When phenylalanine (Phe) cannot be metabolized by the body, a typical diet that would be healthy for people without<unk>  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<unk>  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<unk>  Classical<unk> , and its less severe forms "mild<unk> " 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<unk>  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<unk>  <unk>  and mild hyperphenylalaninemia (also known as "hyperphe" or "mild HPA"), a less severe accumulation of phenylalanine. Compared to classic<unk>  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<unk>  affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological problems associated with<unk> . 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<unk>  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 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 who suffer from 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<unk>  (without dihydrobiopterin involvement), prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four genes. They are known as HPABH4A, HPABH4B, HPABH4C, and HPABH4D. Metabolic pathways Pathophysiology of<unk> , 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.
Phenylketonuria
Hawkinsinuria
Homocystinuria
Alkaptonuria
3-Methylglutaconic aciduria
2-Hydroxyglutaric aciduria
Alpha-aminoadipic and alpha-ketoadipic aciduria
Aspartylglucosaminuria