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Phenylketonuria (PKU) is the most prevalent disorder caused by an inborn error in amino acid metabolism. Globally, the prevalence of PKU varies widely. It is the first human genetic disease to have effective programs for newborn screening and treatment. Phenylketonuria (PKU) is an autosomal recessive inherited metabolic disorder and is characterized by phenylalanine (Phe) accumulation mostly due to hepatic phenylalanine hydroxylase enzyme (PAH) deficiency, which converts Phe to tyrosine (Try), requiring the cofactor tetrahydrobiopterin (BH4), molecular oxygen and iron. BH4 is the essential cofactor for PAH, as well as for the metabolism of catecholamines, serotonin, and nitric oxide in the central nervous system (CNS). PKU is caused by over 1,000 different gene variants of PAH and the severity of the resulting disease ranges from mild to severe, based on the residual enzyme activity and the level of Phe circulating in the blood (blood Phe). At present, different mutations in the PAH gene located on chromosome 12 in the bands 12q22-q24 have been described.

A genetic disorder that causes build-up of phenylalanine and results in mental disability and abnormalities.


An infant born with phenylketonuria will develop normally for the first few months. If left untreated, symptoms begin to develop by three to six months of age. The natural history of untreated PKU consists of progressive irreversible neurological impairment during infancy and childhood. The most common outcome is severe intellectual disability often associated with a mousy” odor of the urine, breath and sweat, dry skin, eczema, rashes, light complexion with light or blonde hair, skin, and iris pigmentation. There is often growth retardation, microcephaly, and neurological signs including seizures and epilepsy. All untreated patients have behavioral problems including irritability, restlessness, hyperactivity, stereotypy, and anxiety. The severity of the clinical phenotype directly correlates with blood phenylalanine levels that reflect the degree of enzymatic deficiency.

Component comorbidities associated with PKU are myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, hemiplegia or paraplegia, dementia, chronic pulmonary disease, rheumatologic disease, peptic ulcer disease, diabetes without chronic complications, diabetes with chronic complications, renal disease, any malignancy (including leukemia and lymphoma), metastatic solid tumor, mild liver disease, moderate or severe liver disease, and acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV).



Phenylketonuria is diagnosed through a blood test, usually as part of the routine screening tests given to a newborn within the first few days of life. If PKU is present, the level of phenylalanine will be higher than normal in the blood. The test is highly accurate if done when the infant is more than 24 hours old but less than seven days old.


Newborn screening for PKU was initiated in the 1960′s in the U.S. after the development of an assay to detect blood Phe. Early detection by newborn screening can prevent intellectual disability if a PHE-restricted diet is started soon after birth. Since then, newborn screening and early initiation of treatment with a Phe-restricted diet and Phe-free medical foods have successfully prevented severe neurological and neurocognitive impairments. Current treatment guidelines, based upon available clinical research, indicate that individuals with PKU should maintain lifelong metabolic control  with blood Phe levels between 120 and 360 µmol/L which is typically achieved by strict adherence to a Phe-restricted diet and dietary supplementation with Phe-free amino acid fortified medical foods.


A PHE-restricted diet has been applied in patients with PKU for decades and during that time quality and diversity of the diet have improved. Current treatment for PKU involves life-long dietary restrictions in PHE excluding most protein-containing foods. The management of PKU comprises the reduction of dietary intake of Phe by low-protein diets and Phe-free amino acid supplements, and may include low-protein supplements/ foods. Medical foods are an essential component of this diet with the goal of maintaining blood PHE in the range of 120–360 μmol/L. Medical foods for PKU include essential tyrosine and varying quantities of carbohydrates, fat, vitamins, and minerals, and provide the amino acids needed for normal growth and development. Carbohydrate intake stimulates insulin secretion; this hormone increases protein synthesis by increasing amino acid transport into cells, so dietary inclusion of carbohydrates is essential for patients with PKU.

In patients with PKU, every 4-week delay in starting treatment results in a decline of approximately four intelligence quotient (IQ) points, reinforcing the fact that neurological damage  in PKU starts in the first few days after birth. Therefore, the organization of newborn screening and the referral to PKU centers is strongly recommended so that treatment is started no later than 10 days of age.

An experienced metabolic physician and nutritionist team should manage this therapy. It is important to monitor blood Phe and tyrosine (Tyr) levels and to ensure that other nutritional requirements are also being met. Overall, restriction of the intake of natural protein with supplementation of a Phe-free medical formula remains the cornerstone of PKU management.

Glycomacropeptide (GMP) foods provide an alternative to amino acid (AA) formula that may improve bone health, and BH4 permits some individuals with PKU to increase tolerance to dietary phe. Emerging therapeutic approaches are currently in preclinical and clinical trials which include enzyme therapy with PAH enzyme substitution with phe ammonia lyase joined with polyethylene glycol, hepatocyte repopulation, and gene therapy. The future holds promise for new options to allow PKU patients to liberalize their diet and still improve lifelong metabolic control.


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