Phenylketonuria (PKU) is an
inborn error of metabolism
Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
that results in decreased
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
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 am ...
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
.
Untreated PKU can lead to
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 signifi ...
,
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, behavioral problems, and
mental disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
s.
[ It may also result in a musty smell and lighter skin.][ A baby born to a mother who has poorly treated PKU may have heart problems, a ]small head
Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
, and low birth weight
Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an
infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal inten ...
.[
Phenylketonuria is an inherited genetic disorder.][ It is due to mutations in the '' PAH'' gene, which results in low levels of the ]enzyme
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. A ...
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 ...
.[ This results in the buildup of dietary phenylalanine to potentially toxic levels.][ It is ]autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
, meaning that both copies of the gene must be mutated for the condition to develop.[ There are two main types, classic PKU and variant PKU, depending on whether any enzyme function remains.][ Those with one copy of a mutated gene typically do not have symptoms.] Many countries have newborn screening program
Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions ear ...
s for the disease.[
Treatment is with a diet that (1) is low in foods that contain phenylalanine, and which (2) includes special supplements.][ Babies should use a special ]formula
In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwee ...
with a small amount of breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...
.[ The diet should begin as soon as possible after birth and be continued for life.] People who are diagnosed early and maintain a strict diet can have normal health and a normal life span.[ Effectiveness is monitored through periodic blood tests.] The medication sapropterin dihydrochloride
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 ...
may be useful in some.[
Phenylketonuria affects about 1 in 12,000 babies.] Males and females are affected equally. The disease was discovered in 1934 by Ivar Asbjørn Følling
Ivar Asbjørn Følling (23 August 1888 – 24 January 1973) was a Norwegian physician and biochemist. He first described the disease commonly known as Følling's disease or phenylketonuria ( PKU).
Career
He was born at Kvam, Steinkjer in Trønde ...
, with the importance of diet determined in 1935. Gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
, while promising, requires a great deal more study as of 2014.
Signs and symptoms
Untreated PKU can lead to 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 signifi ...
, seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, behavioral problems, and mental disorder
A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...
s.[ It may also result in a musty smell and lighter skin.][ A baby born to a mother who has poorly treated PKU may have heart problems, a ]small head
Microcephaly (from New Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it ...
, and low birth weight
Low birth weight (LBW) is defined by the World Health Organization as a birth weight of an
infant of or less, regardless of gestational age. Infants born with LBW have added health risks which require close management, often in a neonatal inten ...
.[
Because the mother's body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth. The disease is not detectable by physical examination at that time, because no damage has yet been done. Newborn screening is performed to detect the disease and initiate treatment before any damage is done. The blood sample is usually taken by a heel prick, typically performed 2–7 days after birth. This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding.
If a child is not diagnosed during the routine newborn screening test and a phenylalanine-restricted diet is not introduced, then phenylalanine levels in the blood will increase over time. Toxic levels of phenylalanine (and insufficient levels of tyrosine) can interfere with infant development in ways that have permanent effects. The disease may present clinically with ]seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s, hypopigmentation
Hypopigmentation is characterized specifically as an area of skin becoming lighter than the baseline skin color, but not completely devoid of pigment. This is not to be confused with depigmentation, which is characterized as the absence of all pi ...
(excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenylacetone). In most cases, a repeat test should be done at approximately two weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed.
Untreated children often fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
, EEG
Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...
abnormalities, and seizures, and severe learning disabilities
Learning disability, learning disorder, or learning difficulty (British English) is a condition in the brain that causes difficulties comprehending or processing information and can be caused by several different factors. Given the "difficult ...
are major clinical problems later in life. A characteristic "musty or mousy" odor on the skin, as well as a predisposition for eczema
Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...
, persist throughout life in the absence of treatment.
The damage done to the brain if PKU is untreated during the first months of life is not reversible. It is critical to control the diet of infants with PKU very carefully so that the brain has an opportunity to develop normally. Affected children who are detected at birth and treated are much less likely to develop neurological problems or have seizures and intellectual disability (though such clinical disorders are still possible including asthma, eczema, anemia, weight gain, renal insufficiency, osteoporosis, gastritis, esophagus, and kidney deficiencies, kidney stones, and hypertension). Additionally, major depressive disorders occur 230% higher than controls; dizziness and giddiness occur 180% higher; chronic ischemic heart disease, asthma, diabetes, and gastroenteritis occur 170% higher; and stress and adjustment disorders occur 160% higher. In general, however, outcomes for people treated for PKU are good. Treated people may have no detectable physical, neurological, or developmental problems at all.
Genetics
PKU is an autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
metabolic genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
. As an autosomal recessive disorder, two PKU allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
s are required for an individual to experience symptoms of the disease. For a child to inherit PKU, both the mother and father must have and pass on the defective gene. If both parents are carriers for PKU, there is a 25% chance any child they have will be born with the disorder, a 50% chance the child will be a carrier and a 25% chance the child will neither develop nor be a carrier for the disease.[
PKU is characterized by ]homozygous
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 ...
or compound heterozygous In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disorders, genetic disease in a heterozygous state; that is, an organism is a compound h ...
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s in the gene for the hepatic enzyme 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), rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
(Phe) to the amino acid 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 Gr ...
(Tyr). When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate
Phenylpyruvic acid is the organic compound with the formula C6H5CH2C(O)CO2H. It is a keto acid.
Occurrence and properties
The compound exists in equilibrium with its E- and Z-enol tautomers. It is a product from the oxidative deamination of p ...
(also known as phenylketone), which can be detected in the urine
Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra.
Cel ...
.
Carriers of a single PKU allele do not exhibit symptoms of the disease but appear to be protected to some extent against the fungal toxin ochratoxin A
Ochratoxin A—a toxin produced by different ''Aspergillus'' and ''Penicillium'' species — is one of the most-abundant food-contaminating mycotoxins. It is also a frequent contaminant of water-damaged houses and of heating ducts. Human exposure ...
. This accounts for the persistence of the allele in certain populations in that it confers a selective advantage—in other words, being a heterozygote is advantageous.
The PAH gene is located on chromosome 12
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the to ...
in the bands 12q22-q24.2. As of 2000, around 400 disease-causing mutations had been found in the PAH gene. This is an example of allelic genetic heterogeneity Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by diffe ...
.[
]
Pathophysiology
When phenylalanine (Phe) cannot be metabolized by the body, a typical diet that would be healthy for people without PKU causes abnormally high levels of Phe to accumulate in the blood, which is toxic to the brain. If left untreated (and often even in treatment), complications of PKU include severe intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
, as well as physical symptoms such as a "musty" odor, eczema, and unusually light skin and hair coloration.
Classical PKU
Classical PKU, and its less severe forms "mild PKU" and "mild hyperphenylalaninemia" are caused by a mutated gene for the enzyme
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. A ...
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), which converts the amino acid phenylalanine ("Phe") to other essential compounds in the body, in particular tyrosine. Tyrosine is a conditionally essential 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 am ...
for PKU patients because without PAH it cannot be produced in the body through the breakdown of phenylalanine. Tyrosine is necessary for the production of neurotransmitters like epinephrine, norepinephrine, and dopamine.
PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as "hyperphe" or "mild HPA"), a less severe accumulation of phenylalanine. Compared to classic PKU patients, patients with "hyperphe" have greater PAH enzyme activity and are able to tolerate larger amounts of phenylalanine in their diets. Without dietary intervention, mild HPA patients have blood Phe levels higher than those with normal PAH activity. There is currently no international consensus on the definition of mild HPA, however, it is most frequently diagnosed at blood Phe levels between 2–6 mg/dL.
Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
(BBB) via the large neutral amino acid transporter (LNAAT). If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. As these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of 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 v ...
, causing 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 signifi ...
.
Recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology are slightly suboptimal even for patients who are treated and maintain their Phe levels in the target range, if their diet is not supplemented with other amino acids.
Classic PKU affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological problems associated with phenylketonuria. Differences in white matter development are observable with magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
. Abnormalities in gray matter can also be detected, particularly in the motor and pre-motor cortex, thalamus and the hippocampus.
It was recently suggested that PKU may resemble amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.
Tetrahydrobiopterin-deficient hyperphenylalaninemia
A rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency
Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing in ...
, which occurs when the PAH enzyme is normal, and a defect is found in the biosynthesis or recycling of the cofactor 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 ...
(BH4). BH4 is necessary for proper activity of the enzyme PAH, and this coenzyme
A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's role as a catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can be considered "helper molecules" that ass ...
can be supplemented as treatment. Those with this form of hyperphenylalaninemia may have a deficiency of tyrosine (which is created from phenylalanine by PAH), in which case treatment is supplementation of tyrosine to account for this deficiency.
Levels of dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
can be used to distinguish between these two types. 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 ...
is required to convert Phe to Tyr and is required to convert Tyr to 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 ...
via the enzyme tyrosine hydroxylase
Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and t ...
. L-DOPA, in turn, is converted to dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
. Low levels of dopamine lead to high levels of prolactin
Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...
. By contrast, in classical PKU (without dihydrobiopterin involvement), prolactin levels would be relatively normal.
As of 2020, tetrahydrobiopterin deficiency was known to result from defects in five genes.
Metabolic pathways
The enzyme 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 ...
normally converts 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 am ...
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
into the amino acid 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 Gr ...
. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase
Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α- keto acid. They are important in the synthesis of amino acids, which form proteins.
Function and mechanism
An amino acid ...
pathway with glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
. Metabolites include phenylacetate, phenylpyruvate
Phenylpyruvic acid is the organic compound with the formula C6H5CH2C(O)CO2H. It is a keto acid.
Occurrence and properties
The compound exists in equilibrium with its E- and Z-enol tautomers. It is a product from the oxidative deamination of p ...
and phenethylamine
Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however most patients are diagnosed via newborn screening.
Screening
PKU is commonly included in the newborn screening
Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions e ...
panel of many countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. Screening for PKU is done with bacterial inhibition assay (Guthrie test
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 ...
), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry
Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more mass analyzers are coupled together using an additional reaction step to increase their abilities to analyse chemical samples. A com ...
(MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to 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 Gr ...
, the ratio will be elevated in PKU.
Treatment
PKU is not curable. However, if PKU is diagnosed early enough, an affected newborn can grow up with normal brain development by managing and controlling phenylalanine ("Phe") levels through diet, or a combination of diet and medication.
Diet
People who follow the prescribed dietary treatment from birth may (but not always) have no symptoms. Their PKU would be detectable only by a blood test. People must adhere to a special diet low in Phe for optimal brain development. Since Phe is necessary for the synthesis of many proteins, it is required for appropriate growth, but levels must be strictly controlled.
Optimal health ranges (or "target ranges") are between 120 and 360 μmol/L or equivalently 2 to 6 mg/dL. This is optimally to be achieved during at least the first 10 years, to allow the brain to develop normally.
The diet requires restricting or eliminating foods high in Phe, such as soybeans
The soybean, soy bean, or soya bean (''Glycine max'') is a species of legume native to East Asia, widely grown for its edible bean, which has numerous uses.
Traditional unfermented food uses of soybeans include soy milk, from which tofu and ...
, egg white
Egg white is the clear liquid (also called the albumen or the glair/glaire) contained within an egg. In chickens it is formed from the layers of secretions of the anterior section of the hen's oviduct during the passage of the egg. It forms arou ...
s, shrimp
Shrimp are crustaceans (a form of shellfish) with elongated bodies and a primarily swimming mode of locomotion – most commonly Caridea and Dendrobranchiata of the decapod order, although some crustaceans outside of this order are refer ...
, chicken breast
Chicken is the most common type of poultry in the world. Owing to the relative ease and low cost of raising chickens—in comparison to mammals such as cattle or hogs—chicken meat (commonly called just "chicken") and chicken eggs have beco ...
, spirulina, watercress
Watercress or yellowcress (''Nasturtium officinale'') is a species of aquatic flowering plant in the cabbage family Brassicaceae.
Watercress is a rapidly growing perennial plant native to Europe and Asia. It is one of the oldest known leaf ve ...
, fish
Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of li ...
, nuts, crayfish
Crayfish are freshwater crustaceans belonging to the clade Astacidea, which also contains lobsters. In some locations, they are also known as crawfish, craydids, crawdaddies, crawdads, freshwater lobsters, mountain lobsters, rock lobsters, mu ...
, lobster
Lobsters are a family (biology), family (Nephropidae, Synonym (taxonomy), synonym Homaridae) of marine crustaceans. They have long bodies with muscular tails and live in crevices or burrows on the sea floor. Three of their five pairs of legs ...
, tuna
A tuna is a saltwater fish that belongs to the tribe Thunnini, a subgrouping of the Scombridae (mackerel) family. The Thunnini comprise 15 species across five genera, the sizes of which vary greatly, ranging from the bullet tuna (max length: ...
, turkey
Turkey ( tr, Türkiye ), officially the Republic of Türkiye ( tr, Türkiye Cumhuriyeti, links=no ), is a list of transcontinental countries, transcontinental country located mainly on the Anatolia, Anatolian Peninsula in Western Asia, with ...
, legume
A legume () is a plant in the family Fabaceae (or Leguminosae), or the fruit or seed of such a plant. When used as a dry grain, the seed is also called a pulse. Legumes are grown agriculturally, primarily for human consumption, for livestock f ...
s, and lowfat cottage cheese
Cottage cheese is a curdled milk product with a mild flavor and a creamy, non-homogeneous, soupy texture. It is made from skimmed milk by draining the cheese, as opposed to pressing it to make cheese curd—retaining some of the whey and keeping ...
. Starchy foods, such as potato
The potato is a starchy food, a tuber of the plant ''Solanum tuberosum'' and is a root vegetable native to the Americas. The plant is a perennial in the nightshade family Solanaceae.
Wild potato species can be found from the southern Unit ...
es and corn
Maize ( ; ''Zea mays'' subsp. ''mays'', from es, maíz after tnq, mahiz), also known as corn (North American and Australian English), is a cereal grain first domesticated by indigenous peoples in southern Mexico about 10,000 years ago. Th ...
are generally acceptable in controlled amounts, but the quantity of Phe consumed from these foods must be monitored. A corn-free diet may be prescribed in some cases. A food diary is usually kept to record the amount of Phe consumed with each meal, snack, or drink. An "exchange" system can be used to calculate the amount of Phe in a portion of food from the protein content identified on a nutritional information label. Lower-protein "medical food" substitutes are often used in place of normal bread
Bread is a staple food prepared from a dough of flour (usually wheat) and water, usually by baking. Throughout recorded history and around the world, it has been an important part of many cultures' diet. It is one of the oldest human-made f ...
, pasta
Pasta (, ; ) is a type of food typically made from an unleavened dough of wheat flour mixed with water or eggs, and formed into sheets or other shapes, then cooked by boiling or baking. Rice flour, or legumes such as beans or lentils, are som ...
, and other grain-based foods, which contain a significant amount of Phe. Many fruits and vegetables are lower in Phe and can be eaten in larger quantities. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. The sweetener aspartame
Aspartame is an artificial non-saccharide sweetener 200 times sweeter than sucrose and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with the trade names ...
, present in many diet foods and soft drinks, must also be avoided, as aspartame contains phenylalanine.
Different people can tolerate different amounts of Phe in their diet. Regular blood tests are used to determine the effects of dietary Phe intake on blood Phe level.
Nutritional supplements
Supplementary "protein substitute" formulas are typically prescribed for people PKU (starting in infancy) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. Tyrosine, which is normally derived from phenylalanine and which is necessary for normal brain function, is usually supplemented. Consumption of the protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein catabolism
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
from releasing Phe stored in the muscles and other tissues into the blood. Many PKU patients have their highest Phe levels after a period of fasting (such as overnight) because fasting triggers catabolism. A diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood Phe levels, since a nutritionally insufficient diet may also trigger catabolism. For all these reasons, the prescription formula is an important part of the treatment for patients with classic PKU.
Evidence supports dietary supplementation with large neutral amino acids (LNAAs). The LNAAs (e.g. leu, tyr, trp, met, his
His or HIS may refer to:
Computing
* Hightech Information System, a Hong Kong graphics card company
* Honeywell Information Systems
* Hybrid intelligent system
* Microsoft Host Integration Server
Education
* Hangzhou International School, in ...
, ile
Ile may refer to:
* iLe, a Puerto Rican singer
* Ile District (disambiguation), multiple places
* Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria
* Interlingue (ISO 639:ile), a planned language
* Isoleucine, an amino acid
* Anothe ...
, val, thr) may compete with phe for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
into the brain. Its use is limited in the US due to the cost but is available in most countries as part of a low protein / PHE diet to replace missing nutrients.
Another interesting treatment strategy is casein glycomacropeptide (CGMP), which is a milk peptide naturally free of Phe in its pure form CGMP can substitute for the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids. The fact that CGMP is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention and increased satiety compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved when CGMP substitutes part of the free amino acids and this may help ensure improved compliance to the PKU diet.
Furthermore, CGMP contains a high amount of the Phe-lowering LNAAs, which constitutes about 41 g per 100 g protein and will therefore help maintain plasma phe levels in the target range.
Enzyme substitutes
In 2018, the FDA approved an enzyme substitute called pegvaliase
Pegvaliase, sold under the brand name Palynziq, is a medication for the treatment of the genetic disease phenylketonuria. Chemically, it is a pegylated derivative of the enzyme phenylalanine ammonia-lyase that metabolizes phenylalanine to reduce ...
which metabolizes phenylalanine. It is for adults who are poorly managed on other treatments.[
]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 ...
(BH4) (a cofactor for the oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of phenylalanine) when taken by mouth can reduce 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 c ...
levels of this amino acid in some people.
Mothers
For women with PKU, it is important for the health of their children to maintain low Phe levels before and during pregnancy. Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. PKU-affected women themselves are not at risk of additional complications during pregnancy.
In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 mg/dL, anecdotal reports indicate that the mothers may experience adverse effects, including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.[lsuhsc.edu](_blank)
Genetics and Louisiana Families
Epidemiology
The average number of new cases of PKU varies in different human populations. United States Caucasians are affected at a rate of 1 in 10,000. Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births. A 1987 study from Slovakia reports a Roma
Roma or ROMA may refer to:
Places Australia
* Roma, Queensland, a town
** Roma Airport
** Roma Courthouse
** Electoral district of Roma, defunct
** Town of Roma, defunct town, now part of the Maranoa Regional Council
*Roma Street, Brisbane, a ...
population with an extremely high incidence of PKU (one case in 40 births) due to extensive inbreeding. It is the most common amino acid metabolic problem in the United Kingdom.
History
Before the causes of PKU were understood, PKU caused severe disability in most people who inherited the relevant mutations. Nobel and Pulitzer Prize winning author Pearl S. Buck
Pearl Sydenstricker Buck (June 26, 1892 – March 6, 1973) was an American writer and novelist. She is best known for ''The Good Earth'' a bestselling novel in the United States in 1931 and 1932 and won the Pulitzer Prize for the Novel, Pulitze ...
had a daughter named Carol who lived with PKU before treatment was available, and wrote an account of its effects in a book called ''The Child Who Never Grew.'' Many untreated PKU patients born before widespread newborn screening are still alive, largely in dependent living homes/institutions.
Phenylketonuria was discovered by the Norwegian
Norwegian, Norwayan, or Norsk may refer to:
*Something of, from, or related to Norway, a country in northwestern Europe
* Norwegians, both a nation and an ethnic group native to Norway
* Demographics of Norway
*The Norwegian language, including ...
physician Ivar Asbjørn Følling
Ivar Asbjørn Følling (23 August 1888 – 24 January 1973) was a Norwegian physician and biochemist. He first described the disease commonly known as Følling's disease or phenylketonuria ( PKU).
Career
He was born at Kvam, Steinkjer in Trønde ...
in 1934 when he noticed hyperphenylalaninemia (HPA) was associated with intellectual disability. In Norway, this disorder is known as Følling's disease, named after its discoverer. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease.
In 1934 at Rikshospitalet
Oslo University Hospital, Rikshospitalet is one of the four main campuses of Oslo University Hospital in Oslo, Norway. It was an independent hospital, ''Rigshospitalet'', later spelled ''Rikshospitalet'' ("The National Hospital"), from 1826 to 2009 ...
, Følling saw a young woman named Borgny Egeland. She had two children, Liv and Dag, who had been normal at birth but subsequently developed intellectual disability. When Dag was about a year old, the mother noticed a strong smell to his urine. Følling obtained urine samples from the children and, after many tests, he found that the substance causing the odor in the urine was phenylpyruvic acid. The children, he concluded, had excess phenylpyruvic acid in the urine, the condition which came to be called phenylketonuria (PKU).
His careful analysis of the urine of the 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 he had found in eight other patients. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid
Benzoic acid is a white (or colorless) solid organic compound with the formula , whose structure consists of a benzene ring () with a carboxyl () substituent. It is the simplest aromatic carboxylic acid. The name is derived from gum benzoin, wh ...
, which led him to conclude that the compound contained a benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...
ring. Further testing showed the melting point
The melting point (or, rarely, liquefaction point) of a substance is the temperature at which it changes state from solid to liquid. At the melting point the solid and liquid phase exist in equilibrium. The melting point of a substance depends ...
to be the same as phenylpyruvic acid
Phenylpyruvic acid is the organic compound with the formula C6H5CH2C(O)CO2H. It is a keto acid.
Occurrence and properties
The compound exists in equilibrium with its E- and Z-enol tautomers. It is a product from the oxidative deamination of p ...
, which indicated that the substance was in the urine.
In 1954, Horst Bickel
Horst Bickel (28 June 1918 – 1 December 2000) was a German medical doctor.
With Guido Fanconi, he characterized Glycogen storage disease type XI in 1949.
He was also involved in the development of treatments for phenylketonuria. In 1951, Bic ...
, Evelyn Hickmans and John Gerrard published a paper that described how they created a diet that was low in phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
and the patient recovered.[ Bickel, Gerrard and Hickmans were awarded the ]John Scott Medal
John Scott Award, created in 1816 as the John Scott Legacy Medal and Premium, is presented to men and women whose inventions improved the "comfort, welfare, and happiness of human kind" in a significant way. "...the John Scott Medal Fund, establish ...
in 1962 for their discovery.
PKU was the first disorder to be routinely diagnosed through widespread newborn screening
Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions e ...
. Robert Guthrie
Robert Guthrie, MD, Ph.D. (June 28, 1916 – June 24, 1995) was an American microbiologist, best known for developing the bacterial inhibition assay used to screen infants for phenylketonuria at birth, before the development of irreversible n ...
introduced the newborn screening test for PKU in the early 1960s. With the knowledge that PKU could be detected before symptoms were evident, and treatment initiated, screening was quickly adopted around the world. Ireland was the first country to introduce a national screening programme in February 1966, Austria also started screening in 1966 and England in 1968.
In 2017 the European Guidelines were published. They were called for by the patient organizations such as the . They have received some critical reception.
Etymology and pronunciation
The word ''phenylketonuria'' uses combining forms of ''phenyl
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
'' + ''ketone
In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
'' + '' -uria''; it is pronounced .
Research
Other therapies are currently under investigation, including gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
.
Biomarin is currently conducting clinical trials to investigate PEG-PAL (PEGylated recombinant phenylalanine ammonia lyase
The enzyme phenylalanine ammonia lyase (EC 4.3.1.24) catalyzes the conversion of L-phenylalanine to ammonia and ''trans''-cinnamic acid.:
:L-phenylalanine = ''trans''-cinnamate + NH3
Phenylalanine ammonia lyase (PAL) is the first and committed ...
or 'PAL') is an enzyme substitution therapy in which the missing PAH enzyme is replaced with an analogous enzyme that also breaks down Phe. PEG-PAL is now in Phase 2 clinical development.
See also
* Hyperphenylalanemia
* Lofenalac
Lofenalac (pronunciation:Lo-fen-alac) is a registered, trademarked infant powder formula prescribed to replace milk in the diets of phenylketonuria sufferers in the infant and child stage. It is not recommended for non-PKU patients. In 1972, Lofe ...
* Tetrahydrobiopterin deficiency
Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing in ...
* ''Flowers for Algernon
''Flowers for Algernon'' is a short story by American author Daniel Keyes, later expanded by him into a novel and subsequently adapted for film and other media. The short story, written in 1958 and first published in the April 1959 issue of ''T ...
'', which features a character who has phenylketonuria
References
External links
*
{{Amino acid metabolic pathology
Intellectual disability
Autosomal recessive disorders
Amino acid metabolism disorders
Skin conditions resulting from errors in metabolism
Disorders causing seizures
Biology of attention deficit hyperactivity disorder
Rare diseases
Wikipedia medicine articles ready to translate
Newborn screening