Phenylketonuria (Inborn Error of Metabolism) for USMLE

Phenylketonuria explained for Medical Students and USMLE. Discussing Pathophysiology, Sign, Symptoms, Clinical Findings, Diagnosis, Treatment and Management. Phenylketonuria is an inborn error of disease.
Phenylketonuria is an inborn error of metabolism meaning that patient is missing key enzyme required for amino acid phenylalanine. This is the most common inborn error of metabolism and it is autosomal recessive trait. First lets discuss how phenylalanine is degraded by the body. The enzyme Phenylalanine hydroxylase PAH converts the Amino Acid into Tyrosine. The only different is that Tyrosine has an OH group right at the edge. It does require the cofactor tetrabiopterin cofactor also known as BH4. This needs to be recycled and there are enzymes to recycle the BH4.
If there is more than 20mg/dL of phenylalanine in the blood it will convert to pheylacetate and pheylpyruvate which are phenylketones and will become excreted into urine. These are not contributing the undelrying pathology bu serve as a good marker of severity.
There are theree types of Phenylketonuria, Classic, Hypophenylalanemia and Malignant Phenylketonuria
CLASSIC PHENYLKETONURIA
There is greater than 20mg/dL of phenylalanine in the blood. Therefore there will be the presence of phenylketones. Generally associated with a complete loss of the enzyme phenylalanine hydroxylase.
HYPERPHENYLALANEMIA
20mg/dL of Phenylalanine. This milder and there will be no ketones in the urine.
MALIGNANT PHENYLKETONURIA
More resistant to treatment because the phenylalanine hydroxylase enzyme is okay, but there is a lot of producing or recycling of tetrahydrobiopterin.
The Clinical presentation in classic phenylketonuria is that initially at birth the infant is normal, however, there is a gradual worsening of symptoms. At presentation the patient will start vomiting, generally it is so severe that it may be confused with pyloric stenosis. As the patient gets older the CNS issues become more prevalent. IQ drops by 10 points. Also there are abnomral movements such as seizure, athetosis, rocking back and forth. MRI may show some demyelination in the brain, light skin becuase a lack of tyrosine which is required to make melanin and also corresponds with light eyes and hair loss. There is also a musty smell.
With hyperphenelalanemia they are asymptomatic and there is a slow and progressive brain damage. In malignant phenylketonuria and there are other symptoms related to BH4 cofactor which is also a cofactor for Tyrosine to be converted to Dopamine and Tryptophan to be converted to Serotonin and Arginine to be converted to Nitric Oxide Synthase (NO Synthase). Clinically Deterioration even with dietary changes of restricted phenylalanine. CNS findings will be related to hypotonia such as inability to hold their head up. There is also elevated PRL and EPS are noted.
Diagnostic test is called BH4 loading test. Give patient 20mg/kg of BH4 and check Phenylalanine level. If it normalize in 4-8 hour than it is probably due to BH4. Treatment is more complex becuase they need to recieve the Neurotransmitters, and Prolactin.
Treatment and Management of Phenylketonuria. Primarily diet restriction and there are some commercially available products to remove the phenylalanine. Tyrosine supplement to prevent hypotyrosinemia. Leads to defeiciencies of Iron, Zinc, Selenium and Essential Amino Acids. There they should monitor. Still debate whether they can stop at adolescents.
Must avoid apartame which is a sweetener found in soft drinks and vitamins. Sarpropterin is a BH4 analog and it seems to help certain patients and not others. It will help if there is some phenylalanine hydroxylase activity. Also they can recieve Large Neutral Amino Acids (LNAA) such are Arginine, Methionine, Threonine which competes with phenylalanine which goes to the brain.
If pregnant it is more important to monitor phenylalanine intake there is increased risk of mental retardation such as microcephaly, congenital heart disease and Intrauterine Growth Restriction. Must maintain Phenylalanine free diet.
Prognosis is good if detect in first month they can have normal IQ and this is why it is screened at birth. Sometimes there is a minimal decrease in IQ, especially if 360umol/L. There are some psychological disorders such as agoraphobia. counseling is also very important especially as they get older and monitor their own diet.

[@feliciayodiutama6527]

Thank you very much for the video. It helps me to understand a lot more about my child who is born with BH4 deficiency (PTPS deficiency specifically).

[@maramal-shahrani1956]

very informative and nice presentation

[@danaghazaleh9117]

Very comprehensive :)

[@magdahassan8052]

Thanks' alot...

[@wahidexplains]

Very good video on PKU yet

[@marvoht]

Excellent video. Can you explain why you would supplement them w/ Phenylalanine if they already have excessive amounts of it?

[@thestudyspot]

+tee h You wouldn't supplement Phenylalanine, you would restrict phenylalanine. That is important to prevent progression of the disease. However, you do need to supplement Tyrosine because there is no other way for you body to produce Tyrosine without Phenylalanine as a precursor.

[@marvoht]

.

[@marvoht]

the study spot right, what i meant is that why would their diet consist of 20-30mg/kg/day of Phenylalanine when they already have excessive amounts of it..

[@marvoht]

b/c we are currently learning about it & I came across that in my slides & was a bit confused

[@melissaarana4933]

Do people with hi levels or Phenylketonuria in there blood do they experience a lot of food sensitivities ? Please let me know very important to my experiences….

[@thestudyspot]

+Melissa Arana I haven't come across anything that makes such a link.

[@user-zk4th8pj5r]

Hello i have 2 questions, first why phenylketonuria cause mental retardation microcephaly and mousy odor, second is dopamine differentiatate types phenylketonuria, is dopamine has link with phenylketonuria