Hyperphenylalaninemia is a

medical condition A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

characterized by mildly or strongly elevated

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', '' number concentration'', ...

s of the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

phenylalanine in the

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the cir ...

Phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also re ...

(PKU) can result in severe hyperphenylalaninemia. Phenylalanine concentrations ( he are routinely screened in

newborn An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

s by the

neonatal heel prick The neonatal heel prick is a blood collection procedure done on newborns. It consists of making a pinprick puncture in one heel of the newborn to collect their blood. This technique is used frequently as the main way to collect blood from neonat ...

(Guthrie test), which takes a few drops of blood from the heel of the infant. Standard heconcentrations in unaffected persons are about 60 µM: heconcentrations in persons with untreated phenylketonuria may be many times that (600µM to 2400µM), which indicate that the child is at risk for severe

intellectual disability Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...

. Phenylketonuria is classed as an autosomal recessive condition: in

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

form, heshows a moderate elevation, perhaps two-fold over that of unaffected

homozygotes Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

, which is classified as hyperphenylalaninemia ('' hyper-'' + ''phenylalanine'' + '' -emia'' = high hein blood).

Symptoms and signs

The coloration of the skin, hair, and eyes is different in children with PKU. This is caused by low levels of tyrosine, whose metabolic pathway is blocked by deficiency of PAH. Another skin alteration that might occur is the presence of irritation or dermatitis. The child's behaviour may be influenced as well due to augmented levels of phenethylamine which in turn affects levels of other amines in the brain. Psychomotor function may be affected and observed to worsen progressively.

Cause

People with the genotype for PKU are unaffected

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...

, because maternal circulation prevents buildup of he After birth, PKU in newborns is treated by a special diet with highly restricted phenylalanine content. Persons with genetic predisposition to PKU have normal mental development on this diet. Previously, it was thought safe to withdraw from the diet in the late teens or early twenties, after the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

was fully developed; recent studies suggest some degree of relapse, and a continued phenylalanine-restricted diet is now recommended. PKU or hyperphenylalaninemia may also occur in persons without the PKU genotype. If the mother has the PKU genotype but has been treated so as to be asymptomatic, high levels of hein the maternal blood circulation may affect the non-PKU fetus during gestation. Mothers successfully treated for PKU are advised to return to the herestricted diet during pregnancy. A small subset of patients with hyperphenylalaninemia shows an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid; however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal

phenylalanine hydroxylase Phenylalanine hydroxylase. (PAH) () is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class ...

(PAH)

enzymatic Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

activity but have a deficiency in dihydropteridine reductase (DHPR), an enzyme required for the regeneration of

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin ...

(THB or BH₄), a cofactor of PAH. Less frequently, DHPR activity is normal but a defect in the biosynthesis of THB exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, THB is also a cofactor for two other hydroxylation reactions required in the syntheses of neurotransmitters in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

: the hydroxylation of

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...

to 5-hydroxytryptophan and of

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...

L-dopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

. It has been suggested that the resulting deficit in the CNS neurotransmitter activity is, at least in part, responsible for the neurologic manifestations and eventual death of these patients. Hyperphenylalaninemia most is commonly diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center. Some cases in adult women have been detected using maternal screening programs or following birth of children with birth defects. Elevated phenylalanine levels are associated with neuropsychological effects.

Diagnosis

Treatment

Maintain plasma phenylalanine values in therapeutic range of 120 to 360 mM using a diet that restricts phenylalanine but otherwise nutritionally complete. Treatment for life is recommended to reduce the risk of long term neuropsychiatric problems and reduce the risk of maternal PKU syndrome.

Outcome

With treatment the outcome is excellent. Most infants with classic PKU who are treated within the first 10 days of life achieve normal intelligence. However learning problems are more frequent than in unaffected peers.

References

External links

{{Medical resources , ICD10 = {{ICD10, E, 70, 1, e, 70 (also includes non-classic PKU) , ICD9 = {{ICD9, 270.1 (PKU) , ICDO = , OMIM = 261600 , OMIM_mult = {{OMIM, 261630, , none , MeshID = D010661 , Orphanet = 238583 Endocrine diseases