Back to METABOLIC DISORDERSHyperphenylalaninemias result from impaired conversion of phenylalanine to tyrosine. Phenylketonuria is the most common and clinically important disease of this group. It is characterized by severe mental retardation and increased concentration of phenylalanine in blood and urine. In the latter, metabolites of phenylalanine are also found.
Pathogenesis
Phenylalanine is converted to tyrosine by an enzime complex called phenylalanine hydroxylase, which is completely expressed, in humans, in the liver only. Therefore, phenylalanine and oxygen are substrates for the enzime, which requires a reduced pteridine, tetrahydrobiopterin (THBT), as a cofactor. Tyrosine and dihydrobiopterin (DHBT) are the end products of this reaction. DHBT is reconverted to THBT by a second enzime, dihydropteridine reductase. In classic phenylketonuria, activity of hydrxylase apoenzime is almost totally deficient. Six mutations in the gene which expresses the enzime are responsible for its reduced activity, including missense changes, splicing defects and partial deletions. There are other forms, although uncommon, of hyperphenylalaninemias. Benign hyperphenylalaninemias result from two mechanisms: (1) a partial deficiency of expression of the enzime complex or (2) from delayed maturation of the hydroxylase apoenzime. The latter form is called transient phenylketonuria. Another form, malignant hyperphenylalaninemia, result from a lack of THBT, due to defects in its synthesis and deficiency of dihydropteridine reductase. In these cases, persistently impaired hydroxylating activity occurs, but in presence of normal phenylalanine hydroxylase.
The consequences of impaired hydroxylating activity are phenylalanine accumulation in blood and reduced tyrosine formation. In classic untreated phenylketonuria and its malignant (THBT deficient) forms, phenylalanine plasma concentration higher than 20 mg/dl occurs, which in turn activate alternate pathways of phenylalanine metabolism, leading to formation of metabolites like phenylacetate, phenylpiruvate, phenyllactate and others. Plasma concentrations of several other amino acids are moderately reduced, probably secondary to inhibition of gastrointestinal absortion or inhibition of renal tubular reabsortion by the excess phenylalanine in blood fluids. The severe brain damage appears to be related to phenylalanine accumulation in CNS, which leads to (1) inhibition of transport of other amino acids required for neuronal protein synthesis, (2) impaired polyribossome formation or stabilization, (3) reduced myelin synthesis and (4) inadequate formation of norepinephrine and serotonin. Besides, phenylalanine inhibits competitively tyrosinase, a key enzime for melanin synthesis. This block plus reduction of tyrosine synthesis account for hypopigmentation of hair and skin.
Hyperphenylalaninemias occur in 1 in 10,000 births. Classic phenylketonuria accounts for two thirds of them. It is an autossomal recessive disease, widely distributed among whites and orientals. It is rare in blacks. Heterozygous carriers are clinically assymptomatic, but may have slightly increased plasmatic phenylalanine concentration. The other hyperphenylalaninemias are also autossomal recessive diseases.
No abnormalities are present at birth. Children with classic phenylketonuria experiments progressive impairment of cerebral function, seizures and hyperactivity. Abnormalities on the EEG, mousy odor of the skin, hair and urine (due to phenylacetate accumulation), tendency to hypopigmentation and eczema complete the terrible clinical picture. Children with the transient phenylketonuria and with the benign form do not usually show the clinical consequences of untreated classic phenylketonuria. Those children with THBT deficiency have the worst prognostic, since seizures appears earlier in the course of the disease, followed by progressive cerebral and basal ganglia dysfunction, which includes signs and symptons like rigidity, chorea, spasms and hypotonia. Most die from secondary infection within a few years despite of treatment.
Women with phenylketonuria who have been treated since infancy are now becoming pregnant. More than 90% of their offspring are markedly retarded, may have congenital abnormalities such as microcephaly, growth retardation and heart defects. Since these children are heterozygous, most of the abnormalities are due to intrauterin exposition to high phenylalanine concentrations. This syndrome is called maternal phenylketonuria.
To prevent the development of mental retardation, diagnosis must be done and dietary therapy must be started before the child is 30 days of age. There are screening determinations of blood phenylalanine concentrations through the guthrie bacterial inhibition assay. Infants with high values are followed up with more quantitative assays (fluorimetric and chromatographic). In classic phenylketonuria and THBT deficiency values of plasmatic phenylalanine greater than 20 mg/dl are observed. In transient phenylketonuria and the benign variant, values are lower but above the control value (1 mg/dl). In transient phenylketonuria, values return to normal within 3 to 4 months. In the benign variant , dietary therapy produces a more profound fall in plasma phenylalanine than that seen in classic phenylketonuria. THBT deficiency must be considered in any child who experiments progressive mental retardation despite dietary therapy. There is a sharp fall in plasma phenylalanine when THBT is given to these children, and no chemical response in children with classic phenylketonuria.
Dietary therapy is accomplished by a special diet in which the bulk of protein is substituted for an artificial amino acid mixture low in phenylalanine. Some natural foods should supplement this diet and, as a consequence, an amount of phenylalanine is provided so that growth is not prejudicated and tolerable levels of phenylalanine in blood result. Plasma phenylalanine are usually mantained between 3 and 12 mg/dl.
The diet must start in the first month of life and should be continued indefinetly, to be maximally effective. Despite these efforts, modest nervous system dysfunction is often seen. The transient and benign forms do not need long-term dietary restrictions. Patients with THBT deficiency do not benefit from phenylalanine restriction, as mentioned earlier. However, they may be helped by a combined regimen which includes phenylalanine restriction with supplements of levodopa and 5-hydroxy-tryptophan.
In maternal phenylketonuria, the clinical consequences may be minimized by instituting dietary phenylalanine restriction prior to conception and continuing such treatment throghout gestation.
Rosenberg L E: Inherited disorders of amino acid metabolism, in Harrisonīs Principles of Internal Medicine, 12th ed. New York, McGraw-Hill, 1991, pp 1869-1873.
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