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Alkaptonuria
1.
2.
3. Alkaptonuria (black urine
disease, black bone disease,
or alcaptonuria) is a rare
inherited genetic disorder in
which the body cannot
process the amino acids
phenylalanine and tyrosine,
which occur in protein.
4. • It is caused by a mutation in
the HGD gene for the enzyme
homogentisate 1,2-
dioxygenase (EC 1.13.11.5); if
a person inherits abnormal
copies from each parent (it is
a recessive condition) the
body accumulates an
intermediate substance
called homogentisic acid in
the blood and tissues.
5. OH
OH
CH2
COOH
HGO
homogentisic acid
CH CH
C
O
CH2
C
O
CH2 COOH
maleylacetoacetic acid
HOOC
Homogentisic acid is an intermediate in the degradation pathway of
phenylalanine. The reaction is catalysed by homogentisate dioxygenase
(HGO).
A deficiency of HGO causes
alkaptonuria
6. Homogentisic acid and its
oxidized form alkapton are
excreted in the urine,
giving it an unusually dark
color. The accumulating
homogentisic acid causes
damage to cartilage
(ochronosis, leading to
osteoarthritis) and heart
valves as well as
precipitating as kidney
12. Defect here causes
Type I Tyrosinemia
Defect here causes
alkaptonuria
Catabolic pathway for phenylalanine and
tyrosine
Homogentisate
dioxygenase
Fumarylacetoacetate
hydrolase
13. Mutations in the HGD gene cause
alkaptonuria.
• The HGD gene provides instructions for making an enzyme
called homogentisate oxidase.
• This enzyme helps break down the amino acids phenylalanine
and tyrosine, which are important building blocks of proteins.
• Mutations in the HGD gene impair the enzyme's role in this
process. As a result, a substance called homogentisic acid,
which is produced as phenylalanine and tyrosine are broken
down, accumulates in the body.
• Excess homogentisic acid and related compounds are deposited
in connective tissues, which causes cartilage and skin to
darken.
• Over time, a buildup of this substance in the joints leads to
14. WHAT ARE THE SYMPTOMS OF TYROSINEMIA?
The clinical features of the disease ten to fall into two
categories, acute and chronic.
In the so-called acute form of the disease, abnormalities
appear in the first month of life. Babies may show poor weight
gain, an enlarged liver and spleen, a distended abdomen,
swelling of the legs, and an increased tendency to bleeding,
particularly nose bleeds.
Jaundice may or may not be prominent. Despite vigorous
therapy, death from hepatic failure frequently occurs between
three and nine months of age unless a liver transplantation is
performed.
Tyrosinemia is diagnosed by a blood and urine test.
Tyrosinemia is treated by a low protein diet (low in
phenylalanine, methionine and tyrosine) and a drug called
NTCB.
Editor's Notes
.
We now know from studying the pathways in the fungus Aspergillus that the deficiency of this enzyme HGO is responsible for the disease alkaptonuria which results in an accumulation of the enzyme substrate homogentisic acid.
Pathway of catabolism of phenylalanine and tyrosine showing the enzymes responsible for each stage.
Tyrosinemia is treated by a low protein diet (low in phenylalanine, methionine and tyrosine) and a drug called NTCB. This drug is an inhibitor which blocks the metabolism of phenylalanine and tyrosine. Although the drug is not a cure, it manages the disease. The only cure for Tyrosinemia is a liver transplant.
WHAT ARE THE SYMPTOMS OF TYROSINEMIA?
The clinical features of the disease ten to fall into two categories, acute and chronic.
In the so-called acute form of the disease, abnormalities appear in the first month of life. Babies may show poor weight gain, an enlarged liver and spleen, a distended abdomen, swelling of the legs, and an increased tendency to bleeding, particularly nose bleeds. Jaundice may or may not be prominent. Despite vigorous therapy, death from hepatic failure frequently occurs between three and nine months of age unless a liver transplantation is performed.
Some children have a more chronic form of tyrosinemia with a gradual onset and less severe clinical features. In these children, enlargement of the liver and spleen are prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting and diarrhoea occur frequently. Affected patients usually develop cirrhosis and its complications. These children also require liver transplantation.
