Hypoxanthine guanine phosphoribosyltransferase deficiency

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disorder caused by mutations in the HPRT1 gene. This gene is essential for the salvage pathway of purine metabolism, which recycles purines into nucleotides. When HPRT is deficient, the body cannot properly recycle purines, leading to an accumulation of uric acid and associated complications. HPRT deficiency manifests in a spectrum of clinical presentations, from the severe Lesch-Nyhan syndrome to the milder Kelley-Seegmiller syndrome.

Etiology and Pathophysiology

HPRT deficiency is an X-linked recessive disorder, meaning the mutated gene is located on the X chromosome. Males, having only one X chromosome, are primarily affected, while females can be carriers. The HPRT1 gene mutation leads to reduced or absent activity of the HPRT enzyme. This enzyme is crucial for the purine salvage pathway, which recycles hypoxanthine and guanine into IMP (inosine monophosphate) and GMP (guanosine monophosphate), respectively. Without functional HPRT, these purines are instead converted into uric acid, leading to hyperuricemia and the potential for gout, kidney stones, and renal failure.

Clinical Manifestations

The clinical spectrum of HPRT deficiency ranges from severe to mild, primarily based on the level of enzyme activity.

Lesch-Nyhan Syndrome

Lesch-Nyhan syndrome represents the severe end of the spectrum, characterized by overproduction of uric acid, neurological dysfunction, and behavioral abnormalities. Symptoms include self-mutilating behaviors, such as lip and finger biting, neurological impairment, and motor dysfunction. Cognitive development may vary widely among affected individuals.

Kelley-Seegmiller Syndrome

Kelley-Seegmiller syndrome denotes the milder form of HPRT deficiency. Individuals typically present with hyperuricemia, gout, and kidney problems but do not exhibit the severe neurological and behavioral symptoms seen in Lesch-Nyhan syndrome.

Diagnosis

Diagnosis of HPRT deficiency involves clinical evaluation and laboratory tests. Elevated levels of uric acid in blood and urine are indicative but not definitive. Enzyme activity assays in red blood cells can confirm the diagnosis by demonstrating reduced or absent HPRT activity. Genetic testing for mutations in the HPRT1 gene provides a definitive diagnosis and can help identify carrier status in females.

Treatment

There is no cure for HPRT deficiency, and treatment focuses on managing symptoms and preventing complications. Medications such as allopurinol can help reduce uric acid levels. Neurological and behavioral symptoms require a multidisciplinary approach, including physical therapy, medications, and behavioral interventions. Supportive care is crucial for improving quality of life.

Prognosis

The prognosis for individuals with HPRT deficiency varies. Those with Lesch-Nyhan syndrome often have a reduced life expectancy due to renal failure and complications from self-injurious behavior. Individuals with Kelley-Seegmiller syndrome can have a normal life expectancy with appropriate management of hyperuricemia and its complications.

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