DiagnosisClinical DiagnosisArts syndrome, part of the spectrum of PRPS1-related disorders that includes PRS superactivity, X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), and DFNX1 nonsyndromic hearing loss and deafness (DFN2) (see Table 2), is characterized by the following:Intellectual disabilityProfound congenital sensorineural hearing impairmentEarly-onset hypotoniaDelayed motor developmentAtaxia Optic atrophy Liability to infections, especially of the upper respiratory tractTestingSerum concentration of uric acid. Although serum uric acid concentration in males with Arts syndrome tends to be low (0.13-0.16 mmol/L), it is still within the normal range (0.12-0.35 mmol/L) [de Brouwer et al 2007].Note: (1) Serum uric acid concentration is not zero because PRS-II, which has the same enzyme activity as PRS-I, is active in tissues such as liver, which consequently will result in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of PRS superactivity, in which serum uric acid concentration is usually high. Purine analysis in urine Urine hypoxanthine is undetectable in Arts syndrome. When individuals with Arts syndrome are on a low purine diet, the uric acid to creatinine ratio in urine may also tend to be at the lower end of normal, but not zero.The concentrations of other purines in urine are within the normal range. Phosphoribosylpyrophosphate synthetase (PRS) enzyme activity in erythrocytes and fibroblasts. In individuals with Arts syndrome, PRS enzyme activity is:Completely absent in erythrocytes because PRS-I is the only isoform present [de Brouwer et al 2007]; Significantly lower in fibroblasts than in controls [de Brouwer et al 2007]. Molecular Genetic Testing Gene. PRPS1, encoding the enzyme phosphoribosyl pyrophosphate synthetase I, is the only gene known to be associated with Arts syndrome. Clinical testingSequence analysis. Sequencing of the seven exons of the coding region of PRPS1 in the two families known to have Arts syndrome identified a missense mutation in each [de Brouwer et al 2007]. Table 1. Summary of Molecular Genetic Testing Used in Arts SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test Availability Affected MalesCarrier FemalesPRPS1Sequence analysisPoint mutations100% 2100% 2Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Two families reported to date [de Brouwer et al 2007]Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.To determine if a missense mutation represents a pathologic mutation, it may be necessary to look for biochemical evidence of Arts syndrome by measuring the serum concentration of uric acid and purines in the urine. Testing Strategy To establish the diagnosis in a probandSuggestive findingsSerum uric acid concentration lower than averageAbsent/low hypoxanthine on analysis of purines in the urine Definitive diagnosis. Identification of a disease-causing mutation on sequence analysis of PRPS1 Research only. Absence of PRS enzyme activity in erythrocytesCarrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family. Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder, most notably late-onset (age >20 years) hearing impairment. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or (b) molecular genetic testing by sequence analysis if an affected male is not available for testing.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersThe spectrum of PRPS1-related disorders includes four phenotypes – PRS superactivity, CMTX5, DFNX1 nonsyndromic hearing loss and deafness (DFN2), and Arts syndrome – previously thought to be distinct entities (Table 2).Table 2. Major Clinical Findings in PRPS1-Related Disorders by PhenotypeView in own windowPhenotypeGouty Arthritis 1Peripheral NeuropathyIntellectual DisabilitySNHLOtherPRS superactivity, infantile onset+–++Hypotonia, ataxiaPRS superactivity, late juvenile/early adult onset+––––CMTX5–+–Early onsetOptic neuropathyDFNX1 nonsyndromic hearing loss and deafness (DFN2)–––Profound postlingual/congenital–Arts syndrome–++Profound congenitalHypotonia, ataxia, optic atrophy, risk for infectionSNHL= sensorineural hearing loss1. Associated with hyperuricemia, hyperuricosuriaPRS superactivity. The PRS superactivity phenotype can be divided into a severe and a mild phenotype. The severe phenotype is characterized by infantile or early-childhood-onset hyperuricemia and hyperuricosuria, which results in gouty arthritis that is usually accompanied by a variable combination of intellectual disability, sensorineural hearing loss, hypotonia, and ataxia. Carrier females in families with the severe form of PRS superactivity can also show one or more of these features [García-Pavía et al 2003]. The milder phenotype is characterized by late-juvenile- or early-adult-onset hyperuricemia and hyperuricosuria. Obvious neurologic findings are not present. CMTX5. CMTX5 is characterized by peripheral neuropathy, early-onset sensorineural hearing impairment, and progressive optic neuropathy starting between ages eight and 13 years [Rosenberg & Chutorian 1967, Kim et al 2007]. Progressive hypotonia, gait disturbances, and loss of deep-tendon reflexes with an onset between ages ten and 12 years have also been reported. Affected individuals have normal intellect. Carrier females do not have symptoms of CMTX5.DFN2. Individuals with DFNX1 nonsyndromic hearing loss and deafness (DFN2) have postlingual progressive nonsyndromic hearing loss, although in one family congenital profound nonsyndromic hearing loss was reported [Lui et al 2009]. Affected individuals have normal intellect. Carrier females do not manifest symptoms.}

Natural History Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing impairment, and progressive optic atrophy [Arts et al 1993, de Brouwer et al 2007]. At birth these symptoms can be present in various combinations. All symptoms except for the visual impairment become apparent in the first two years of life. Visual impairment usually becomes obvious after age two years. Delayed motor nerve conduction velocities and an electromyography suggestive of denervation develop during early childhood and are consistent with clinical findings that suggest peripheral neuropathy. Affected males usually have mild to moderate intellectual disability; however, cognitive abilities can be difficult to assess in the presence of combined visual and hearing impairment. Liability to infections, especially upper-respiratory tract infections, resulted in death before age six years in 12 of 15 boys from the two Dutch families reported with Arts syndrome. During infection, the slowly progressive muscle weakness is punctuated by acute deterioration in muscle strength, which may result in respiratory failure requiring mechanical ventilation. Carrier females can show isolated and/or milder manifestations, most notably late-onset (> age 20 years) hearing impairment; however, ataxia, hypotonia, and hyperreflexia have been reported as well [Arts et al 1993]. Other MRI shows no recognizable abnormalities, such as reduction of white matter in the brain, which would be indicative of demyelination [de Brouwer et al 2007].Sural nerve biopsy in a five-year-old boy with Arts syndrome from the original Dutch family showed a loss of myelinated fibers, but no signs of demyelination or axonal degeneration [Arts et al 1993]. Sural nerve biopsy of a two-year-old boy from the Australian family, who had absent lower-limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy, showed mild paranodal demyelination indicative of peripheral neuropathy [de Brouwer et al 2007]. Autopsy of one individual who died at age five and a half years revealed complete absence of myelinated axons in the posterior columns of the spinal cord, although their number and appearance were normal in the other tracts [Arts et al 1993]. A number of dorsal root nerves showed the same abnormalities as posterior columns. No abnormalities were seen in the brain stem or in the gray and white matter of the cerebral and cerebellar hemispheres.

Genotype-Phenotype CorrelationsComputer-assisted molecular modeling showed that mutations causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I. Mutations that result in PRS superactivity disturb either one or both allosteric sites that are involved in the inhibition of PRS I enzyme activity. Mutations that lead to DFNX1 nonsyndromic hearing loss and deafness (DFN2) either disturb local stability of PRS I or moderately affect interactions in the trimer interface.

Differential DiagnosisArts syndrome can be distinguished clinically from PRS superactivity by the presence of gouty arthritis in the latter. In Arts syndrome purine production is low/normal, whereas in PRS superactivity purine overproduction is a primary manifestation. Because dietary purine contributes significantly to urinary uric acid, a standard low purine diet is required for the biochemical diagnosis of purine over- or underproduction.Arts syndrome can be distinguished clinically from CMTX5 because CMTX5 does not have intellectual disability or recurrent infections. Arts syndrome and CMTX5 cannot be distinguished using results of serum uric acid testing. Arts syndrome can be distinguished clinically from DFNX1 nonsyndromic hearing loss and deafness (DFN2) because individuals with DNF2 do not have intellectual disability or recurrent infections. Arts syndrome and DFN2 cannot be distinguished using biochemical testing. Other disorders similar to Arts syndrome have not been described, except perhaps for spinocerebellar ataxia, X-linked 3, although the features and progression in this disorder seem to be somewhat different [Schmidley et al 1987]. Moreover, this disorder has not been assigned to a specific region on the X chromosome; thus, it remains to be seen whether it may be caused by PRPS1 mutations as well.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).MalesCarrier females

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Arts syndrome, the following evaluations are recommended:Neurologic evaluation for manifestations of hypotonia, ataxia, presence/absence of tendon reflexesAudiometry for evidence of hearing lossEye examination for evidence of optic atrophyAssessment of intellectual abilitiesAnalysis of the family pedigree for other possible affected individuals and carrier femalesTreatment of ManifestationsIntellectual disability. An individualized educational support program tailored to the patient’s needs and based on assessment of cognitive abilities should be provided. Sensorineural hearing loss. See Deafness and Hereditary Hearing Loss Overview, Management. Cochlear implantation in the two affected Australian males was associated with improved communication skills.Optic atrophy. No treatment is available. Ataxia. See Hereditary Ataxias, Management.Prevention of Secondary ComplicationsBecause of immune system compromise in males with Arts syndrome, the following are recommended:An annual influenza immunization Routine immunizations against other common childhood infections (e.g. measles, mumps)SurveillanceCognitive impairment appears to be non-progressive, but repeat neuropsychologic assessments are recommended to help guide educational support programs.Although the sensorineural deafness appears to be static (albeit very severe), regular audiologic assessment is recommended so that educational support can be optimized.Visual impairment appears to be progressive; thus, regular evaluation by an ophthalmologist is recommended.Evaluation of Relatives at RiskFemales at risk of being carriers should be evaluated for the family-specific PRPS1 mutation because clinical manifestations observed in carriers may only become apparent at a later age.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationDietary S-adenosylmethionine (SAM) supplementation could theoretically alleviate some of the symptoms of Arts syndrome by providing an oral source purine nucleotide precursor that is not PRPP dependent. Furthermore, SAM is known to cross the blood-brain barrier. An adult with HPRT deficiency has been reported to benefit neurologically from SAM administration without untoward side effects [Glick 2006]. An open-label clinical trial of SAM in two Australian brothers (ages 14 and 13 in 2010) with Arts syndrome is continuing [J Christodoulou et al, unpublished data; approved by the ethics and drug committees, Children's Hospital at Westmead, Sydney, Australia]. Oral SAM supplementation is presently set at 30 mg/kg/day. The brothers appear 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 has been noted. Mildly affected carrier females from families with Arts syndrome may also benefit from SAM supplementation in their diet, although this remains to be tested. Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Arts Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPRPS1Xq22​.3Ribose-phosphate pyrophosphokinase 1IPN Mutations, PRPS1
PRPS1 @ LOVD
PRPS1 homepage - Leiden Muscular Dystrophy pagesPRPS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Arts Syndrome (View All in OMIM) View in own window 301835ARTS SYNDROME; ARTS 311850PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1Normal allelic variants. PRPS1 consists of seven exons that code for PRS-I, a protein of 318 amino acid residues. Only one isoform has been described for PRS-I.Pathologic allelic variants. To date, only two mutations have been identified (see Table 3), resulting in missense changes at the protein level.Table 3. Selected PRPS1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference SequenceNormalc.336T>Cp.(=) ^{2(Val112Val)NM_002764​.3
NP_002755​.1Pathologicc.398A>Cp.Gln133Proc.455T>Cp.Leu152ProSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. p.(=) designates that protein has not been analyzed, but no change is expected.Normal gene product. PRS-I catalyzes the synthesis of phosphoribosyl pyrophosphate (PRPP) from ATP and ribose-5-phosphate. PRPP is essential for the de novo synthesis of purine, pyrimidine, and pyridine nucleotides. For purine synthesis, PRPP is utilized as a substrate for PRPP amidotransferase, which is the first step in the de novo purine synthesis pathway, producing purine nucleotides such as ATP and GTP, and serves specifically as the rate-limiting reaction for purine nucleotide synthesis in vivo. PRPP is also essential for pyrimidine nucleotide synthesis, where it acts as cofactor for uridine monophosphate synthetase, which converts orotic acid into UMP, the precursor of other pyrimidine nucleotides including UTP, CTP, and TTP. Finally, PRPP is utilized for pyridine nucleotide synthesis by nicotinate phosphoribosyl transferase and nicotinamide phosphoribosyl transferase, which add a ribonucleotide moiety to nicotinic acid and nicotinamide respectively, which in turn are converted into the important cofactor NAD.Apart from de novo synthesis of purine, pyrimidine, and pyridine nucleotides, PRPP is also essential for the salvage of purine bases by hypoxanthine guanine phosphoribosyl transferase and adenine phosphoribosyl transferase. This mechanism ensures efficient reutilization of purine bases and nucleosides, since de novo purine nucleotide synthesis using PRPP as the substrate requires in total of seven moles of ATP for generation of each mole of nucleotide, whereas salvage requires only one mole of ATP, for the synthesis of PRPP.Abnormal gene product. In silico molecular modeling predicted that both missense mutations would result in a loss of PRS-I activity, which was accordingly demonstrated by in vitro PRS enzyme assays in erythrocytes and fibroblasts from the Australian family and fibroblasts from the Dutch kindred. This was reflected by undetectable urine hypoxanthine and reduced plasma uric acid levels in the two patients from the Australian family.}