phenylketonuria phenylketonuria phenylketonuria (pku) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. untreated pku can lead to intellectual disability, seizures, behavioral problems, and mental disorders. 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, and low birth weight. phenylketonuriaother namesphenylalanine hydroxylase deficiency, pah deficiency, følling diseasephenylalaninespecialtymedical genetics, pediatrics, dieteticssymptomswithout treatment intellectual disability, seizures, behavioral problems, mental disorders, musty odorusual onsetat birthtypesclassic, variantcausesgenetic (autosomal recessive)diagnostic methodnewborn screening programs in many countriestreatmentdiet low in foods that contain phenylalanine; special supplementsmedicationsapropterin dihydrochloride, pegvaliaseprognosisnormal health with treatmentfrequency~1 in 12,000 newborns phenylketonuria is an inherited genetic disorder. it is caused by mutations in the pah gene, which can result in inefficient or nonfunctional phenylalanine hydroxylase, an enzyme responsible for the metabolism of excess phenylalanine. this results in the buildup of dietary phenylalanine to potentially toxic levels. it is autosomal recessive, 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 programs 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 with a small amount of breast milk. 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 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, with the importance of diet determined in 1935. gene therapy, while promising, requires a great deal more study as of 2014. signs and symptoms abnormally small head (microcephaly) untreated pku can lead to intellectual disability, seizures, behavioral problems, and mental disorders. 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, and low birth weight. 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 seizures, hypopigmentation (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, eeg abnormalities, and seizures, and severe learning disabilities are major clinical problems later in life. a characteristic "musty or mousy" odor on the skin, as well as a predisposition for eczema, 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 phenylketonuria is inherited in an autosomal recessive fashion pku is an autosomal recessive metabolic genetic disorder. as an autosomal recessive disorder, two pku alleles 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 or compound heterozygous mutations 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 (tyr). when pah activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine. 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. 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 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. 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, 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 phenylalanine hydroxylase (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 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 (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, causing intellectual disability. 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. 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 diseases, such as alzheimer's disease and parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine. tetrahydrobiopterin-deficient hyperphenylalaninemia main article: tetrahydrobiopterin deficiency a rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency, which occurs when the pah enzyme is normal, and a defect is found in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (bh4). bh4 is necessary for proper activity of the enzyme pah, and this coenzyme 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 can be used to distinguish between these two types. tetrahydrobiopterin is required to convert phe to tyr and is required to convert tyr to l-dopa via the enzyme tyrosine hydroxylase. l-dopa, in turn, is converted to dopamine. low levels of dopamine lead to high levels of prolactin. 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 pathophysiology of phenylketonuria, which is due to the absence of functional phenylalanine hydroxylase (classical subtype) or functional enzymes for the recycling of tetrahydrobiopterin (new variant subtype) utilized in the first step of the metabolic pathway. the enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. 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 pathway with glutamate. metabolites include phenylacetate, phenylpyruvate and phenethylamine. 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 blood is taken from a two-week-old baby to test for phenylketonuria pku is commonly included in the newborn screening 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), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (ms/ms). measurements done using ms/ms determine the concentration of phe and the ratio of phe to tyrosine, 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, egg whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, legumes, and lowfat cottage cheese. starchy foods,