers of the defect.
Management and treatment
Maternal PKU is managed by a strict low-Phe diet (commonly ≤ 6 g/day natural protein is tolerated in the early stages of pregnancy but PHE amount is dependent on PKU severity), together with a Phe-free L-amino acid supplement and sufficient energy intake to ensure adequate maternal weight gain during pregnancy. The protein equivalent from amino acid and natural protein should supply ≥ 70 g/ day protein. Nausea and vomiting during the early phases of pregnancy is common and may lead to inadequate intake of amino acid and energy and subsequently unsatisfactory blood Phe control.
Prognosis
Prognosis is favorable if blood Phe concentrations are kept strictly below 360 micromol/L before and during the entire pregnancy.

                            Last update: 
                            December 2020


                            - Expert reviewer(s): 
                            Pr Nenad BLAU