Dermatologic Manifestations of Phenylketonuria 

Phenylketonuria (PKU) was discovered and described by Folling in 1934. It is the most common inborn error of amino acid metabolism. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine (Phe) in the plasma (>1200 µmol/L; reference range, 35-90 µmol/L) and to excretion of phenylpyruvic acid (approximately 1 g/d) and phenylacetic acid in the urine. Phe has ketogenic and gluconeogenic intermediates that contribute to the glucose pool, which can play a role in normal brain development and function. In many countries, phenylketonuria is detected by screening newborns. Patients treated with a diet low in Phe can lead a normal life.

In most patients, the classic type of phenylketonuria (PKU) is caused by a deficiency of PAH, resulting in increased levels of Phe in body fluids. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of Phe. PAH requires a nonprotein cofactor termed tetrahydrobiopterin (BH₄), and the rate-limiting step in the synthesis of BH₄ is guanosine triphosphate cyclohydrolase I (GTP-CH I). PAH crystallizes as a tetramer, with each monomer consisting of a catalytic domain and a tetramerization domain. Examination of the mutations causing phenylketonuria reveals that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains.

Other types of phenylketonuria include phenylketonuria caused by impaired synthesis of BH₄, GTP-CH I, 6-pyruvoyl tetrahydropterin (6-PTS), or dihydropteridine reductase (DHPR). Patients with the BH₄ cofactor deficiency have more severe neurologic problems that are not completely corrected by the dietary reduction of Phe.

The learning disabilities in patients with phenylketonuria who are adequately treated may result from reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes.

Frequency

United States

The incidence of classic phenylketonuria (PKU) is approximately 1 case per 15,000 births.

International

The prevalence in the general population is approximately 4 cases per 100,000 individuals, and the incidence is 350 cases per million live births. Approximately 0.04-1% of the residents in mental retardation clinics are affected by phenylketonuria (PKU). A high incidence is reported in Turkey (approximately 1 case in 2,600 births), the Yemenite Jewish population (1:5,300), Scotland (1:5,300), Estonia (1:8,090),^[1] Iceland (1:8,400), Hungary (1:11,000), Denmark (1:12,000), France (1:13,500), United Kingdom (1:14,300), Norway (1:14,500), China (1:17,000), Italy (1:17,000), Chile (1:18,916), Canada (1:20,000), Minas Gerais State in Brazil (1:20,000),^[2] and former Yugoslavia (1:25,042).^[3] A low incidence is reported in African Americans (1:50,000), Finland (< 1:100,000),^[4] and Japan (1:125,000).^[5]

Mortality/Morbidity

Patients with phenylketonuria (PKU) who have not been treated have severe mental retardation. Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment.

Race

Phenylketonuria (PKU) is common in whites and Asians and is rare in blacks.

Sex

No sexual predilection exists for phenylketonuria (PKU). Untreated maternal PKU increases the risk for developmental problems in offspring.

Age

Phenylketonuria (PKU) can commonly be recognized in newborns with the help of newborn screening programs.