Phenylketonuria (PKU)

Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.:541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH enzymatic activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.

Amino acids are the building blocks for body proteins. ‘Essential’ amino acids can only be obtained from the food we eat as our body does not normally produce them. In ‘classic PKU’, the enzyme that breaks down phenylalanine phenylalanine hydroxylase, is completely or nearly completely deficient. This enzyme normally converts phenylalanine to another amino acid, tyrosine. Without this enzyme, phenylalanine and its’ breakdown chemicals from other enzyme routes, accumulate in the blood and body tissues. Although the term ‘hyperphenylalaninemia’ strictly means elevated blood phenylalanine, it is usually used to describe a group of disorders other than classic PKU. These other disorders may be caused by a partial deficiency of the phenylalanine breakdown enzyme or the lack of another enzyme important to the processing of this amino acid. A normal blood phenylalanine level is about 1 mg/dl. In classic PKU, levels may range from 6 to 80mg/dl, but are usually greater than 30mg/dl. Levels are somewhat less in the other disorders of hyperphenylalaninemia. Chronically high levels of phenylalanine and some of its breakdown products can cause significant brain problems. Classic PKU is the most common cause of high levels of phenylalanine in the blood and will be the primary focus of this topic sheet.


The mean incidence of PKU varies widely in different human populations. In Turkey, 1 in 2600 births (the highest rate in the world) show PKU; in Ireland, 1 in 4,500, 1 in 13,000 in Norway, and fewer than one in 100,000 in Finland. In the United States, about 1 in 15,000 births shows classical PKU. The incidence is relatively high in Italy, China, and Yemen

Classic PKU and the other causes of hyperphenylalaninemia affect about one of every 10,000 to 20,000 Caucasian or Oriental births. The incidence in African Americans is far less. These disorders are equally frequent in males and females.

Since its discovery, there have been many advances in its treatment. It can now be successfully managed by the patient under ongoing medical supervision to avoid the more serious side effects. If, however, the condition is left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. In the past, PKU was treated with a low-phenylalanine diet. Latter-day research now has shown diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Phe levels to a safe range and monitoring diet and cognitive development. Lowering of Phe levels to a safe range may be achieved by combining a low-Phe diet with protein supplements. There is currently no cure for this disease; however, some treatments are available with varying success rates. In general, PKU is detected through newborn screening and diagnosed by a geneticist. PKU clinics around the world provide care for PKU patients to optimize Phe levels, dietary intake, and cognitive outcomes.

Newborns with phenylketonuria initially don’t have any symptoms. Without treatment, though, babies usually develop signs of PKU within a few months. Phenylketonuria symptoms can be mild or severe and may include:

*Mental retardation
*Behavioral or social problems
*Seizures, tremors or jerking movements in the arms and legs)
*Stunted growth
*Skin rashes (eczema)
*Small head size (microcephaly)
*A musty odor in the child’s breath, skin or urine, caused by too much phenylalanine in the body

*Fair skin and blue eyes, because phenylalanine cannot transform into melanin — the pigment responsible for hair and skin tone

Varying severity
The most severe form of the disorder is known as classic PKU. Children with untreated classic PKU usually develop obvious, permanent mental retardation.

Less severe forms of PKU — sometimes called mild or moderate PKU — have a smaller risk of significant brain damage, but most children with these forms of the disorder still require a special diet to prevent mental retardation and other complications.

Pregnancy and PKU
A woman who has PKU and becomes pregnant is at risk of another form of the condition called maternal PKU. Many people with PKU used to stop following a low-phenylalanine diet during their teen years, as was directed by doctors at the time. But, doctors now know that if a woman doesn’t follow the diet during pregnancy, blood phenylalanine levels can become very high and harm the developing fetus. Because of this, and other reasons, doctors recommend that anyone with PKU follow the low-phenylalanine diet for life.

Although babies born to mothers with high phenylalanine levels may have complications at birth, most don’t actually inherit PKU and won’t need to follow a PKU diet after birth. However, these babies are at risk of being born with:

*Mental retardation
*Abnormally small head (microcephaly)
*Heart defects
*Low birth weights
*Behavioral problems


A genetic mutation causes PKU. The defective gene contains the instructions for making an enzyme needed to process the amino acid called phenylalanine. Amino acids are the building blocks for protein. In a person with PKU, this gene is defective, causing a complete or near-complete deficiency of the enzyme. Without the enzyme necessary to process phenylalanine, a dangerous buildup of this amino acid can develop when a person with PKU eats foods that are high in protein, such as milk, cheese, nuts or meats. This can eventually lead to serious health problems.
For a child to inherit PKU, both the mother and father must have and pass on the defective gene. This pattern of inheritance is called autosomal recessive. It’s possible for a parent to have the defective gene, but not have the disease. This is called being a carrier. Most often, PKU is passed down the family tree by parents who are carriers of the disorder, but don’t know it.

.For women affected with PKU, it is essential 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 mental retardation as a result.  PKU-affected women themselves are not at risk from 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 micromol/deciliter) 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 micromol/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 micromol/dL, anecdotal reports indicate the mothers may suffer 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.   Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep her Phe levels low. More research is needed. US scientist announced in June 2010 that they would be conducting a thorough investigation on the mutation of genes in the human genome. Their top priority is PKU, as it has become increasingly common, and sufferers often bear children who will be carriers of the recessive gene, and may themselves live past the age of sixty.
Risk factors:
Both parents must pass along a copy of the mutated PKU gene for their child to develop the condition. If only one parent has the PKU gene, there’s no risk of passing PKU to a child. The gene defect occurs mainly in people of Northern European and Native American ancestry. It’s much less common in blacks, Asians and Hispanics.

Children of mothers who have PKU but who didn’t follow the PKU diet during pregnancy also may be affected. Although these children don’t often have PKU, they do have consequences of the high level of phenylalanine in the mother’s blood.

PKU can be easily detected with a simple blood test. Most states require a PKU screening test for all newborns. The test is generally done with a heelstick shortly after birth.

If the initial screening test is positive, further blood and urine tests are required to confirm the diagnosis.

•The objective in diagnosing or treating the disorder is to prevent mental retardation.

•Serum phenylalanine levels greater than 4 mg/dl is abnormal, the normal values is 2 mg/dl. Significant brain damage usually occurs when levels are greater than 10 – 15 mg/dl


If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling Phe levels through diet, or a combination of diet and medication. Optimal health ranges (or “target ranges”) are between 120 and 360 µmol/L, and aimed to be achieved during at least the first 10 years. When Phe cannot be metabolized by the body, abnormally high levels accumulate in the blood and are toxic to the brain. When left untreated, complications of PKU include severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as ADHD.

All PKU patients must adhere to a special diet low in Phe for optimal brain development. “Diet for life” has become the standard recommended by most experts. The diet requires severely restricting or eliminating foods high in Phe, such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk and other dairy products. Starchy foods, such as potatoes, bread, pasta, and corn, must be monitored. 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, present in many diet foods and soft drinks, must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. As the child grows up these can be replaced with pills, formulas, and specially formulated foods. (Since Phe is necessary for the synthesis of many proteins, it is required for appropriate growth, but levels must be strictly controlled in PKU patients.) In addition tyrosine, which is normally derived from phenylalanine, must be supplemented.

The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in certain patients. The company BioMarin Pharmaceutical has produced a tablet preparation of the compound sapropterin dihydrochloride (Kuvan), which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges.[17] Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat. After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Some researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial to patients with PKU.

Several other therapies are currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). In the past, PKU-affected people were allowed to go off diet after approximately eight, then 18 years of age. Today, most physicians recommend PKU patients must manage their Phe levels throughout life.
The outlook depends on how early an infant with PKU is diagnosed and begins the special diet, as well as how strictly and consistently the diet is followed throughout life. Infants with PKU who are identified within the first few days after birth and are put on a strict diet before 3 weeks of age have the best prognosis and usually do not experience severe developmental delay or mental retardation.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose



One thought on “Phenylketonuria (PKU)

  1. Asianmart

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