What is Phenylalanine Hydroxylase Deficiency? Phenylalanine hydroxylase deficiency (PAH deficiency), also called phenylketonuria (PKU), is an inherited disease in which the body cannot properly process the amino acid phenylalanine due to a deficient enzyme called phenylalanine hydroxylase. PAH deficiency is caused by mutations in the PAH gene. Phenylalanine is found in proteins and some other foods. If individuals with PAH deficiency do not get treatment, phenylalanine can accumulate to harmful levels, which can cause irreversible intellectual disability, seizures, developmental delay, and behavioral problems. PAH deficiency causes a spectrum of disorders ranging from severe to nearly asymptomatic. The severity depends on the level of phenylalanine in the blood. It can be difficult to predict how severely affected a child will be based on the particular genetic mutations they carry. Children with any form of PAH deficiency should be evaluated by a specialist immediately after birth. Classic Form Classic PAH deficiency is the most common and severe form. Individuals with classic PAH deficiency produce little to no phenylalanine hydroxylase and are at risk for accumulating high levels of phenylalanine in their blood. If PAH deficiency is not promptly diagnosed and treated with a special diet, intellectual disability will occur, along with a number of other symptoms including a small head, seizures, behavioral problems, a "mousy" or "musty" odor, abnormal gait, low bone density, and red, itchy skin (eczema). These are all avoidable if the proper diet is instituted shortly after birth and maintained throughout the lifespan. Mild Forms Individuals who produce higher amounts of phenylalanine hydroxylase may have milder forms of PAH deficiency but are still at risk of developing the symptoms associated with classic PAH deficiency. Other names for the mild form include variant PKU or non-PKU hyperphenylalaninemia. Though the symptoms may be milder, there is still a risk for impaired mental development if the child's intake of phenylalanine is not monitored. Some individuals with mild PAH deficiency are able to tolerate a normal diet and do not require treatment. This will vary from person to person and must be determined by a medical professional based on the levels of phenylalanine in the person’s blood. How Common is Phenylalanine Hydroxylase Deficiency? The prevalence of PAH deficiency is 1 in 10,000 in Caucasians, and it is more common in individuals of Turkish and Irish descent. How is Phenylalanine Hydroxylase Deficiency Treated? The degree of enzyme deficiency varies among people with PAH deficiency, and therefore the treatment must also be individualized based on the levels of phenylalanine in the blood. An infant with any form of PAH deficiency should be evaluated immediately after birth to determine whether or not he or she requires treatment. A blood test can reveal the amount of functioning phenylalanine hydroxylase in the body, and this will indicate the amount of phenylalanine the person can safely consume. While individuals with classic PAH deficiency must adhere to a strict low-phenylalanine diet, others with milder forms can safely consume small amounts of the amino acid, and for some, treatment may not even be necessary. Generally speaking, a diet low in protein and free from phenylalanine is important in preserving mental function in a person with classic PAH deficiency. Phenylalanine-free formulas are available for infants. Maintaining appropriate levels of phenylalanine in the brain can be achieved through blood testing and diet adjustment. This must be closely supervised by medical professionals. In most cases, this special diet must be maintained for life. Individuals with any form of PAH deficiency should avoid consuming aspartame, an artificial sweetener containing phenylalanine. Women with PAH deficiency who become pregnant must be particularly careful to maintain safe levels of phenylalanine in their bodies to avoid birth defects in their children. Ideally, this begins prior to conception. In late 2007, the medication sapropterin dihydrochloride (brand name: Kuvan) was approved by the FDA to treat patients with PAH deficiency. For some patients, it can enhance the activity of the deficient enzyme and lower levels of phenylalanine in the body, allowing for a relaxation of the dietary restrictions. Some individuals with the disease do not respond to the drug; however, those who do respond to this treatment usually have milder forms of the disease. What is the Prognosis for a Person with Phenylalanine Hydroxylase Deficiency? If an individual with PAH deficiency is treated early and consistently, the prognosis can be excellent. Many with PAH deficiency have gone on to lead normal lives with normal intelligence and a normal lifespan. If treatment does not begin early or is not adequately maintained, a person with a more severe form of PAH deficiency is at risk for severe and irreversible brain damage. Individuals with mild forms of PAH deficiency may lead a normal life without treatment. Other names forphenylalanine hydroxylase deficiency Folling disease Hyperphenylalaninemia Oligophrenia phenylpyruvica Phenylalaninemia Phenylketonuria References Mitchell et al., 2011, Genet Med, 13(8):697-707, PMID: 21555948 Online Mendelian Inheritance in Man, OMIM , 2016, http://www.omim.org/261600 Regier et al., 2017, https://www.ncbi.nlm.nih.gov/books/NBK1504/ Scriver, 2007, Hum Mutat, 28(9):831-45, PMID: 17443661 Vockley et al., 2014, Genet Med, 16(2):188-200, PMID: 24385074 Resources Genetics Home Reference Explanations of an extensive number of genetic diseases written for everyday people by the U.S. government's National Institutes of Health.. National PKU News A website founded and run by a dietician specializing in PKU, the National PKU News provides up-to-date, accurate news and information to families and professionals dealing with the disease. Address: National PKU News PO Box 43552 Montclair, NJ 07043 Phone: (973) 619-9160 March of Dimes The nation's leading nonprofit, the March of Dimes, publishes a fact sheet on PKU, dedicated to improving the health of babies by reducing birth defects, premature birth, and infant mortality. Address: 1275 Mamaroneck Avenue White Plains, NY 10605 Phone: 914-997-4488 (national office) Children's PKU Network A nonprofit group focused on educating the public about PKU and supporting children with the disease. Address: 3790 Via de la Valle, Suite 120 Del Mar, CA 92014 Phone: (858) 756-0079 (858) 509-0767 National Human Genome Research Institute A division of the National Institutes of Health that is well-known for having mapped the human genome. This page on PKU has information about the disease as well as links to numerous other PKU-related organizations.