The cardinal clinical feature is mental retardation. The patients are asymptomatic until the initiation of dietary phenylalanine. Currently the overt phenylketonuria is rare with the advent of widespread screening at birth. If missed the symptoms are insidious until early infancy, with delayed milestones. The children also suffer from the other neurological diseases such as epilepsy. There is also be a “mosy” smell in urine due to the metabolite phenylacetic acid.

Screening is usually done in the first week of life. This is done by checking the phenylalanine and tyrosine levels. Blood levels are typically high (>20g/dl), but the wide variability in the phenylalanine levels over a 24 hour period may necessitate repeat sampling [6].

Laboratory studies

The most useful method is via tandem-mass spectrometry, as this method can also measure other amino acid levels such as tyrosine. Any abnormal levels will require immediate action and appropriate referral

Imaging

There is white matter injury apparent on phenylketonuria patients. The severity of the injury is related to the treatment status. There are new techniques that may be able to estimate the phenylalanine level on magnetic resonance spectroscopy.

Genetic testing

Molecular analysis may be used to identify mutations on the enzyme locus and predict enzyme activity in some cases. All patients with a diagnosis of phenylketonuria require genetic counselling.

Management of patients with phenylketonuria should be provided by an experienced team of nutritionists, social workers, psychologists, metabolic specialists, and pediatricians [7].

Dietary

The mainstay of therapy is dietary restriction of phenylalanine. This requires use of feeds that are deficient in phenylalanine, (with tyrosine supplementation) but supply adequate nutrition. These substitutes have to meet the requirement for development and optimal growth. Phenylalanine level are followed closely from initially one to two times a week and once a month in the older children and adults (but this is subject to local guidelines). Normal levels being the desired targets. Compliance may be an issue in older children and adults due to the poor taste of these substitutes and supplements. The diet restriction are for life for optimal outcomes.

There are currently a number of other strategies are being developed especially for patients who cannot adhere to the strict diet. It has been noted that ingestion of large amounts of neutral amino acids maybe beneficial by competing with phenylalanine at the blood brain barrier [8].

Pharmacotherapy

Patients with residual activity may benefit from administration of tetrahydrobiopterin (BH4) cofactor [9]. Upcoming treatments include Phenylalanine ammonia lyase, which is injectable. It is currently in the testing phase, but the optimism is guarded currently and more testing will be required.

The prognosis is excellent if the condition is identified early and the correct management is instituted and maintained strictly. There is a direct relationship between the phenylalanine levels and IQ levels especially in the early years when there is brain development. If left untreated the intellectual disability can be substantial.

Deficiency of the hepatic enzyme phenylalanine hydroxylase causes accumulation of phenylalanine and its metabolites. Phenylalanine hydroxylase is required for the conversion of the amino acid phenylalanine to tyrosine with tetrahydrobiopterin (deficiency of tetrahydrobiopterin accounts for about 2% of phenylketonuria) being used as a co-factor necessary for the activity of phenylalanine hydroxylase.

The incidence of this condition is approximately 1 in every 13,550 to 19,000 births and is less common in individuals of African descent. Information from intellectual disability clinics show 0.04-1% of the patients are affected by phenylketonuria.

The enzyme accounts for about two thirds of the disposal of the amino acid with the rest being used protein synthesis [2]. The tyrosine levels are usually normal to low. The extent of the deficiency depends on the enzyme activity, complete deficiency causes phenylketonuria, with residual enzyme activity causing mild phenylketonuria.

In total enzyme deficiency usual results in serum levels of phenylalanine above 20mg/dl. Residual activity lead to levels to of about 10 to 20mg/dl [3].
The mechanism of mental retardation of is not known, but a number of theories have been proposed including, oxidative stress, affecting neuronal development. Other theories postulate metabolites of phenylalanine (phenylacetate and phenylpyruvate) which may inhibit neuronal growth [4].

Individuals with a strong family history of this enzyme deficiency need be tested and get counselled (genetic) before conceiving. [10]

Phenylketonuria is an inborn error in the metabolism of the aromatic amino acid phenylalanine. It is caused by the deficiency of a liver enzyme that causes accumulation of the amino acid. The enzyme is called phenylalanine hydroxylase. If not identified early can lead to mental retardation [1].
It has autosomal recessive mode of inheritance, with mutations in the gene coding for phenylalanine hydroxylase located on chromosome 12. More than 400 mutations have been identified.

Definition: Phenylketonuria is a genetic disease that is caused by a deficiency in an enzyme that breaks down a dietary protein building block (amino acid) called phenylalanine. Lack of this enzyme means that body cannot break this amino acid down and it accumulates with the body causing symptoms, mostly to the brain.

Cause: It is caused by a deletion in the gene that gives the instruction for making the enzyme. This deletion is passed down from parents (who are carriers and sufferers) to their children.

Symptoms: Patients with phenylketonuria suffer from mental retardation due to the high levels of the phenylalanine hindering brain development, especially in the younger years when the brain is growing. The bones may also be affected. Patients may have delayed milestones, such as sitting, walking and speech development. They may also suffer from seizures and have behavioral problems.

Diagnosis: It is diagnosed by a blood test that is done during the first week of life.

Treatment and follow-up: Treatment involves many people, but the mainstay of treatment is total restriction of food that contain the amino acid phenylalanine. This is done by giving medical substitutes that contain all the other necessary proteins and nutrients required for optimal growth and deployment. If the diet is followed the patients are expected to have normal intellect and lives. Anybody diagnosed will require genetic testing and counselling before they can have a baby. Regular testing of the phenylalanine is required to monitor progress of the patients.

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