51. Disturbances of amino acid metabolism

These disorders are mostly congenital disorders, meaning the symptoms occur already from birth. Amino acids are important for the brain, so most of these cause mental problems. The most important disorders of amino acid metabolism are:

• Disorders of amino acid transport
  • Hartnup disease
  • Cystinuria
  • Methionine malabsorption syndrome
• Disorders of amino acid metabolism
  • Phenylketonuria
  • Tyrosinosis
  • Alkaptonuria
  • Albinism
  • Oxalosis
  • Maple syrup urine disease
  • Homocystinuria

Amino acids are transported into cells by active transport. Different transporter proteins exist for six types of amino acids:

• Group I – neutral amino acids – Ala, Ser, Tyr, Phe
• Group II – neutral amino acids – Met, Leu, Val, Ile
• Group III – Imino-acids – Gly, Pro, hydroxyproline
• Group IV – Acidic amino acids – Glu, Asp
• Group V – Basic amino acids – Lys, Arg, Orn
• Group VI – Cysteine

This means that for example glutamate and aspartate are transported by the same transporter proteins. Methionine, leucine, valine and isoleucine are all transported by the same transporter protein, and so on. This means that in theory, if you consume very much of an amino acid in one group will the absorption of the other amino acids in the same group be competitively inhibited.

This is especially problematic if a lot of non-essential amino acids are consumed and not a lot of essential ones, potentially causing competitive inhibition of the absorption of the essential ones, causing deficiency. Like, if you consume a lot of alanine will you inhibit the absorption of the essential amino acid phenylalanine.

Disorders of amino acid transport

Disorder	Substrate affected	Tissues affected	Symptoms
Hartnup disease	Tryptophan	Intestine	Pellagra-like symptoms (3 D’s)
Cystinuria	Cystine	Kidney	Cystine kidney stones
Methionine malabsorption syndrome	Methionine	Intestine	Diarrhoea, mental retardation

Disorders of amino acid metabolism

Disorder	Enzyme affected	Symptoms
Phenylketonuria	Phenylalanine hydroxylase	Mental retardation
Tyrosinosis (tyrosinaemia type II)	Tyrosine aminotransferase	Mental retardation
Alkaptonuria	Homogentisate 1,2-dioxygenase	Black pigmentation of urine and skin, mental retardation
Albinism	Tyrosinase	Hypopigmentation, visual problems
Oxalosis	Enzymes that convert glycine into oxalate	Calcium oxalate stones
Maple syrup urine disease	Branched-chain α-ketoacid dehydrogenase complex	Mental retardation, demyelination, sweet-smelling urine
Homocystinuria	Cystathionine β-synthase, others	Delayed growth, mental retardation, others

Phenylketonuria

Phenylketonuria (PKU) is characterized by the deficiency of phenylalanine hydroxylase. This increases the levels of phenylalanine and its by-products. These by-products impair the CNS, causing mental retardation. Excess phenylketonuria inhibits transport of other, important amino acids, which are essential for brain development.

Treatment involves a phenylalanine-free diet. New-borns are screened for their blood phenylalanine levels.

A special type of phenylketonuria is malignant phenylketonuria, where the defect is the deficiency of THB (tetrahydrobiopterin), a cofactor. This condition is more severe than classic PKU.

Homocystinuria

Homocystinuria is classically characterised by deficiency of cystathionine β-synthase, but deficiency of other enzymes may cause it as well. It causes elevated level of homocysteine in the blood (hyperhomocysteinaemia) and urine.

Hyperhomocysteinaemia may also occur in folic acid and B12 deficiency. Whether caused by vitamin deficiency or genetic defects are the consequences the same:

• Homocysteine has a prothrombic effect
• It promotes atherosclerosis – by increases LDL oxidation
• It interferes with collagen polymerization