What causes alkaptonuria?

From the Guidelines

Alkaptonuria is caused by a deficiency of the enzyme homogentisic acid dioxygenase, which is associated with mutations in the HGD gene. This enzyme plays a crucial role in the breakdown of homogentisic acid, a byproduct of tyrosine metabolism [ 1 ]. The deficiency of this enzyme leads to the accumulation of homogentisic acid in the body, resulting in the characteristic symptoms of alkaptonuria, including darkening of connective tissues (ochronosis) and dark urine.

Key Points

• The HGD gene provides instructions for making the enzyme homogentisate 1,2-dioxygenase [ 1 ]
• Mutations in the HGD gene lead to a deficiency of this enzyme, causing alkaptonuria
• Homogentisic acid accumulates in the body due to the enzyme deficiency, leading to ochronosis and other symptoms
• Alkaptonuria is inherited in an autosomal recessive pattern, requiring two copies of the mutated gene to develop the condition

Pathophysiology

The tyrosine degradation pathway involves several enzymes, including homogentisic acid dioxygenase [ 1 ]. A deficiency of this enzyme, as seen in alkaptonuria, leads to the accumulation of homogentisic acid, which is then oxidized and deposited in connective tissues, causing ochronosis. The accumulated homogentisic acid is also excreted in urine, resulting in dark urine upon exposure to air.

Inheritance Pattern

Alkaptonuria is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the mutated HGD gene (one from each parent) to develop the condition [ 1 ]. Parents who carry one mutated copy are typically unaffected carriers. The condition is rare, affecting approximately 1 in 250,000 to 1 in 1,000 people worldwide.

From the Research

Causes of Alkaptonuria

The causes of alkaptonuria can be summarized as follows:

• Alkaptonuria is a rare, autosomal-recessive disease of tyrosine degradation resulting from accumulation of homogentisic acid (HGA) within the body due to deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase 2.
• The disease is caused by mutations in the HGD gene, which encodes the homogentisate 1,2-dioxygenase enzyme 3, 4, 5, 6.
• The HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, leading to multisystemic clinical symptoms 4.
• The identified mutations in the HGD gene can affect the activity of the enzyme by decreasing the stability of individual protomers, disrupting protomer-protomer interactions, or modifying residues in the region of the active site 3.

Genetic Basis

The genetic basis of alkaptonuria involves:

• Mutations in the HGD gene, which maps to the human chromosome 3q21-q23 6.
• A variety of mutations have been identified, including missense variants, deletions, and other types of mutations 3, 4, 5.
• The mutations can be inherited in an autosomal recessive pattern, meaning that an individual must inherit two copies of the mutated gene (one from each parent) to develop the disease 2, 5.

Prevalence and Distribution

The prevalence and distribution of alkaptonuria can be described as:

• Alkaptonuria has a very low prevalence (1:100,000-250,000) in most ethnic groups, but there are countries such as Slovakia and the Dominican Republic where the incidence of this disorder is higher 6.
• The disease has been reported in various populations, including Egyptian, Turkish, and Italian patients 4, 5.