Phenylketonuria

Phenylketonuria:

• It is an autosomal recessive metabolic disorder, where the level of hepatic enzyme phenylalanine hydroxylase is low, therefore phenylalanine cannot be converted to tyrosine.
• Phenylalanine accumulates in the blood, cerebrospinal fluid and tissues.
• Accessory metabolic pathways start operating which convert phenylalanine to phenylpyruvic acid, phenyl-lactic acid and o-hydroxyphenyl-acetic acid.
• Restriction of phenylalanine in the diet is the mainstay of treatment of phenylketonuria.

Phenylalanine hydroxylase which converts phenylalanine to tyrosine is deficient in phenylketonuria.

The most common cause of hyperphenylalaninemia is deficiency of the enzyme phenylalanine hydroxylase, which catalyzes the conversion of phenylalanine to tyrosine.

Ref: Barsh G. (2010). Chapter 2. Genetic Disease. In S.J. McPhee, G.D. Hammer (Eds), Pathophysiology of Disease, 6e.

Guthrie Test:
It is a rapid screening test.

Certain strains of bacillus subtilis need phenylalanine as an essential growth factor.

Bacteria cannot grow in a medium devoid of phenylalanine.

Bacterial growth is proportional to the  phenylalanine content in the patient’s blood.

• Ferric chloride Test: Phenyl ketones in urine can be detected by this test. A transient blue-green color is a positive test.
• Nitroprusside Test is used for the colour reaction of amino acid Sulfhydryl group (Cysteine.)

Ans. is ‘b’ i.e., Phenylalanine hydroxylase

Ans. is ‘a’ i.e., Limit intake of substrate for the enzyme

o The goal of therapy is to reduce phenylalanine in the body; formulas low in or free of this amino acid acid are available commercially. The diet should be started as soon as diagnosis is established. It is generally accepted that infants with persistent plasma levels of phenylalanine > 6 mg/ dL (360 mole /L) should be treated with a phenylalanine­restricted diet similar to that for classic PKU. No dietary restriction is currently recommended for infants whose phenylalanine levels are between 2 and 6 mg/dL. Plasma concentrations of phenylalanine in treated patients should be maintained as close to normal as possible.

o The duration of diet therapy is also controversial. Discontinuation of therapy, even in adulthood, may cause deterioration of IQ and cognitive performance. The current recommendation is that all patients be kept on a phenylalanine­restricted diet for life.

o Oral administration of the cofactor tetrahydrobiopterin (BH,) to patients with milder forms of hyperphenylalaninemia due to phenylalanine hydroxylase deficiency may reduce plasma levels of phenylalanine without the need to remain on a low phenylalanine diet. Significant reduction in plasma phenylalanine levels (>30%) also has been observed in some patients with classic PKU following administration of a single dose of oral BI-1, (10 mg/ kg).

Ans. is ‘a’ i.e., Green

Diagnosis

o Elevated phenylalanine levels

o Elevated blood tyrosine level

o Presence of urinary metabolites of phenylalanine

o Guthrie’s Test             

It detects the presence of phenylalanine in serum

o FeCI, –> It detects the presence of phenylalanine in urine. FeCl₃ is added to patients urine. If it contains phenylalanine, it will turn green.

o 2-4 Dinitrophenol hydrazine –> gives yellow precipitate with old urine.

Ans. is `b’ i.e., Reduced tendon reflexes

Reflexes are hyperactive.

“The primary symptom of untreated phenylketonuria (i.e. mental retardation) is the result of consuming foods that contain phenylalanine, which is toxic to brain tissue”

Phenylaketonuria

• It is an autosomal recessive disorder due to deficiency of phenylalanine hydroxylase.
• As a result phenylalanine is not metabolized by hydroxylase, and metabolism is shifted to alternative pathyway and there is increased concentration of phenylalanine, phenylpyruvate, phenylacetate and phenyl-lactate.
• Because phenylalanine is not converted into tyrosine, tyrosine becomes an essential amino acid.
• Classical phenylketonuria is due to deficiency of phenylalanine hydroxylase. Milder form may be caused by deficiency of dihydrobiopterin reductase that produces tetrahydrobiopterin, a cofactor for phenylalanine hydroxylase.

Clinical presentation

• The babies are normal at birth but may present with vomiting. Gradually mental retrardation and growth retardation develop. Baby has light complexion with blue iris. Other features are microcephaly, rash, hypertonia, seizures, exaggerated tendon reflex, wide spaced teeth, enamel hypoplasia and hyperactivity.
• There is musty or mousy odour of urine and other body secretions due to presence of phenylketones.
• Pregnant females with increased pheynlalanine (maternal phenylketonuria) may cause mental retardation, microcephaly, growth retardation and CHDs in babies.

Ans. is `b’ i.e., AR