PKU and Homocystinuria

Question 1

What is PKU

Answer 1

PKU, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body.

• Deficiency in phenylalanine hydroxylase
• Autosomal recessive. Affected gene is on chromosome 12
• Accumulation of phenylalanine in tissue, plasma & urine
• Phenylketones in urine
• Musty smell

Question 2

How rare is PKU

Answer 2

Most common inborn error of amino acid metabolism (~1 in15,000 births)

Question 3

What are the effected pathways from PKU

Answer 3

• Noradrenaline
• Adrenaline
• Dopamine
• Melanin
• Thyroid hormone
• Protein synthesis

Question 4

What are the symptoms from PKU

Answer 4

Symptoms*
* Severe intellectual disability
* Developmental delay
* Microcephaly (small head)
* Seizures
* Hypopigmentation

Question 5

How does PKU effect brain development

Answer 5

• Phenylalanine is a large neutral amino acid (LNAA)
• Competes for transport across the blood brain barrier via Large Neutral Amino Acid Transporter (LNAAT)
• Excess phenylalanine can saturate this transporter
• Levels of other LNAA in the brain
  decreased
• Protein/neurotransmitter synthesis inhibited
• Brain development affected
• Causes mental retardation

Question 6

How do you treat PKU

Answer 6

• Strictly controlled low phenylalanine diet
• Avoid artificial sweeteners (these contain
  phenylalanine)
• Avoid high protein foods such as:
• Meat
• Milk
• Eggs

Question 7

What is Homocystinurias

Answer 7

• Defect in cystathione β- synthase
• Homocysteine can’t be metabolised into Cystathionine then into Cysteine
• Build up in Methionine
• Affects connective tissue, muscles, CNS, CVS

Question 8

How rare is Homocystinurias
and what sort of disorder is it

Answer 8

• Autosomal recessive disorders.
• Incidence ~1 in 344,000

Question 9

What is -
Cysteine
Cystine
Homocysteine
Homocystine

Answer 9

• Cysteine is one of the 20 amino acids that make proteins.
• Cystine is two cysteine amino acids bound together by a disulphide bond
• Homocysteine is a homologue of cysteine differing by an additional methylene bridge (CH2). Homocysteine is synthesized from methionine by the removal of the terminal methyl group and is a non-protein amino acid.
• Homocystine is two homocysteines joined together by a disulphide bond (i.e. the oxidized form of homocysteine). The form of homocysteine that appears in the urine of homocystinuria patients is mostly (~98%) homocystine (hence the name homocystinuria).

Question 10

Homocystinuria vs Marfan syndrome

Answer 10

• Marfan syndrome is a genetic disorder of connective tissue.
• Some of the clinical features of homocystinuria, such as lens dislocation and skeletal deformities, are similar in Marfan syndrome.
• High levels of homocysteine affect connective tissue and bone (mechanism by which this occurs is not known).
• Excess homocysteine causes damage to collagen and elastic fibres in connective tissue by binding to lysine residues in proteins.
• Metabolites of methionine are toxic to neurones and cause neurological dysfunction
• Symptoms in homocystinuria which are not seen in Marfan syndrome.