Phenylalanine Metabolism & PKU: Symptoms, Diagnosis, Treatment

Phenylalanine is one of the important amino acids which needs to be provided in the diet. Once the required amount of phenylalanine is used, it is converted or degraded into other products that are subsequently used for producing other metabolites in the body.

Phenylalanine Tyrosine Cycle

• Phenyl Hydroxylase is the enzyme which converts phenylalanine into Tyrosine.
• Tyrosine hydroxylase and tyrosinase are two enzymes that can react with tyrosine to produce dopa.
• Dopa can be converted to melanin (black colour pigment present in skin and hair follicles) by the enzyme tyrosinase.
• Dopa can also be converted into dopamine which is one of the main neurotransmitters in the body.
• Tyrosine can be converted to 4-OH pyruvate by the enzyme tyrosine aminotransferase.
• 4-OH pyruvate is further converted into 2,5 dihydroxy phenylpyruvate by the enzyme 4, hydroxyphenylpyruvate dioxygenase.
• Homogentisic acid is produced from 2,5 dihydroxy phenyl pyruvate.
• Homogentisic acid is converted into maleylacetoacetate by the enzyme homogentisic acid oxidase.
• Maleylacetoacetate is converted into fumarylacetoacetate.

Fumarylacetoacetate is converted into fumarate + acetoacetate by the enzyme fumarylacetoacetate hydroxylase

• A deficiency of phenylalanine hydroxylase enzyme can result in phenylketonuria.
• A deficiency of tyrosine aminotransferase will result in Tyrosinemia type 2.
• A deficiency of 4- hydroxyphenylpyruvate dioxygenase will result in Tyrosinemia type 3.
• A deficiency of homogentisic acid oxidase will result in Alkaptonuria.
• Tyrosinemia type 1 is caused by a lack of fumarylacetoacetate hydroxylase.
• Deficiency of either tyrosine or tyrosinase hydroxylase tyrosinase will result in defective melanin formation called Albinism.

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Phenylketonuria (PKU)

• It is a disorder that shows autosomal recessive inheritance.
• The gene for phenylketonuria is present on chromosome 12q.23.2 (long arm of chromosome 12).
• Phosphate Alanine hydroxylase (PAH) deficiency is the cause of almost 95% of phenylketonuria cases.
• About 1-3% of cases may arise due to the deficiency of a substance called Tetrahydrobiopterin (Bh4).
• BH4 is a cofactor for PAH.
• Consequently, tyrosine and its derivatives are not produced, and phenylalanine accumulates to a dangerous amount that damages the brain.
• If tyrosine is not there, melanin will not be formed and hence, a patient may develop albinism.
• The reason behind mental retardation and seizures is mainly due to CNS toxicity produced by high phenylalanine levels.
• Normally, tyrosine is not an essential amino acid but in phenylketonuria, tyrosine becomes an essential amino acid.
• In phenylketonuria, ketone derivatives of phenylalanine tend to pass into urine producing a musty odour.
• Here, phenylalanine produces two metabolites called phenylpyruvate and phenylacetate.
• These two metabolites are excreted in the urine and phenylacetate is responsible for the musty or mousy odour of urine.
• There is no CNS toxicity associated with phenylpyruvate or phenylacetate.

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Types of Phenylketonuria (PKU)

1. PKU is classified into three types based on the severity
2. Based on serum phenylalanine levels (unrestricted diet).

Clinical Features of PKU

Normal Birth Infancy

• Microcephaly
• Delayed milestones → Intellectual dysfunction (e.g. MR)
• Seizures (25%)
• ADHD/Autism – Like
• Persistent vomiting
• Eczematous/seborrheic Rash
• Fair skin, Blonde hair, blue eyes
• Short stature

Rare

• Osteopenia
• Teeth-↑enamel
  • Widely spaced teeth
• These children are normal at the time of birth but as the diet increases like breast milk or
• protein contained in which phenylalanine is there when it goes into the body, it will not convert to tyrosine and the features of PKU will appear.
• Normal at birth but in infancy, features will develop like Microcephaly.
• A delayed milestone that will progress to intellectual dysfunction (mental retardation)
• Seizures are common in 25% of cases in all types of PKU.
• ADHD/ or autism-like features.
• The frequent episodes of persistent vomiting.
• Eczematous/seborrheic rash.
• Fair skin, blonde hair, and blue eyes because the pigment is not formed.
• Short stature because physical development is also late.
• In rare- osteoporosis, teeth change due to a decrease in enamel production and widely spaced teeth.

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Tetrahydrobiopterin Deficiency

• In addition to acting as a cofactor for PAH, DH4 is also a cofactor for Tyrosine hydroxylase and tryptophan hydroxylase.
• Thus, these patients develop PKU with additional problems of low dopamine and serotonin in the brain.

Features Include

• Extrapyramidal signs: choreoathetosis, axial and truncal hypotonia, hypokinesia.
• Feeding difficulties and autonomic abnormalities.
• Raised prolactin levels.
• Hypersalivation, convulsions, intellectual impairment, and swallowing issues.
• The symptoms are frequently progressive and exhibit noticeable daily fluctuations.

Rx

1. Dietary restriction of phenylalanine
2. L-dopa supplementation (+ carbidopa)
3. 5-hydroxytryptophan supplementation

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Atypical Variants of PKU

• Deficiency of tetrahydrobiopterin (BH4) seen in 1-2% of patients.
• The patients not also have PKU but also have some other CNS manifestations which can be equally severe because BH4 is not only the cofactor for phenylalanine hydroxylase but also involved in the formation of dopamine and serotonin.
• These patients along with high phenylalanine also have CNS deficiency of serotonin and dopamine and hence these patients have more CNS manifestations than classical PKU.
• Deficiency of tetrahydro pteridine reductase which is involved in the metabolism of tetrahydrobiopterin.
• Deficiency of 6-pyruvoyl DHAP synthase.

Maternal PKU 

• Develop complications in their babies which are directly correlated with elevated maternal blood phenylalanine levels during pregnancy.
• Features in children born to mothers with severe PKU include :
  • Intellectual disability and microcephaly
  • Growth retardation
  • Congenital malformations
  • Congenital heart diseases (VSD, PDA, TOF, TGA, HLHS)

• Elevated maternal blood phenylalanine levels during pregnancy.
• TGA in maternal PKU.

Diagnostics

• The older test performed is known as Guthrie's test.
• The preferred test for screening is tandem mass spectrometry (TMS) which is performed on dried blood spots (DBS).
• If the screening procedure is done, it should be done between 24-48 hours of the life cycle.
• Other tests - The ferric chloride test which gives green discoloration.
• Urine for metabolites to check phenyl acetate and phenylpyruvate.
• The golden standard for PKU is serum phenylalanine levels.

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Treatment

1. Mainstay- strict dietary restriction of phenylalanine, which needs to be given lifelong.
2. Supplementation of the long neutral amino acid (LNAA) is a new therapy which is being used. 
3. When the phenylalanine level is high in the blood then this phenylalanine utilizes transporters and crosses the blood brain barrier.
4. LNAA consists of a mixture of histidine, leucine, isoleucine, valine, tyrosine, etc.
5. A trial of synthetic BH4 analogues can also be given - Sapropterin dihydrochloride which is used for the treatment of PKU.

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FDA approved.

• One of the trials that is not yet FDA-approved in some of the trials in the US is recombinant phenylalanine ammonia lyase.
• It claims that this substance can degrade phenylalanine into ammonia and cinnamic acid, and hence it can be helpful in reducing the total body level of phenylalanine.
• Recombinant phenylalanine ammonia-lyase is given in the form of an injectable.

FAQ’S

Q. Is genetic counseling recommended in PKU?

Ans. Yes, counseling would help families to understand complications and changes in PKU, and it mainly helps parents who are carriers or who have a child with diagnosed PKU.

Q. Why does urine smell change in PKU?

Ans. In PKU, urine odor was mousy, usually due to increased levels of phenylalanine and its metabolites in the body.

Hope you found this blog helpful for your NEET SS Pediatrics Inborn Error of Metabolism Preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.