Phosphoribosylpyrophosphate Synthetase Superactivity
Summary
Clinical characteristics.
Phosphoribosylpyrophosphate synthetase (PRS) superactivity is characterized by hyperuricemia and hyperuricosuria and is divided into a severe phenotype with infantile or early-childhood onset and a milder phenotype with late-juvenile or early-adult onset. Variable combinations of sensorineural hearing loss, hypotonia, and ataxia observed in the severe type are not usually present in the mild type. In the mild type, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.
Diagnosis/testing.
Detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis in individuals with both the severe early-onset phenotype and the milder late-juvenile/adult-onset phenotype. Identification of a hemizygous PRPS1 pathogenic variant on molecular genetic testing establishes the diagnosis only in individuals with the severe early-onset form, which comprises approximately one fourth of the group of individuals with PRS superactivity.
Management.
Treatment of manifestations: Hyperuricemia and hyperuricosuria are treated with: allopurinol or febuxostat to reduce uric acid formation and thus serum urate and urinary uric acid; high daily fluid intake; and, as needed, potassium citrate to alkalinize the urine. Dietary recommendations include emphasis on low-fat dairy and complex carbohydrate-containing foods and avoidance of the foods and medications discussed below. Sensorineural hearing loss and ataxia are managed in the routine manner.
Prevention of primary manifestations: Hyperuricemia and hyperuricosuria can be prevented with a xanthine oxidase inhibitor such as allopurinol and a low-purine, low-fructose diet. (Note: These interventions have no known beneficial effect on hearing loss or neurologic impairment.)
Surveillance: Monthly measurement of 24-hour urinary uric acid excretion or a spot urinary urate/creatinine ratio helps in assessing the response to treatment; once a normal serum urate concentration is achieved, serum urate concentration should be monitored at a minimum annually to assure that target urate concentration is maintained; a 24-hour urine should be monitored at a minimum annually for urate and xanthine particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); repeat audiometry as indicated; routine neurologic evaluations as indicated.
Agents/circumstances to minimize or avoid: High-purine meats (i.e., red and organ meats), shellfish, oily fish (e.g., anchovies, sardines); beer; high-fructose corn syrup-containing beverages and foods; dehydration; if possible, urate-retaining medications (e.g., low-dose aspirin, thiazide diuretics).
Evaluation of relatives at risk: Screen at-risk relatives (regardless of gender) with measurement of serum urate concentration; 24-hour urinary uric acid excretion or spot urine uric acid to creatinine ratio; and an audiology evaluation.
Genetic counseling.
PRS superactivity is inherited in an X-linked manner. If the mother has a pathogenic variant, the chance of transmitting the PRPS1 pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and have a range of clinical manifestations. Males pass the pathogenic variant to all of their daughters and none of their sons. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.
Diagnosis
Suggestive Findings
The mild phenotype of PRS superactivity should be suspected in a juvenile or adult male proband with the following:
- Gouty arthritis (Note: Absence of gout does not exclude PRS superactivity.)
- Significant hyperuricemia (see Table 1)
- Significantly elevated daily urinary uric acid excretion (see Table 1)
- Uric acid urolithiasis
The severe phenotype of PRS superactivity should be suspected in a male infant or young child with the following clinical features in addition to the above findings:
- Intellectual disability
- Sensorineural hearing impairment
- Hypotonia
- Ataxia
Table 1.
Serum Urate Concentration and 24-Hour Urinary Uric Acid Excretion in PRS Superactivity
| Phenotype | Serum Urate (mg/dL or µmol/L) 1 | Urinary Uric Acid (mg/24 hrs) 2 |
|---|---|---|
| Infantile onset | Increased | Significantly elevated |
| Juvenile/adult onset | Increased | Significantly elevated |
| Normal adult male >12y | 3.5-7.2 mg/dL or 210-430 µmol/L 3 | 250-750 mg or 1.5-4.5 mmol per 24 hours; 4 200-500 mmol urate/mol creatinine |
| Normal adult female | 2.6-6.0 mg/dL or 150-360 µmol/L | Same as adult male |
| Normal child ≤12y | 2.0-5.5 mg/dL or 120-330 µmol/L | 300-1400 mmol urate/mol creatinine |
| Normal infant <2y | 2.0-5.5 mg/dL or 120-330 µmol/L | 300-1800 mmol urate/mol creatinine |
- 1.
Serum and urine urate ranges are divided into child and adult. Recommended values here are from one specialist referral center; age and urate cutoffs vary locally.
- 2.
The ratio of urinary uric acid to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
- 3.
Male and female adult serum urate ranges differ.
- 4.
"Normal" values vary by age and weight. Values given in table are for a "standard" diet with no medications influencing serum urate levels.
Establishing the Diagnosis
Male proband. The mild phenotype is established in a juvenile or adult by identifying increased PRS-I enzyme activity at all inorganic phosphate (Pi) concentrations, normal dinucleotide (ADP/GDP) inhibition of enzyme activity, normal Km for Pi activation, and increased PRPS1 transcript (e.g., by northern analysis or quantitative real-time PCR) and PRS-I isoform (isoelectric focusing/western blotting).
PRS-I enzyme activity causing the mild phenotype can be analyzed in fibroblasts, lymphoblasts, and erythrocytes (see Table 2) [Losman et al 1984, Becker et al 1987, Becker et al 1992, Torres et al 1996].
Note: Molecular genetic testing by PRPS1 sequence analysis is not helpful in establishing the diagnosis in individuals with juvenile/adult onset as pathogenic variants within the PRPS1 coding sequence leading to elevated PRPS1 mRNA levels have not been identified as yet.
The severe phenotype is established in an infant or young child by identifying abnormal Pi activation of PRS-I enzyme activity in fibroblasts or lymphoblasts, but not erythrocytes (see Table 2), with increased affinity for Pi and decreased dinucleotide (ADP/GDP) inhibition of activity.
Identification of a hemizygous PRPS1 pathogenic variant on molecular genetic testing confirms the diagnosis (see Table 3).
Female proband. The diagnosis of PRS superactivity is usually established in a female proband with gout, sensorineural hearing impairment, and the identification of a heterozygous pathogenic variant in PRPS1 by molecular genetic testing (see Table 3).
Table 2.
Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity
| Phenotype | PRS-I Enzyme Activity | Fibroblast Nucleotide Levels 1 | ||
|---|---|---|---|---|
| Fibroblasts | Lymphoblasts | Erythrocytes | ||
| Infantile onset | High | High | Usually low 2 | High |
| Juvenile/adult onset | High | Normal | High | High |
Becker et al [1986]
- 1.
Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)
- 2.
PRPS1 pathogenic variants (usually in the infantile-onset type) that lead to defective allosteric regulation of the activity of the PRS-I isoform contribution to total PRS activity, enhanced enzyme affinity for inorganic phosphate (Pi) (especially at concentrations <2-4 mmol/L), and reduced inhibition of activity by ADP and GDP are observed in cultured fibroblasts and lymphoblasts. However, PRS-I enzyme activity in erythrocytes is usually reduced or deficient because of instability of the mutated enzyme in red blood cells.
Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Single-gene testing. Perform sequence analysis of PRPS1.
- A multigene panel that includes PRPS1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing and/or use of a multigene panel fails to confirm a diagnosis in an individual with features of PRS superactivity.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 3.
Molecular Genetic Testing Used in PRS Superactivity
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PRPS1 | Sequence analysis 3, 4 | 7 of 30 5 |
| Gene-targeted deletion/duplication analysis 6 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis
- 5.
Five males with metabolic and neurodevelopmental abnormalities in infancy or early childhood; one male with onset of metabolic (but not neurodevelopmental) features in the teen years; one woman with late childhood-onset gout who was heterozygous for a PRPS1 pathogenic variant. All of the respective PRPS1 pathogenic variants resulted in defects in the allosteric regulation of PRS-I enzyme activity by nucleotides and Pi (see Table 2) No PRPS1 pathogenic variant has been identified in the majority of affected individuals, who are largely in the juvenile- and adult-onset groups.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
PRS superactivity can be divided into a severe phenotype and a mild phenotype.
The severe phenotype is characterized by infantile- or early-childhood-onset hyperuricemia and hyperuricosuria. Uric acid crystalluria or a urinary stone is commonly the first metabolic clinical event and gouty arthritis is usually a later event if serum urate concentration is not controlled. Commonly, the clinical picture is dominated by events not directly ascribable to hyperuricemia or hyperuricosuria – usually variable combinations of sensorineural hearing loss, intellectual disability, hypotonia, and ataxia [Becker et al 1988].
The milder phenotype is characterized by late juvenile- or early adult-onset gouty arthritis or uric acid urolithiasis with hyperuricemia and hyperuricosuria. Obvious neurologic findings are usually not present.
Renal impairment can potentially result from uric acid crystal deposition in the renal collecting system or from urate crystal deposition in the renal interstitium.
Kidney stones and acute renal failure as a result of obstructive uropathy from uric acid crystal deposition (stones or gravel) were described in the first family identified [Sperling et al 1972]; the renal failure resolved with treatment of the obstruction.
Heterozygous females in families with the severe form of PRS superactivity can also show the metabolic and/or neurodevelopmental features of the disease [García-Pavía et al 2003].
Genotype-Phenotype Correlations
Pathogenic variants that result in PRS superactivity disturb either one or both allosteric sites that are involved in the inhibition of PRS-I enzyme activity.
Pathogenic variants that lead to DFNX1 either disturb local stability of PRS-I or moderately affect interactions in the trimer interface.
Computer-assisted molecular modeling has shown that pathogenic variants causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I.
Penetrance
Penetrance is complete in hemizygous males.
Nomenclature
"PRPP synthetase (PRS) superactivity" is the name originally applied to the overall disorder. With the increasing recognition of two varieties of defects – that is, single-nucleotide variants (SNVs) in PRPS1 and accelerated transcription of the normal PRPS1 (with an enzyme of normal kinetic characteristics) – it has been suggested that the term PRS "overactivity" become the overall name and that "superactivity" refer only to the phenotype associated with PRPS1 SNVs. However, the distinction has not gained wide recognition.
Prevalence
No prevalence has been estimated. To date, 30 individuals with PRS superactivity have been described worldwide [Becker 2008].
Differential Diagnosis
Purine and pyrimidine disorders. Disorders of purine and pyrimidine metabolism that overlap with PRPS1-related disorders are hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) deficiency (see also Lesch-Nyhan Syndrome) and S-adenosylhomocysteine hydrolase (AHCY) deficiency [Baric et al 2004].
Table 5.
Disorders of Purine and Pyrimidine Metabolism that Overlap with PRPS1-Related Disorders
| Clinical Finding | PRS Superactivity | HPRT Deficiency | AHCY Deficiency | |
|---|---|---|---|---|
| Neurologic | Intellectual disability | + | ± | – |
| Ataxia | ± | – | – | |
| Hypotonia | ± | ± | + | |
| Delayed motor development | ± | + | + | |
| Loss of deep tendon reflexes | – | – | + | |
| Hearing impairment | + | – | – | |
| Uric acid overproduction | Gout | + | + | – |
| Kidney stones | + | + | – | |
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended:
- All individuals. Consultation with a clinical geneticist and/or genetic counselor
- Juvenile/adult onset
- Serum uric acid concentration
- Joint examination for evidence of gout; generally, evaluation of joint integrity only, except during an acute flare of arthritis or an individual with chronic deformity or tophus formation following multiple attacks
- Assessment of renal function and renal structural integrity (e.g., renal ultrasound examination)
- Infantile onset. In addition to evaluations listed under Juvenile/adult onset:
- Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
- Audiometry for evidence of hearing loss, a critical differential point
Treatment of Manifestations
Hyperuricemia and hyperuricosuria in individuals with PRS superactivity can be reduced by treatment with the following:
- Reduced intake of red and organ meats, poultry, and shellfish [Choi et al 2004], oily fish (e.g. anchovies, sardines), beer, avoidance of high-fructose corn syrup-containing foods and drinks, and increased low-fat dairy intake
- Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis – see Prevention of Secondary Complications.
- Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis. Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
- High daily fluid intake (i.e., ≥2 L/day in the adult)
- Potassium citrate (usually administered 4x/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [Becker 2008]. Xanthinuria does not respond to urinary alkalinization.
Note: The interventions described only prevent/treat gout and the other metabolic complications of hyperuricemia; they have no known beneficial effect on hearing loss or neurodevelopmental impairment.
Sensorineural hearing loss is managed in the usual manner (see Deafness and Hereditary Hearing Loss Overview, Management).
Ataxia is managed in the usual manner (see Hereditary Ataxias, Management).
Prevention of Primary Manifestations
Gout and renal lithiasis caused by chronically elevated serum and urine uric acid, the result of purine overproduction, can be reduced by a xanthine oxidase inhibitor.
Some neurologic attributes of the severe form of the disease may be preventable by early treatment with S-adenosylmethionine (SAM), although this is experimental (see Therapies Under Investigation).
Prevention of Secondary Complications
By analogy to individuals with Lesch-Nyhan syndrome, who also have marked purine overproduction, xanthine oxidase inhibition with allopurinol or febuxostat may result in the formation of xanthine urinary tract stones. These radiolucent stones can be confused clinically with uric acid stones. If residual symptoms of urolithiasis occur in PRS superactivity despite the achievement of goal serum urate concentrations, a stone should be isolated for analysis and/or urinary xanthine concentration should be measured. Management of this pharmacologically induced complication includes reduction in daily allopurinol or febuxostat dosing, with the possible need to accept serum urate concentrations higher than the usual goal range (<6.0 mg/dL; 360 μmol/L).
Surveillance
Monthly measurement of 24-hour uric acid excretion in the urine is particularly helpful in the assessment of the response to treatment. Alternatively, a spot urinary urate/creatinine ratio can be informative if accessibility to samples is restricted.
Once a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored at a minimum annually to assure that the targeted concentration is maintained.
A 24-hour urine should also be monitored at a minimum annually for urate and xanthine concentrations particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); plasma xanthine is cleared efficiently and does not accumulate.
Audiometry should be repeated as deemed appropriate by treating audiologist/otolaryngologist.
Neurologic evaluation should be performed annually or more frequently as recommended by the treating neurologist.
Note: Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized and urinary xanthine does not routinely exceed its solubility (~1 mmol/L).
Agents/Circumstances to Avoid
The following should be avoided:
- Red and organ meats, shellfish, or oily fish (e.g. anchovies, sardines) in excess; beer, high-fructose corn syrup-enriched foods and drinks [Choi et al 2004]
- Dehydration
- If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics
Evaluation of Relatives at Risk
It is appropriate to screen apparently asymptomatic older and younger at-risk relatives (regardless of gender) of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.
Evaluations include:
- Molecular genetic testing if the pathogenic variant in the family is known;
- If the pathogenic variant in the family is not known, measurement of serum urate concentration; 24-hour urinary uric acid excretion or spot urine uric acid/creatinine ratio; and an audiology evaluation. Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of uric acid/creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of higher renal clearance of urate, however the urine urate excretion is abnormally high for age in all individuals.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Dietary S-adenosylmethionine (SAM) supplementation may theoretically alleviate some of the neurologic symptoms of severe PRS superactivity by providing an oral source of purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. Although PRS superactivity exhibits high purine nucleotides (adenylates/guanylates) in some cells, these are low in red blood cells, which rely on purine salvage metabolism, and are believed to be low in the brain, which also relies on purine salvage metabolism.
An adult with Lesch-Nyhan syndrome has been reported as benefiting neurologically from SAM administration without untoward side effects [Glick 2006].
For an open-label clinical trial of SAM in two Australian brothers (from ages 14 and 13 in 2010) with Arts syndrome [Christodoulou et al, unpublished data] (approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia), oral SAM supplementation was set at 30 mg/kg/day. The boys appeared to have had significant benefit from this therapy based on decreased number of hospitalizations and stabilization of nocturnal BIPAP requirements; however slight deterioration in their vision was noted. Eventually, they both died of respiratory failure at the ages of 19 and 18 years in association with a severe lower respiratory tract infection.
Mildly affected heterozygous females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Whether treatment with SAM supplementation would benefit individuals with allelic disorders (PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5) remains to be investigated.
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