NORD gratefully acknowledges Paldeep S. Atwal, MD, FACMG, FRCP(UK), FRCP(Glasg), Clinical & Biochemical Geneticist, Director, The Atwal Clinic: Genomic & Personalized Medicine, for assistance in the preparation of this report.
Phenylketonuria (PKU) is an inborn error of metabolism that is detectable during the first days of life with appropriate blood testing (routine newborn screening). PKU is characterized by absence or deficiency of an enzyme (phenylalanine hydroxylase) that is responsible for processing the essential amino acid phenylalanine. (Amino acids, the chemical building blocks of proteins, are essential for proper growth and development.) With normal enzymatic activity, phenylalanine is converted to another amino acid (tyrosine), which is then utilized by the body. However, when the phenylalanine hydroxylase enzyme is absent or deficient, phenylalanine abnormally accumulates in the blood. These increased levels of phenylalanine are toxic to brain tissue.
Symptoms associated with PKU are typically absent in newborns. Affected infants may be abnormally drowsy and listless (lethargic) and have difficulties feeding. In addition, untreated infants with PKU tend to have unusually light eyes, skin, and hair (light pigmentation) and may develop a rash that appears similar to eczema, an inflammatory skin condition that may be characterized by itching, redness, and blistering in affected areas.
Without treatment, most infants with PKU develop intellectual disability that is typically severe. Those with untreated PKU may also develop additional neurologic symptoms, such as episodes of uncontrolled electrical activity in the brain (seizures), abnormally increased activity (hyperactivity), poor coordination and a clumsy manner of walking (gait), abnormal posturing, aggressive behavior, or psychiatric disturbances. Additional symptoms and findings may include nausea, vomiting, and a musty or "mousy" body odor due to the presence of a by-product of phenylalanine (phenylacetic acid) in the urine and sweat.
To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life. Most experts recommend that a phenylalanine-restricted diet should be life-long in persons with classical PKU. Classical PKU refers to persons with 2 severe pathogenic variants of the phenylalanine hydroxylase gene.
Infants with PKU typically appear normal at birth. With early screening and diet treatment, affected individuals may never show symptoms of PKU. However, untreated newborns with this disorder who are not diagnosed in the first days of life may be weak and feed poorly. Other symptoms of PKU may include vomiting, irritability, and/or a red skin rash with small pimples (eczematoid). These infants with this disorder generally have a musty or “mousy” body odor caused by phenylacetic acid in the urine and/or perspiration.
If children with PKU are not treated, developmental delay may be obvious at several months of age. The average IQ of untreated children is usually less than 50. High levels of phenylalanine interfere with a chemical in the body that is responsible for maintaining pigmentation (melanin). Therefore, affected children usually have a fair complexion and light hair. Symptoms of autism are not uncommon in untreated persons.
Neurological symptoms are present in only some patients with PKU and may vary greatly. Seizures occur in about 25 percent of older children and abnormalities appear on brain wave tests (EEG) in 80 percent of patients. Jerky muscle movements (spasticity), abnormally tight muscles (hypertonicity), and/or increased deep tendon reflexes are among the most frequent neurological symptoms. About 5 percent of children with symptoms of PKU become physically disabled. Slow writhing movements, involuntary muscle movements, and tremors occur in some cases.
Untreated females with this disorder often have spontaneous abortions or fetal growth delays (intrauterine growth retardation). Children of women with PKU may have an abnormally small head (microcephaly) and/or congenital heart disease, and a variety of facial abnormalities. There is a strong relationship between the severity of these symptoms and high levels of phenylalanine in the mother. As a result, all women with PKU who have stopped treatment should return to the diet before conception and continue on the diet throughout any pregnancy. This dietary management should be closely monitored by a metabolic geneticist and metabolic dietitian.
PKU is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
More than 300 different changes (mutations) in the PKU gene have been identified. Because the different mutations result in varying degrees of elevation in blood phenylalanine, the diet of each child must be adjusted to the individual tolerance for the amino acid. Laboratory tests in infants with PKU typically confirm plasma levels of phenylalanine that are ten to 60 times above normal levels.
The symptoms of PKU develop because of a defective liver enzyme, phenylalanine hydroxylase. This enzyme enables phenylalanine to be metabolized into tyrosine. Intellectual disability in PKU is a direct result of elevated levels of phenylalanine in the brain which causes the destruction of the fatty covering (myelin) of individual nerve fiber in the brain. It can also cause depression by reducing the levels of dopamine and serotonin in the brain.
PKU is a rare disorder that affects males and females in equal numbers. The reported incidence of PKU from newborn screening programs ranges from one in 13,500 to 19,000 newborns in the United States. The incidence varies in other parts of the world. PKU affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry.
Newborn screening for PKU is required by law in the United States and in most hospitals in developed countries. The test requires a drop of blood taken from the baby’s heel. It is also possible to detect if a child is carrying a single abnormal gene that causes PKU (heterozygotes).
The goal of treatment for PKU is to keep plasma phenylalanine levels within 120-360 umol/L (2-6 mg/dL). This is generally achieved through carefully planned and monitored diet. Limiting the child’s intake of phenylalanine must be done cautiously because it is an essential amino acid. A carefully maintained diet can prevent intellectual disability as well as neurological, behavioral, and dermatological problems. Treatment must be started at a very young age (under 3 months), or some degree of intellectual disability may be expected. However, even some late-treated children have done quite well. Studies have repeatedly demonstrated that children with PKU who are treated with a low phenylalanine diet before the age of three months do well, with an IQ in the normal range.
If people with PKU stop controlling their dietary intake of phenylalanine, neurological changes usually occur. IQs may decline. Other problems that may appear and become severe once dietary regulation is stopped include difficulties in school, behavioral problems, mood changes, poor visual-motor coordination, poor memory, poor problem-solving skills, fatigue, tremors, poor concentration, and others such as depression.
After years of controversy, there now is nearly universal acceptance among clinicians treating PKU that the diet needs to be continued indefinitely. Also, many clinicians believe that adults with PKU who stopped the diet in childhood or beyond need to return to the diet. Many young adults have restarted the diet and found improvement in mental clarity as a result of lowered blood phenylalanine levels.
A Consensus Panel convened by the National Institutes of Health (NIH) in October 2000 concluded that it is important for people affected by PKU to adhere to the special diet beyond childhood. In a statement issued at the conclusion of its three-day meeting, the panel noted that dietary control of PKU is one component of a lifelong treatment program that should include regular blood tests and regular visits to a PKU clinic.
Because phenylalanine occurs in practically all natural proteins, it is impossible to adequately restrict the diet using natural foods alone without compromising health. For this reason, special phenylalanine-free food preparations are helpful. There are a number of phenylalanine-free formulas available in the U.S. and in other countries. Foods high in protein, such as meat, milk, fish and cheese are typically not allowed on the diet. Naturally low protein foods such as fruits, vegetables, and some cereals are allowed in limited quantities.
If the intake of phenylalanine is too severely limited in people with PKU, vitamin B-12 deficiency and symptoms of phenylalanine deficiency may develop. These may include fatigue, aggressive behavior, severe loss of appetite (anorexia), and sometimes low iron levels in the blood (anemia). Plasma levels of phenylalanine must be monitored regularly.
In very rare instances, abnormally high levels of phenylalanine may also be caused by a deficiency of tetrahydrobiopterin because of insufficient amounts of either biopterin, an enzyme cofactor, or the enzyme dihydropteridine reductase. Tetrahydrobiopterin is involved in the production of chemicals in the brain (neurotransmitters) such as serotonin, dopamine, and norepinephrine. Low levels of these neurotransmitters could account for the progressive neurological deterioration of children with Tetrahydrobiopterin deficiency, in spite of controlled plasma phenylalanine. (For more information on Tetrahydrobiopterin deficiency, see the Related Disorders section of this report.)
In 2007, Kuvan (sapropterin hydrochloride) was approved by the U.S. Food and Drug Administration (FDA) to treat PKU. Kuvan reduces blood Phe levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin (BH4-) responsive PKU. Kuvan is a pharmaceutical formulation of BH4, the natural cofactor for the PAH enzyme, which stimulates activity of the residual PAH enzyme to metabolize Phe into tyrosine. Kuvan is to be used in conjunction with a Phe-restricted diet. Kuvan is manufactured by BioMarin Pharmaceutical Inc.
In 2018, Palynziq (pegvaliase-pqpz) was approved by the FDA for adults with PKU. Palynziq is an enzyme therapy for patients who have uncontrolled blood Phe concentrations on current treatment. Palynziq is manufactured by BioMarin Pharmaceutical Inc.
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