Clinical Diagnosis

In males with DFNX1 nonsyndromic hearing loss and deafness, part of the spectrum of PRPS1-related disorders, the hearing loss is:

• Sensorineural

• Bilateral moderate to profound

• Prelingual or postlingual in onset

• Progressive or non-progressive

Additional findings:

• Audiograms associated with PRPS1-related deafness are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies.

• Temporal bone computed tomography reveals no abnormal findings.

• Vestibular function is normal

• In female carriers hearing can be normal or abnormal.

Testing

Phosphoribosylpyrophosphate synthetase (PRS) enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [Torres et al 1996]. Depending on the tissue specimen and the assay(s) employed, PRS enzyme activity may result from varying contributions of three different enzyme isoforms (PRS-I, PRS-II, PRS-III) that are encoded by three different genes (PRPS1, PRPS2, PRPS1L1), respectively. Therefore, PRS activity refers to measurement of total activity present in the cell/tissues. Assay of PRS-I enzyme activity separately from that of the other two isoforms (PRS-II and PRS-III) is possible only in erythrocytes, because it is the only PRS enzyme expressed. See Molecular Genetics for details.

PRS-I activity in erythrocytes and total PRS activity in cultured fibroblasts from affected males was decreased by 44%-45% (i.e., 55%-56% activity remained) in comparison to that of normal male family members and unrelated controls. Such testing is available on a research basis only.

Uric acid concentration in urine and plasma in affected males and carrier females from a Chinese family with DFNX1 nonsyndromic hearing loss and deafness (GZ-Z052) were within the reference range [Liu et al 2010].

Molecular Genetic Testing

Gene. PRPS1, encoding ribose-phosphate pyrophosphokinase 1 (PRS-I; formerly phosphoribosyl pyrophosphate synthetase I), is the only gene in which mutations are known to cause DFNX1 nonsyndromic hearing loss and deafness (previously known as DFN2).

Clinical testing

• Sequence analysis. Sequencing of the seven exons of the coding region and the intron/exon boundaries of PRPS1 in four families with DFNX1 nonsyndromic hearing loss and deafness identified four different missense mutations [Liu et al 2010].

Table 1. Summary of Molecular Genetic Testing Used in DFNX1 Nonsyndromic Hearing Loss and Deafness

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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	Sequence variants 2	100% 3, 4	100% 3, 5	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. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Four families reported to date

4. Lack of amplification by PCR prior to sequence analysis can suggest a putative exon(s) or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

5. Sequence analysis cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a male proband

• Auditory tests identifying hearing loss that is bilateral and moderate to profound; prelingual or postlingual in onset; and either progressive or non-progressive

• Identification of a disease-causing PRPS1 mutation

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; reported findings included either symmetric or asymmetric hearing loss that varied from mild to moderate in degree. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities if available.

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 three additional phenotypes: PRS superactivity, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and Arts syndrome, previously thought to be distinct entities (see 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 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 findings of CMTX5.

Arts syndrome is characterized by intellectual disability, early-onset hypotonia, ataxia, delayed motor development, profound congenital sensorineural hearing impairment, and optic atrophy [de Brouwer et al 2007]. Susceptibility to infections, especially of the upper respiratory tract, often results in early death. Carrier females can show a single manifestation or milder manifestations (e.g., hearing impairment, ataxia, hypotonia, and/or hyporeflexia) than affected males.

Natural History

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 2010].

Affected individuals have normal intellect.

Hearing in female carriers can be normal or abnormal. Affected carriers exhibited either symmetric or asymmetric hearing loss that varied from mild to moderate.

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 is 100% in males.

Prevalence

Prevalence has not been determined. Four families with DFNX1 have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with DFNX1 nonsyndromic hearing loss and deafness, the following evaluations are recommended:

• Pure tone audiograms, auditory brain stem response testing

• Assessment of the vestibular function

• Analysis of the family history to identify obligate carrier females and other males who may be affected

Treatment of Manifestations

Sensorineural hearing loss

• Cochlear implantation in affected males can improve auditory and oral communication skills.

• See Deafness and Hereditary Hearing Loss Overview.

Surveillance

Hearing loss in DFNX1 is prelingual or postlingual and progressive, regular audiologic evaluation is recommended to assess hearing status and progression of hearing loss.

Testing of Relatives at Risk

It is appropriate to evaluate at-risk males at birth with detailed audiometry to assure early diagnosis and treatment of hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.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

DFNX1 nonsyndromic hearing loss and deafness is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• The father of an affected male will not have the disease nor will he be a carrier of the mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the disease-causing mutation cannot be detected in her leukocyte DNA, she has germline mosaicism. Although germline mosaicism in obligate carrier females has not been reported to date, it remains a possibility.

• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo mutation, in which case the mother is not a carrier. The frequency of de novo mutations is not known.

Sibs of a proband

• The risk to sibs depends on the carrier status of the mother.

• If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and may have hearing loss.

• If the proband is a simplex case (i.e., a single occurrence in a family) and if the disease-causing mutation cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo mutation arose, information that could help determine genetic risk status of the extended family.

Carrier Detection

Carrier testing for at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

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. 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, van Bokhoven H. 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]
2. García-Pavía P, Torres RJ, Rivero M, Ahmed M, García-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]
3. 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]
4. Liu 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. 2010;86:65–71. [PMC free article: PMC2801751] [PubMed: 20021999]
5. Rosenberg RN, Chutorian A. Familial opticoacoustic nerve degeneration and polyneuropathy. Neurology. 1967;17:827–32. [PubMed: 6069085]
6. Torres RJ, Mateos FA, Puig JG, Becker M. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method. Clin Chim Acta. 1996;245:105–12. [PubMed: 8646809]

Revision History

• 4 August 2011 (me) Review posted live

• 31 March 2011 (xzl) Original submission