Clinical Guidance

Because the amount of residual HGprt enzyme activity correlates with the severity of the phenotype , some general genotype-phenotype correlations are seen. LND is associated with complete or near-complete loss of enzyme activity from the following types of HPRT1 variants:

• Loss-of-function variants such as nonsense variants or frameshift variants due to small or large insertions or deletions

• Missense variants with absent or near-absent enzyme activity. These variants may reduce enzyme activity through different mechanisms including impaired kinetic properties, impaired dimerization of HGprt subunits required for functional activity, and poor protein stability.

• Most (but not all) splice site variants that result in major changes in the protein coding region

Source: GeneReviews — "HPRT1 Disorders"

Diagnostic Criteria

Suggestive Findings HPRT1 disorders, which are associated with deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), should be suspected in males with the following clinical and supportive laboratory findings. Clinical findings Table 1. HPRT1 Disorders: Clinical Findings by Phenotype HPRT1Phenotype | Clinical Findings

Source: GeneReviews — "HPRT1 Disorders"

Differential Diagnosis

Lesch-Nyhan disease (LND). When fully developed with the three clinical elements of uric acid overproduction, neurologic dysfunction, and cognitive and behavioral disturbances, the diagnosis of LND is straightforward. There are no other genetic causes of the full phenotype. The main diagnostic difficulties arise during early stages when all the features are not yet apparent, and in individuals who have milder phenotypes. The index of suspicion is raised when developmental delay is associated with evidence of overproduction of uric acid, such as hyperuricemia, uric acid nephrolithiasis or crystals in the urine, or gouty arthritis. LND is first suspected when self-injurious behavior emerges.

Source: GeneReviews — "HPRT1 Disorders"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and the needs in an individual diagnosed with an HPRT1-related phenotype, the evaluations summarized in , , and are recommended. These tables begin with HPRT1-related hyperuricemia (HRH) because these needs are shared by all phenotypes. adds the needs for neurologic assessment in HPRT1-related neurologic dysfunction (HND). Since neurologic involvement varies considerably, the assessment must be tailored to individual needs. adds the needs for behavioral assessment in Lesch-Nyhan disease (LND). Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with HPRT1 Disorders: HRH

Clinical Guidance

Avoid the following:

• Probenecid and other drugs that reduce serum uric acid concentration by increasing renal excretion of uric acid; these drugs increase the risk of precipitation of uric acid in the urinary system and may cause acute renal failure.

• Certain chemotherapy agents, such as methotrexate, that block synthesis or use of purines. Individuals with all HPRT1 disorders are especially sensitive to these agents, since all tissue purines derive from purine synthesis when HGprt-mediated purine salvage is deficient.

• Periods of relative dehydration because they concentrate purine metabolites in the urinary system and increase the risk for renal stones or urate nephropathy

Source: GeneReviews — "HPRT1 Disorders"

Therapies Under Investigation

Numerous small-scale studies have reported benefits from a wide array of therapies including various types of mouth guards and dental appliances, deep brain stimulation, bone marrow transplantation, gabapentin, carbamazepine, S-adenosylmethionine, risperidone, and others. In all instances, follow-up experiences have not confirmed a significant long-term benefit. Because of their follow-on nature and frequent negative outcome, these attempts to confirm benefits often are not published. However, many families post their experience online using social media and, by searching these posts, the clinician can get a good feel for the likelihood that an experimental therapy will have a positive (or negative) impact on the affected individual and their family . Search ClinicalTrials.

Source: GeneReviews — "HPRT1 Disorders"

Surveillance Guidelines

HPRT1 disorders are not clinically progressive. For example, overproduction of uric acid does not get worse with time. However, chronic overproduction of uric acid over years may lead to cumulative pathology in the kidneys and/or joints, especially if hyperuricemia is not well controlled. Therefore, some surveillance is important for all HPRT1 disorders. Sudden worsening of renal function should lead to suspicion for new stones or a secondary process. Similarly, new or worsening neurologic problems are not expected over time . Some evolution of the neurologic problems occurs in the first few years of life, which reflects development of the nervous system in response to a static insult and is not a neurodegenerative process. Some evolution of disability may occur with aging, analogous to cerebral palsy. Sudden worsening of neurologic status therefore should be investigated for secondary causes. The behavioral phenotype may wax and wane in severity over the years. Sudden worsening occurs with stress, for example relating to the pain of a kidney stone or change in social environment. In very young children with HND, self-injurious behavior may emerge, leading to reclassification of the diagnosis to LND. This behavior typically emerges between age two and four years but may be delayed until the teenage years. Table 9. Recommended Surveillance for Individuals with HPRT1 Disorders: HRH

Source: GeneReviews — "HPRT1 Disorders"