Phenylketonuria

Limiting the substrate for deficient enzyme [Ref: Lippincott Blocher?! 3/e p268; Harper 28/e p254; Harrison 17/e p2470]

Classical (typel) phenylketonuria is caused by deficiency of phenylalanine hydroxylase enzyme. The reaction catalyzed by this enzyme is:

Deficiency of phenylalanine hydroxylase results in accumulation of phenylalanine and its byproducts (i.e.

Phenyllactate, phenylacetate and phenylpyruvate). Elevated levels of phenylalanine and its byproducts would lead to severe mental retardation if not treated in infancy.
Treatment consists of a special diet low in phenylalanine. (diet must also be supplemented with tyrosine; since tyrosine becomes an essential amino acid due to deficiency of phenylalanine hydroxylase)

Initiation of dietary treatment of classic phenylketonuria must occur before the child is 3 weeks of age. 1

A child presenting with microcephaly blue eyes, fair skin, mental retardation and a positive ferric chloride test typically describes a patient with Phenylketonuria.

Ref: Textbook of Biochemistry for Medical Students, By D. M. Vasudevan.M.D, DM Vasudevan, Page 208; Harrison’s – 16th Edition, Page 2333

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 ‘c’ i.e., Phenylketonuria

Microcephaly

o Microcephaly is defined as a head circumference that measures more than three standard deviation below the mean for age.

Causes of microcephaly

Primary (genetic)                                                              Secondry (Nongenetic)

o Familial (autosomal recessive)                              o Radiation

o Autosomal dominant                                            o Alcohol

o Down syndrome                                                   o Phenytoin

o Edward syndrome                                                 o Infection —> Rubella, CMV, Toxoplasma 

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

Ans. is ‘a’ i.e., Phenylketonuria

Clinical manifestations of phenylketonuria

o Normal at birth

o Symptoms occur after 1 months –

i)           Mental retardation —-> Not present at birth, develops gradually.

ii)          Neurological signs -4 Irritability, tremors, convulsions, hyperkinesis and muscular hypertonia & Exagerated reflex.

iii)        Blond hair, blue iris, fair skin.

iv)        Musty or mousy body odour.

v)         Vomiting

vi)        Microcephaly

vii)       Enamel hypoplasia & Growth retardation

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.

Individuals living with PKU must keep their intake of phenylalanine extremely low to prevent mental retardation and other metabolic complications.

However, phenylalanine is the precursor for tyrosine synthesis.

Without phenylalanine, tyrosine cannot be made and so tyrosine becomes essential in the diet of PKU patients.

Ans:A.)Phenylketonuria

Phenylketonuria

Biochemical Defect :

• An autosomal recessive disorder caused by multiple loss-of-function mutations in phenylalanine hydroxylase or decreased tetrahydrobiopterin, a cofactor for the enzyme.

Pathophysiology :

• Phenylalanine hydroxylase is responsible for converting phenylalanine into tyrosine .
• When this enzyme is deficient, phenylalanine builds up. High levels of phenylalanine lead to severe brain damage by competitively inhibiting amino acid transport required for protein synthesis, impairing polyribosome stabilization, reducing myelin production, and decreasing the formation of norepinephrine and serotonin.
• Phenylalanine is also a competitive inhibitor of tyrosinase, a key enzyme in the pathway of melanin synthesis, and thereby leads to hypopigmentation of the hair and skin.

Clinical Manifestations :

• Mental and growth retardation ; microcephaly; decreased pigmentation (blonde and blue-eyed) ; eczema; “mousy” body odor; heavy perspiration; mousy urine odor; hypertonia,hyperreflexia.

Lab findings: Phenylketones detected in urine (phenylacetate, phenyllactate, and phenyl-pyruvate); positive Guthrie test (measures phenylalanine in blood) at birth.

Treatment Decreased intake of phenylalanine (avoid aspartame, which is found in Nutrasweet) and increased dietary tyrosine (essential amino acids for patients with this disorder).

“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