Phenylketonuria

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the enzyme phenylalanine hydroxylase (PAH). This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylketones, which are detected in the urine.

Left untreated, this condition can cause problems with brain development, leading to progressive mental retardation and seizures. However, PKU is one of the few genetic diseases that can be controlled by diet. A diet low in phenylalanine and high in tyrosine can bring about a nearly total cure.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Phenylketonuria was discovered by the Norwegian physician Asbjørn Følling in 1934^[1] when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Følling’s disease, named after its discoverer.^[2] Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of two affected siblings led him to request many physicians near Oslo to test the urine of other affected patients. This led to the discovery of the same substance that he had found in eight other patients. The substance found was subjected to much more basic and rudimentary chemical analysis. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

According to Phe levels PKU can be classified as:^{[1] [2]}

• Mild (mPKU): < 360 μmol/L
• Moderate (moPKU): 360–1200 μmol/L
• Classical (cPKU): >1200 μmol/L

Maternal Phenylketonuria (MPKU)^[3] is a complication of PKU, caused by the teratogenic effects of high levels of Phe in the fetus. MPKU was first described by Charles Dent in 1956.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Classical PKU is caused by a defective gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor 5,6,7,8-tetrahydrobiopterin (BH₄) by the patient.^[1] This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU ^[2].

The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene.^[3]. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).^[4]

PKU is an autosomal recessive genetic disorder, meaning that each parent must have at least one defective allele of the gene for PAH, and the child must inherit two defective alleles, one from each parent. As a result, it is possible for a parent with PKU phenotype to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two defective alleles, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU^[5]. The macaque monkey’s genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence which in humans would be considered the PKU mutation.
File:Autorecessive.svg

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones though the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenylethylamine^[6]. Detection of phenylketones in the urine is diagnostic.

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development in children, leading to mental retardation.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yanira Gavidia, M.D.

PKU is an autosomal recessive disorder caused by mutations in the PAH gene. The mutation results in a deficiency/absence of the phenylalanine hydroxlyase enzyme that normally catalyzes phenylalanine to tyrosine.

• PKU is an autosomal recessive disorder caused by mutations in the PAH gene.
• The mutation results in a deficiency/absence of the phenylalanine hydroxlyase enzyme that normally catalyzes phenylalanine to tyrosine.
• To date, 877 mutations have been identified.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yanira Gavidia, M.D.

Phenylketonuria must be differentiated from other causes of intellectual developmental disability, seizures, anxiety/depression, and characteristic urine odors, such as other inborn errors of metabolism, cerebral palsy, inherited neurotransmitter disorders, and primary seizure disorders.

Phenylketonuria must be differentiated from other causes of intellectual developmental disability, seizures, anxiety/depression, and characteristic urine odors:^[1][2][3][4]

• Cerebral palsy
• Fatty acid oxidation disorders
• Lysosomal disorders
• Hyperhomocysteinemia
• Amino acid disorders
• Creatine deficiencies

• Inherited neurotransmitter and non-neurotransmitter disorders
• Primary seizure disorders

• Urea cycle disorders
• Organic acidurias
• Maple syrup urine disease
• Tyrosinemia type 1

• Maple syrup urine disease
• Methylmalonic acidemia
• Propionic acidemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

The incidence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the population of Ireland^[1] to fewer than one in 100,000 births among the population of Finland.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yanira Gavidia, M.D.

Newborns are usually screened for phenylketonuria between the age of 6 to 14 days using either HPLC or Guthrie test. If results are positive, the test is usually repeated at 2 weeks of age to confirm or rule out the diagnosis.

• Newborns are usually screened at day 6 to 14 following birth
• Neonatal heel prick is used to obtain a blood sample for screening.
• Screening for PKU is by usually either by HPLC test or by Guthrie test.^[1]
• If a test result returns positive, the test is typically repeated at 2 weeks of age to confirm or rule out the diagnosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

If a child is not screened at birth (e.g. in home deliveries), the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a “musty odor” to the baby’s sweat and urine (due to phenylacetate, one of the ketones produced).

Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities and seizures, and severe mental retardation are major clinical problems later in life. A “musty” odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed.

In contrast, affected children who are detected and treated at birth are less likely to develop neurological problems and have seizures and mental retardation, though such clinical disorders are still possible.

Complications are seen both in treated and untreated patients, but are more frequently seen in the second group, and in the patients that are lately diagnosed.

Neurocognitive aspects such as IQ, processing speed, attention, inhibition, and motor control can be affected, PKU is also associated with low self-esteem,lower achievement motivation, decreased autonomy, decreased social competence,  and possible increased risk for depressed mood, generalized anxiety and social isolation.^[1]

Well controlled and early diagnosed PKU has a great prognosis, but it requires a life long dietary restriction and ingestion of amino acid supplement.^[2]

On the other hand, when patients with PKU do not receive treatment, the prognosis is poor, and it greatly affects the neurologic system and intellectual capacity.^[3]

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