Some males showed early-onset (7–20 years of age) moderate hearing loss with an upward sloping audio profile, with low to middle frequency hearing impairment, but retained the ability to hear high frequency sounds, whereas other male patients exhibited profound hearing loss and a flat audio profile with a later onset. Female carriers can be normal or abnormal, but if they were abnormal, their hearing impairment was less profound than the affected males (PMID:26089585).
Tyson et al. (1996) reevaluated a 4-generation British American family with congenital profound sensorineural hearing loss in males, similar to that ascribed to the previously unmapped locus DFN2. In this family, female carriers had a mild/moderate hearing loss affecting ...Tyson et al. (1996) reevaluated a 4-generation British American family with congenital profound sensorineural hearing loss in males, similar to that ascribed to the previously unmapped locus DFN2. In this family, female carriers had a mild/moderate hearing loss affecting the high frequencies. Liu et al. (2010) studied 14 affected and 29 unaffected members of a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss. Age at onset of hearing impairment was between 5 and 15 years for males and in the fifth decade for females. Affected males exhibited symmetric, progressive, severe-to-profound hearing loss with flat-shaped audio profiles at 24 years to 50 years of age. Obligate female carriers had either symmetric or asymmetric hearing loss that varied from mild to moderate in degree
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; 311850.0013) that cosegregated with the ...In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss mapping to the DNF2 locus, Liu et al. (2010) analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; 311850.0013) that cosegregated with the phenotype. Analysis of the PRPS1 gene in the British American DFN2 family previously reported by Tyson et al. (1996) revealed a different missense mutation (A87T; 311850.0014); missense mutations were also detected in DFN2 families previously reported by Manolis et al. (1999) and Cui et al. (2004) (311850.0015 and 311850.0016, respectively)
In males with DFNX1 nonsyndromic hearing loss and deafness, part of the spectrum of PRPS1-related disorders, the hearing loss is:...
DiagnosisClinical 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 onsetProgressive or non-progressiveAdditional 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 normalIn female carriers hearing can be normal or abnormal. TestingPhosphoribosylpyrophosphate 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. 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 TestingGene. 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 testingSequence 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 DeafnessView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected Males Carrier Females PRPS1Sequence analysisSequence variants 2100% 3, 4100% 3, 5Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Four families reported to date4. 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 probandAuditory 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 mutationCarrier 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.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). Table 2. Major Clinical Findings in PRPS1-Related Disorders by PhenotypeView in own windowPhenotypeClinical FindingGouty Arthritis 1Peripheral NeuropathyIntellectual DisabilitySNHL 2OtherPRS super-activityInfantile onset+-+/-++Hypotonia, ataxiaJuvenile / adult onset+--One individual--CMTX5-+-Early onsetOptic neuropathyArts syndrome-++/-Profound, congenitalHypotonia, ataxia, optic atrophy, ↑ risk infectionDFNX1 ---- --Early onset--1. Associated with hyperuricemia, hyperuricosuria2. SNHL = sensorineural hearing lossPRS 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.
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]. ...
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.
Computer-assisted molecular modeling showed that mutations causing Arts syndrome and CMTX5 disturb the ATP binding site of PRS-I. ...
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.
See Deafness and Hereditary Hearing Loss Overview....
Differential DiagnosisSee Deafness and Hereditary Hearing Loss Overview.Hearing loss is an isolated finding in persons with DFNX1 nonsyndromic hearing loss and deafness. DFNX1 is clearly distinguishable from the allelic disorder Arts syndrome because persons with DFNX1 have normal psychomotor development and a normal immune system. (See also Genetically Related Disorders.)Because DFNX1 does not have visual impairment and gait disturbance, it can be distinguished clinically from the allelic disorder CMTX5. (See also Genetically Related Disorders.)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).
To establish the extent of disease and needs of an individual diagnosed with DFNX1 nonsyndromic hearing loss and deafness, the following evaluations are recommended:...
ManagementEvaluations 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 testingAssessment of the vestibular functionAnalysis of the family history to identify obligate carrier females and other males who may be affectedTreatment of ManifestationsSensorineural hearing lossCochlear implantation in affected males can improve auditory and oral communication skills.See Deafness and Hereditary Hearing Loss Overview.SurveillanceHearing loss in DFNX1 is prelingual or postlingual and progressive, regular audiologic evaluation is recommended to assess hearing status and progression of hearing loss. Evaluation of Relatives at RiskIt 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 InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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. DFNX1 Nonsyndromic Hearing Loss and Deafness: 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 DFNX1 Nonsyndromic Hearing Loss and Deafness (View All in OMIM) View in own window 304500DEAFNESS, X-LINKED 1; DFNX1 311850PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1Normal allelic variants. PRPS1 is located on the chromosome band Xq22-q24 and spans 23 kb with seven exons. In control DNA from persons of Korean descent, Kim et al [2007] described a synonymous normal variant, c.447G>A, with an allele frequency of 1.1%. See Table 3.Pathologic allelic variants Table 3. Selected PRPS1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.447G>Ap.(=) 1NM_002764.3 NP_002755.1Pathologicc.193G>Ap.Asp65Asnc.259G>Ap.Ala87Thrc.869T>Cp.Ile290Thrc.916G>Ap.Gly306ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. p.(=) designates that protein has not been analyzed, but no change is expected. Normal gene product. PRPS1 encodes a 318-amino acid protein, the PRS-I (ribose-phosphate pyrophosphokinase 1) enzyme. The enzyme catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis.Abnormal gene product. The PRS-I enzyme activity was shown to be decreased in erythrocytes and cultured fibroblasts from males with DFNX1 nonsyndromic hearing loss and deafness [Liu et al 2010].