Phosphoribosylpyrophosphate synthetase superactivity
Phosphoribosylpyrophosphate synthetase superactivity is a rare genetic disorder characterized by the overproduction of uric acid, leading to gout, kidney stones, and potential neurological complications.
Overview
Phosphoribosylpyrophosphate synthetase superactivity (PRS superactivity) is characterized by the overproduction and accumulation of uric acid—a waste product of normal chemical processes—in the blood and urine. The overproduction of uric acid can lead to gout, a form of arthritis caused by an accumulation of uric acid crystals in the joints. Individuals with PRS superactivity also develop kidney or bladder stones that may result in episodes of acute kidney failure.
There are two forms of PRS superactivity: a severe form that begins in infancy or early childhood, and a milder form that typically appears in late adolescence or early adulthood. In both forms, a kidney or bladder stone is often the first symptom. Gout and impairment of kidney function may develop if the condition is not adequately controlled with medication and dietary restrictions. People with the severe form may also have neurological problems, including:
- Sensorineural hearing loss
- Weak muscle tone (hypotonia)
- Impaired muscle coordination (ataxia)
- Developmental delay
Frequency
PRS superactivity is believed to be a rare disorder. Approximately 30 families with the condition have been reported, with more than two-thirds of these families affected by the milder form of the disease.
Causes
Certain mutations in the PRPS1 gene cause PRS superactivity. This gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1 (PRPP synthetase 1), which helps produce a molecule called phosphoribosyl pyrophosphate (PRPP). PRPP is involved in producing purine and pyrimidine nucleotides, which are building blocks of DNA and RNA, as well as energy sources like ATP and GTP. PRPP synthetase 1 and PRPP also play a key role in recycling purines from the breakdown of DNA and RNA.
- Severe form:PRPS1 gene mutations change single protein building blocks in the PRPP synthetase 1 enzyme, resulting in a poorly regulated, overactive enzyme.
- Mild form: The PRPS1 gene is overactive for reasons that are not well understood, increasing the production of normal PRPP synthetase 1 enzyme and the availability of PRPP.
In both forms, excessive amounts of purines are generated, leading to the accumulation of uric acid. It remains unclear how PRPS1 gene mutations are related to the neurological problems associated with the severe form.
Inheritance
This condition is inherited in an X-linked pattern. The gene is located on the X chromosome. In males, who have only one X chromosome, a mutation in the only copy of the gene causes the disorder. In females, who have two X chromosomes, a mutation in one of the two copies sometimes causes the disorder. In most reported cases, affected individuals have inherited the mutation from a parent, though it may also result from new mutations.