Hyperphenylalaninemia: Description, Causes and Risk Factors:
The presence of abnormally high blood levels of phenylalanine, which may or may not be associated with elevated tyrosine levels, in newborn infants (premature and full-term), associated with the heterozygous state of phenylketonuria, maternal phenylketonuria, or transient deficiency of phenylalanine hydroxylase or p-hydroxyphenylpyruvic acid oxidase.
Hyperphenylalaninemia is the most frequently inherited disorder of amino acid metabolism (prevalence 1:10,000). In France, a nationwide neonatal screening was organized in 1978 to control its efficacy and patient follow-up.
Hyperphenylalaninemia are a group of inherited diseases due to defective phenylalanine hydroxylase (PAH) activity resulting in accumulation of phenylalanine in blood and other tissues. In most cases, HPA results from mutations in the phenylalanine hydroxylase gene. The associated phenotypes range in severity from classic phenylketonuria (PKU) to mild HPA. The remaining cases arise due to a block in the metabolism of the cofactor tetrahydrobiopterin (BH4). BH4 is also the cofactor required for conversion of tyrosine and tryptophan into catecholamine and serotonin. Thus, disorders related to defective metabolism of BH4 could be considered as neurotransmitter diseases.
Hyperphenylalaninemia is caused by defects in the gene that encodes the enzyme phenylalanine hydroxylase, impairing the conversion of phenylalanine to tyrosine. Defects in the same gene also result in classic PKU. Broad genotype/phenotype correlations have been made (i.e., mild or hyperphenylalaninemia alleles vs severe or PKU alleles), although phenylalanine tolerance may vary in unrelated individuals with identical mutations. A small percentage of individuals with elevated phenylalanine levels have normal phenylalanine hydroxylase activity but lack tetrahydrobiopterin, a crucial cofactor.
Most individuals with hyperphenylalaninemia have normal life expectancy. Several studies have identified a linear relationship between the phenylalanine level and intelligence testing and performance. Intelligence quotients seem less affected by benign hyperphenylalaninemia than by PKU, even at seemingly the same levels of serum phenylalanine. This effect may be due to smaller fluctuations of serum phenylalanine concentration.
Approximately 1 in 10,000 neonates born with PKU or milder forms of HPA are identified in the neonatal period through population-screening programs that have been implemented in various countries to treat affected children as early as possible
The signs and symptoms of HPA vary from mild to severe. General symptoms may include:
Delayed mental and social skills.
- Head size significantly below normal.
- Jerking movements of the arms or legs.
- Mental retardation.
- Skin rashes.
- Unusual positioning of hands.
In the neonatal period, presumably due to hyperphenylalaninemia, hypotonia, poor suck, diminished movements, and microcephaly may be present. Generally, beginning several months later, more monoaminergic symptoms appear, including autonomic symptoms (hypersalivation, temperature instability, excessive diaphoresis, and blood pressure lability), oculogyric crises, swallowing difficulties, variable hypokinetic and hyperkinetic movements, seizures, and cognitive impairment.These patients can be detected by neonatal screening for phenylketonuria (PKU).
HPA can be easily detected with a simple blood test. All states in the US require a HPA screening test for all newborns as part of the newborn screening panel. The test is generally done by taking a few drops of blood from the baby before the baby leaves the hospital. If the initial screening test is positive, further blood and urine tests are required to confirm the diagnosis.
Measure plasma phenylalanine and tyrosine levels as soon as possible after an abnormal screening result. An elevated phenylalanine level with low or normal tyrosine level is expected. Remember that patients with liver disease or tyrosinemia typically have elevated phenylalanine and tyrosine levels.
Obtain blood and urine biopterins assays through a qualified laboratory to exclude a tetrahydrobiopterin defect.
Serial monitoring of blood phenylalanine levels (weekly for the first 2 or 3 y of life declining to monthly by the age of 7-8 years) is an essential element of treatment. The choice of therapeutic ranges for blood levels and the duration of diet are still a matter of debate. However, in children <10 years of age, it is universally admitted that the blood phenylalanine levels should be kept between 2 and 5 mg/dL (120-300 ?mol/L). Life-long dietary treatment is quite universally recommended but because of the practical difficulties involved in sustaining a strict diet, many clinics allow a relaxation at some point between adolescence and adulthood. In France, it is recommended to keep the blood phenylalanine levels between 2 and 15 mg/dL (120-600 ?mol/L) until the age of 15-18 y and below 20 mg/dL (1200 ?mol/L) thereafter.
Such a restrictive diet poses nutritional risks and psychological burden that must be monitored by experienced teams that would regularly evaluate the clinical and biological status of patients and offer educational and psychological support. Whatever the decision regarding the diet discontinuation, sustained follow-up is essential for the affected females who are at risk for hyperphenylalaninemia.
Animal studies are underway for injectable phenylamine ammonium lyase, an enzyme substitute. This shows promise as an alternative treatment to control phenylalanine levels.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.