INTRODUCTION

Through prompt and appropriate medical management, affected children

identified through newborn screening can lead normal lives
Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized
by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH).[1]:541 This
enzyme is necessary to metabolize the amino acid phenylalanine ('Phe') to the
amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is
converted into phenylpyruvate (also known as phenylketone), which is detected
in the urine.

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[21] to 1 in 13,000 births in Norway[22] to fewer than one in 100,000 births
among the population of Finland.[23] Turkey, at 1 in 2600, has the highest
incidence rate in the world. The illness is also more common in Italy and China,
as well as in Yemeni populations[24].

Pathophysiology

Classical PKU is caused by a mutated gene for the enzyme phenylalanine

hydroxylase (PAH), which converts the amino acid phenylalanine to other
essential compounds in the body. Other non-PAH mutations can also cause
PKU. This is an example of genetic heterogeneity.

Classical PKU

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.
PAH deficiency causes a spectrum of disorders including classic phenylketonuria
(PKU) and hyperphenylalaninemia (a less severe accumulation of
phenylalanine).[5]

PKU is an autosomal recessive genetic disorder, meaning that each parent must
have at least one mutated allele of the gene for PAH, and the child must inherit
two mutated 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 mutated alleles, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in

experiments into an effective treatment for PKU[6]. 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.[7]

Tetrahydrobiopterin-deficient hyperphenylalaninemia

A rarer form of hyperphenilalaninemia occurs when PAH is normal but there is a

defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4) by
the patient.[8] This cofactor is necessary for proper activity of the enzyme.

Levels of dopamine can be used to distinguish between these two types.

Tetrahydrobiopterin is required to convert phenylalanine to tyrosine, but it is also
required to convert tyrosine to DOPA (via the enzyme tyrosine hydroxylase),
which in turn is converted to dopamine. Low levels of dopamine lead to high
levels of prolactin. By contrast, in classical PKU, prolactin levels would be
relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four
different genes. These types are known as HPABH4A, HPABH4B, HPABH4C,
and HPABH4D.[9]

BIBLIOGRAPHY
• ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases
of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0.
•  ^ DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., Woo, S. L. C.
(1986). "Molecular structure and polymorphic map of the human
phenylalanine hydroxylase gene". Biochemistry 25: 743–749.
doi:10.1021/bi00352a001. PMID 3008810.
•  ^ www.rikshospitalet.no
•  ^ Guldberg, P., Henriksen, K. F., Sipila, I., Guttler, F., de la Chapelle,
A. (1995). "Phenylketonuria in a low incidence population: molecular
characterization of mutations in Finland". J. Med. Genet 32: 976–978.
doi:10.1136/jmg.32.12.976. PMID 8825928.
•  ^ http://emedicine.medscape.com/article/947781-overview
•  ^ http://www.genenames.org Phenylalanine hydroxylase (PAH) gene
summary, retrieved September 8, 2006
•  ^ Oh, H. J., Park, E. S., Kang, S., Jo, I., Jung, S. C. (2004). "Long-
Term Enzymatic and Phenotypic Correction in the Phenylketonuria Mouse
Model by Adeno-Associated Virus Vector-Mediated Gene Transfer".
Pediatric Research 56: 278–284.
doi:10.1203/01.PDR.0000132837.29067.0E. PMID 15181195.
http://www.pedresearch.org/cgi/content/full/56/2/278.
•  ^ Gibbs, Richard A.; Jeffrey Rogers, Michael G. Katze, Roger
Bumgarner, George M. Weinstock, Elaine R. Mardis, Karin A. Remington,
et al. (April 2007). "Evolutionary and Biomedical Insights from the Rhesus
Macaque Genome". Science 316 (5822): 222–234.
doi:10.1126/science.1139247. PMID 17431167.
 http://www.sciencemag.org/cgi/content/full/316/5822/222. Retrieved 2008-
02-26.
•  ^ Surtees, R., Blau, N. (2000). "The neurochemistry of
phenylketonuria". European Journal of Pediatrics 169: S109–13.
doi:10.1007/PL00014370. PMID 11043156.
•  ^ Online 'Mendelian Inheritance in Man' (OMIM) 261640