Phenylketonuria presents one of the most dramatic examples of how the relationship between genotype and phenotype can depend on environmental variables. Phenylketonuria was very first recognized as an inherited cause of mental retardation in 1934, and systematic attempts to deal with the situation were initiated within the 1950s.
The term "phenylketonuria" denotes increased amounts of urinary phenylpyruvate and phenylacetate, which occur when circulating phenylalanine amounts, usually in between 0.06 and 0.one mmol / L, rise above one.a couple of mmol / L. Therefore, the primary defect in phenylketonuria is hyperphenylalaninemia, which by itself has a number of distinct genetic causes. The pathophysiology of phenylketonuria illustrates a number of essential principles in human genetics.
Hyperphenylalaninemia by itself is caused by substrate accumulation, which happens when a regular intermediary metabolite fails to become eliminated correctly and its concentrations turn out to be increased to levels that are toxic. As described later on, one of the most common trigger of hyperphenylalaninemia is deficiency of the enzyme phenylalanine hydroxylase, which catalyzes the conversion of phenylalanine to tyrosine.
People with mutations in phenylalanine hydroxylase generally do not endure from your absence of tyrosine simply because this amino acid could be supplied to the body by mechanisms which are independent of phenylalanine hydroxylase. In other types of phenylketonuria, nevertheless, extra disease manifestations happen like a result of end-product deficiency, which occurs when the downstream product of the specific enzyme is required for a key physiologic procedure.
A discussion of phenylketonuria also helps to illustrate the rationale for, and application of, population-based screening applications for genetic disease. More than 10 million newborn infants per year are tested for phenylketonuria, and also the focus today in treatment has shifted in several respects. Very first, "successful" remedy of phenylketonuria by dietary restriction of phenylalanine is, in basic, accompanied by subtle neuropsychologic defects that happen to be acknowledged only in the last decade.
Therefore, existing investigations concentrate on alternative treatment methods such as somatic gene therapy as nicely as on the social and psychologic elements that affect compliance with dietary management. Second, a generation of females handled for phenylketonuria are now bearing kids, and the phenomenon of maternal phenylketonuria has been recognized by which in utero exposure to maternal hyperphenylalaninemia outcomes in congenital abnormalities regardless of fetal genotype.
The quantity of pregnancies at danger has risen in proportion towards the profitable treatment of phenylketonuria and represents a challenge to public wellness officials, physicians, and geneticists in the future. The incidence of hyperphenylalaninemia varies among various populations. In African Americans, it is about 1: 50,000; in Yemenite Jews, about 1: 5000; and in most Northern European populations, about 1: 10,000.
Postnatal growth retardation, moderate to severe mental retardation, recurrent seizures, hypopigmentation, and eczematous skin rashes constitute the main phenotypic features of untreated phenylketonuria. However, using the advent of widespread newborn screening applications for hyperphenylalaninemia, the major phenotypic manifestations of phenylketonuria these days occur when remedy is partial or when it's terminated prematurely throughout late childhood or adolescence.
In these cases, there's generally a slight but significant decline in IQ, an array of particular overall performance and perceptual defects, and an increased frequency of learning and behavioral problems. New child screening for phenylketonuria is carried out on the little amount of dried blood obtained at 24-72 hours of age.
From your initial screen, there is about a 1% incidence of positive or indeterminate test outcomes, and aa lot more quantitative measurement of plasma phenylalanine is then performed prior to a couple of weeks of age. In neonates who undergo a 2nd round of testing, the diagnosis of phenylketonuria is ultimately confirmed in about 1%, providing an estimated phenylketonuria prevalence of one: 10,000, even though there is great geographic and ethnic variation (see prior discussion).
The false-negative rate of phenylketonuria newborn screening applications is around one: 70; phenylketonuria in these unfortunate people is generally not detected until developmental delay and seizures throughout infancy or early childhood prompt a systematic evaluation for an inborn error of metabolism.
Infants in whom a diagnosis of phenylketonuria is confirmed are generally placed on a dietary regimen by which a semisynthetic formula low in phenylalanine could be combined with regular breast feeding. This regimen is adjusted empirically to maintain a plasma phenylalanine concentration at or beneath 1 mmol / L, which can be nevertheless several times greater than regular but similar to levels observed in so-called benign hyperphenylalaninemia, a biochemical diagnosis which can be not associated with phenylketonuria and has no clinical consequences.
Phenylalanine is definitely an essential amino acid, and even people with phenylketonuria should consume little amounts to prevent protein starvation plus a catabolic state. Most kids need 25-50 mg / kg / d of phenylalanine, and these needs are met by combining organic foods with commercial products created for phenylketonuria treatment.
When nutritional treatment applications were very first implemented, it was hoped that the risk of neurologic damage from your hyperphenylalaninemia of phenylketonuria would have a restricted window and that treatment could be stopped after childhood. However, it now seems that even mild hyperphenylalaninemia in adults (> one.a couple of mmol / L) is associated with neuropsychologic and cognitive deficits; therefore, nutritional remedy of phenylketonuria should most likely be continued indefinitely.
As an increasing quantity of handled females with phenylketonuria reach childbearing age, a new problem-fetal hyperphenylalaninemia by way of intrauterine exposure-has turn out to be apparent. New child infants in this kind of cases exhibit microcephaly and growth retardation of prenatal onset, congenital heart disease, and extreme developmental delay irrespective from the fetal genotype.
Rigorous control of maternal phenylalanine concentrations from before conception until birth reduces the incidence of fetal abnormalities in maternal phenylketonuria, however the level of plasma phenylalanine that is "safe" for a developing fetus is 0.12-0.36 mmol / L-significantly lower than what is regarded acceptable for phenylketonuria-affected children or adults on phenylalanine-restricted diets.
The regular metabolic fate of free of charge phenylalanine is incorporation into protein or hydroxylation by phenylalanine hydroxylase to type tyrosine. Because tyrosine, but not phenylalanine, can be metabolized to create fumarate and acetoacetate, hydroxylation of phenylalanine can be viewed both like a signifies of producing tyrosine a nonessential amino acid and as a mechanism for offering energy by way of gluconeogenesis during states of protein starvation.
In individuals with mutations in phenylalanine hydroxylase, tyrosine becomes an important amino acid. Nevertheless, the clinical manifestations from the disease are caused not by absence of tyrosine (most people get enough tyrosine within the diet in any situation) but by accumulation of phenylalanine.
Transamination of phenylalanine to form phenylpyruvate usually does not happen unless circulating concentrations exceed one.a couple of mmol / L, however the pathogenesis of CNS abnormalities in phenylketonuria is related more to phenylalanine by itself than to its metabolites.
In addition to a direct effect of elevated phenylalanine levels on power production, protein synthesis, and neurotransmitter homeostasis within the developing brain, phenylalanine can also inhibit the transport of neutral amino acids across the blood-brain barrier, leading to a selective amino acid deficiency in the cerebrospinal fluid.
Therefore, the neurologic manifestations of phenylketonuria are felt to become due to a basic effect of substrate accumulation on cerebral metabolism. The pathophysiology of the eczema seen in untreated or partially treated phenylketonuria is not nicely understood, but eczema is really a common function of other inborn errors of metabolism by which plasma concentrations of branched-chain amino acids are elevated.
Hypopigmentation in phenylketonuria is most likely caused by an inhibitory effect of excess phenylalanine about the production of dopaquinone in melanocytes, which can be the rate-limiting step in melanin synthesis. Approximately 90% of infants with persistent hyperphenylalaninemia detected by new child screening have standard phenylketonuria brought on by a defect in phenylalanine hydroxylase (see later on discussion).
From the remainder, most have benign hyperphenylalaninemia, by which circulating levels of phenylalanine are in between 0.1 mmol / L and one mmol / L. Nevertheless, around 1% of infants with persistent hyperphenylalaninemia have defects in the metabolic process of tetrahydrobiopterin (BH4), which is a stoichiometric cofactor for the hydroxylation reaction.
Unfortunately, BH4 is required not just for phenylalanine hydroxylase but also for tyrosine hydroxylase and tryptophan hydroxylase. The items of these latter two enzymes are catecholaminergic and serotonergic neurotransmitters; thus, people with defects in BH4 metabolism endure not just from phenylketonuria (substrate accumulation) but additionally from absence of essential neurotransmitters (end-product deficiency).
Impacted individuals develop a severe neurologic disorder in early childhood manifested by hypotonia, inactivity, and developmental regression and are handled not only with nutritional restriction of phenylalanine but also with nutritional supplementation with BH4, dopa, and 5-hydroxytryptophan.