Clinical Guidance

In the wide and continuous spectrum of clinical manifestations associated with PRPS1 missense variants that result in a loss of function, a relationship between the type (location) of disruption of the PRS-I enzyme and phenotype has been suggested. The most severe phenotypes are caused by variants that are predicted to affect allosteric and active sites, and the milder phenotypes are caused by variants that are predicted to disrupt the structure locally . In females, who predictably have less severe manifestations, the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome .

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"

Diagnostic Criteria

For the purposes of this GeneReview, the terms "male" and "female" are narrowly defined as the individual's biological sex at birth as it determines clinical care . No consensus clinical diagnostic criteria for phosphoribosylpyrophosphate synthetase (PRS) deficiency have been published.

Suggestive Findings

PRS deficiency should be suspected in a male proband with the following clinical and supportive laboratory findings and family history.

Clinical findings in males

• Bilateral sensorineural hearing loss (SNHL) that is moderate to profound; prelingual or postlingual in onset; and progressive or non-progressive. Note: Hearing loss that is moderate to profound in a neonate will be detected by newborn hearing screening; however, hearing loss that is mild will not.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"

Differential Diagnosis

Intellectual disability. The phenotypic features associated with PRPS1-related intellectual disability are not sufficient to diagnose this condition clinically; all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series for genes associated with:

• Autosomal dominant intellectual developmental disorders

• Autosomal recessive intellectual developmental disorders

• Nonsyndromic X-linked intellectual developmental disorders

• Syndromic X-linked intellectual developmental disorders

Hearing loss. See Genetic Hearing Loss Overview. Peripheral neuropathy. See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"

Management Guidelines

No clinical practice guidelines for phosphoribosylpyrophosphate synthetase (PRS) deficiency have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PRS deficiency, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 2. PRS Deficiency: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"

Therapies Under Investigation

Dietary supplementation with S-adenosylmethionine (SAM) has been investigated in individuals with PRPS1-related disorders [Authors, personal observation]. An anecdotal study suggested that co-therapy of SAM and nicotinamide riboside may be of additional clinical benefit . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations listed in are recommended. Table 4. PRS Deficiency: Recommended Surveillance

Source: GeneReviews — "Phosphoribosylpyrophosphate Synthetase Deficiency"