Clinical Guidance

Affected Males

Pathogenic variants in HPRT1 are almost always associated with clinical evidence for overproduction of uric acid (hyperuricemia, nephrolithiasis, and/or gouty arthritis) as well as a range of neurobehavioral phenotypes. Historically, three phenotypes recognized in the spectrum of HPRT1 disorders were Lesch-Nyhan disease (LND) at the most severe end, the intermediate phenotype HPRT1-related neurologic dysfunction (HND), and HPRT1-related hyperuricemia (HRH) at the mild end . In reality, these neurobehavioral phenotypes cluster along a continuum from severe to mild . Overproduction of uric acid is present from birth. The serum uric acid concentration is usually elevated.

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

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

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