Paed - L4 Metabolic disease in children

Question 1

Phenylketonuria – 3

Answer 1

1. From PAH (phenyalanine hydroxyalase) deficiency, which converts S-Phe to S-Tyr
2. Causes S-Phe accumulation, which at high levels can cause neurological defects e.g. small brain size & mental retardation.
3. More subtle injuries occur with milder disease (ADHD, autism)

Question 2

Metabolic pathway for phenylalanine – 3

Answer 2

1. S-Phe to S-Tyr to L-DOPA to Dopamine to Noradrenaline to Adrenaline
2. Pathway occurs in liver
3. Tyr also used to synthesise thyroxine

Question 3

Diagnosis of phenylketonuria - 3

Answer 3

1. Newborns screened after birth using mass spec to quantify levels of S-Phe in the blood.
2. CNS levels appear to determine disease progression.
3. Many different mutations, so genotyping is used, can be difficult to correlate mutations with S-Phe levels & symptoms.

Question 4

Consequences of phenylketonuria – 3

Answer 4

1. Elevated S-Phe levels cause mental retardation. Standard treatment is restrict S-Phe dietary intake.
2. Reduced S-Tyr reduces nuerotransmitter production – possibly responsible for mood disturbance, seizures etc. & hypopigmentation (reduced melanin).
3. Patients prone to fractures due to poor bone metabolism – not clear if due to PKU or malnutrition of restricted diet.

Question 5

Dietary treatment of phenylketonuria – 3

Answer 5

1. Diets low in S-Phe introduced: Start ASAP, is life-long & patients need amino acid supplements. Diet unpalatable so poor compliance.
2. Patients avoid foods containing aspartame, artificial sweetener containing S-Phe.
3. Ideally serum S-Phe level < 360 μM (lower pregnancy due to risks to foetus).

Question 6

Treatment with Large Neutral Amino Acids (LNAAs) – 3

Answer 6

1. Increased levels of LNAAs (tyrosine, tryptophan & branched aliphatic amino acids) decreases S-Phe absorbance from GIT by competing for amino acid transporter allowing access of amino acids to the brain.
2. Inclusion of LNAAs in diet has +influence decision making
3. Treatment often uses glycomacropeptides (a protein derived from milk whey, naturally low in S-Phe & contains LNAAs).

Question 7

Sapropterin as a treatment for PKU – 2

Answer 7

1. Patients w/ milder PKU, where PAH retains some activity respond to BH4 (Sapropterin HCl) supplements, which acts as a cosubstrate whose binding stabilizes enzyme, increasing enzyme activity.
2. Considered positive if a >30% reduction in S-Phe levels are observed.

Question 8

Gene therapy as a treatment for PKU – 5

Answer 8

1. Replaces missing enzyme expression of wild-type enzyme w/in target tissues.
2. Requires safe vector (adenovirus) to deliver gene to patient.
3. In mouse models delivery of gene resulted in reduction of S-Phe levels, but female mice require triple dose.
4. Treatment ineffective after few weeks due to mounting of an immune response to the vector.
5. Non-viral delivery systems usable, but suffer from low efficiency of delivery.

Question 9

Enzyme therapy as a treatment for PKU – 4

Answer 9

1. Can directly replace missing enzyme (PAH) w/ alternative enzymes (bacterial Phenylalanine Ammonia Lyase; PAL) that degrade S-Phe
2. Targets S-Phe in blood, but dosing is gender specific.
3. Enzyme given IV to avoid degradation by proteases in the stomach & is rapidly cleared due to immune reaction.
4. PEGylation of enzyme improves stability.

Question 10

Probiotics as a treatment for PKU – 3

Answer 10

1. Probiotics containing live bacteria expressing recombinant enzyme allow delivery of drug to lower digestive system.
2. Bacteria survive acidic conditions of the stomach but lyse in the lower intestines (alkali pH) to release the enzyme.
3. The enzyme reduces S-Phe levels in the digestive system.