Clinical Diagnosis

Arts 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 disability
• Profound congenital sensorineural hearing impairment
• Early-onset hypotonia
• Delayed motor development
• Ataxia
• Optic atrophy
• Liability to infections, especially of the upper respiratory tract

Testing

Serum 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. Testing of PRS enzyme activity is available on a research basis only. 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 testing

• Sequence 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 Syndrome

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected Males	Carrier Females
PRPS1	Sequence analysis	Point mutations	100% 2	100% 2	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Two families reported to date [de Brouwer et al 2007]

Interpretation of test results

• For 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 proband

• Suggestive findings
  • Serum uric acid concentration lower than average
  • Absent/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 erythrocytes

Carrier 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The 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).

PRS 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 Correlations

Computer-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.

Penetrance

Penetrance in males is complete.

Prevalence

Two kindreds with Arts syndrome have been identified worldwide [de Brouwer et al 2007].

Evaluations 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 reflexes
• Audiometry for evidence of hearing loss
• Eye examination for evidence of optic atrophy
• Assessment of intellectual abilities
• Analysis of the family pedigree for other possible affected individuals and carrier females

Treatment of Manifestations

Intellectual 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 Complications

Because 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)

Surveillance

Cognitive 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.

Testing of Relatives at Risk

Females 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 Investigation

Dietary 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Arts syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• In a family with more than one affected individual, the mother of an affected male is likely to be an obligate carrier.
  • A mother who is a carrier may have a de novo gene mutation or she may have inherited the disease-causing mutation from one of her parents.
• The father of an affected male will have neither the disease nor the mutation.
• When an affected male is the only affected individual in the family several possibilities regarding his mother's carrier status need to be considered:
  • He has a de novo disease-causing mutation in PRPS1 and his mother is not a carrier. The frequency of de novo mutations is not known.
  • His mother has a de novo disease-causing mutation in PRPS1, either as (a) a "germline mutation" (i.e., present at the time of her conception and therefore in every cell of her body); or (b) "germline mosaicism" (i.e., present in some of her germ cells only).
  • His mother has a disease-causing mutation that she inherited from a maternal female ancestor.

Parents of a female proband

• If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
• If the proband's father is asymptomatic, it is possible, but not likely, that he has the mutation in some cells in his body (somatic or germline mosaicism). If her father is asymptomatic and does not have somatic or germline mosaicism for the altered gene, the possible genetic explanations for the origin of the proband's gene mutation are the same as for a male proband with a negative family history.

Sibs of the proband

• The risk to the sibs of a proband depends on the genetic status of the parents.
  • If the mother has a disease-causing mutation, the chance of transmitting the PRPS1 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may or may not be mildly affected.
  • If the father of a female proband is affected, all female sibs will inherit the mutation and may or may not be mildly affected. None of the male sibs will inherit the mutation.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population.
  • If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a male proband. Males with Arts syndrome do not reproduce.

Offspring of a female proband. Females with a PRPS1 mutation have a 50% chance of transmitting the gene to each child; sons who inherit the gene will be affected; daughters have a range of possible phenotypic expression.

Other family members of the proband. If a parent of the proband also has a disease-causing mutation, his or her female family members may be at risk of being carriers (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected depending on their gender and genetic relationship to the proband.

Carrier Detection

Carrier testing is possible if the mutation has been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified before prenatal testing can be performed. Usually fetal sex is determined first and molecular genetic testing is performed if the karyotype is 46,XY.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Arts WF, Loonen MC, Sengers RC, Slooff JL. X-linked ataxia, weakness, deafness, and loss of vision in early childhood with a fatal course. Ann Neurol. 1993;33:535–9. [PubMed: 8498830]
2. de Brouwer AP, Williams KL, Duley JA, van Kuilenburg AB, Nabuurs SB, Egmont-Petersen M, Lugtenberg D, Zoetekouw L, Banning MJ, Roeffen M, Hamel BC, Weaving L, Ouvrier RA, Donald JA, Wevers RA, Christodoulou J. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet. 2007;81:507–18. [PMC free article: PMC1950830] [PubMed: 17701896]
3. García-Pavía P, Torres RJ, Rivero M, Ahmed M, Garcia-Puig J, Becker MA. Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman. Arthritis Rheum. 2003;48:2036–41. [PubMed: 12847698]
4. Glick N. Dramatic reduction in self-injury in Lesch-Nyhan disease following S-adenosylmethionine administration. J Inherit Metab Dis. 2006;29:687. [PubMed: 16906475]
5. Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). Am J Hum Genet. 2007;81:552–8. [PMC free article: PMC1950833] [PubMed: 17701900]
6. Lui X, Han D, Li J, Li X, Han B, Ouyang X, Cheng J, Jin Z, Wang Y, Bitner-Glindzicz M, Kong X, Xu H, Kantardzhieva A, Eavey RD, Seidman CE, Seidman JG, Du LL, Chen ZY, Dai P, Teng M, Yan D, Yuan H. loss-of-function mutations in the PRPS1 gene cause non-syndromic X-linked sensorineural deafness (DFN2). Am J Hum Genet. 2009;86:65–71. [PMC free article: PMC2801751] [PubMed: 20021999]
7. Rosenberg RN, Chutorian A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32. [PubMed: 6069085]
8. Schmidley JW, Levinsohn MW, Manetto V. Infantile X-linked ataxia and deafness: a new clinicopathologic entity. Neurology. 1987;37:1344–9. [PubMed: 3614654]

Suggested Reading

1. Becker MA. Hyperuricemia and gout. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio AB, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 106. New York: McGraw-Hill. Available at www​.ommbid.com. Accessed 10-16-08.

Acknowledgments

The authors are grateful to the families of the Dutch and Australian patients for providing samples used for biochemical and molecular analyses over a number of years.

Revision History

• 29 March 2011 (cd) Revision: edits to Differential Diagnosis
• 4 January 2011 (cd) Revision: changes to therapies under investigation
• 18 November 2010 (me) Comprehensive update posted live
• 21 October 2008 (me) Review posted live
• 3 June 2008 (apmb) Original submission