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Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.

ABSTRACT: OBJECTIVE:The purpose of this review was to evaluate the current literature on phosphoribosylpyrophosphate synthetase 1 (PRPS1)-related diseases and their consequences on hearing function. DESIGN:A literature search of peer-reviewed, published journal articles was conducted in online bibliographic databases. STUDY SAMPLE:Three databases for medical research were included in this review. RESULTS:Mutations in PRPS1 are associated with a spectrum of non-syndromic to syndromic hearing loss. Hearing loss in male patients with PRPS1 mutations is bilateral, moderate to profound, and can be prelingual or postlingual, progressive or non-progressive. Audiogram shapes associated with PRPS1 deafness are usually residual and flat. Female carriers can have unilateral or bilateral hearing impairment. Gain of function mutations in PRPS1 cause a superactivity of the PRS-I protein whereas the loss-of-function mutations result in X-linked nonsyndromic sensorineural deafness type 2 (DFN2), or in syndromic deafness including Arts syndrome and X-linked Charcot-Marie-Tooth disease-5 (CMTX5). CONCLUSIONS:Lower residual activity in PRS-I leads to a more severe clinical manifestation. Clinical and molecular findings suggest that the four PRPS1 disorders discovered to date belong to the same disease spectrum. Dietary supplementation with S-adenosylmethionine (SAM) appeared to alleviate the symptoms of Arts syndrome patients, suggesting that SAM could compensate for PRS-I deficiency.

SUBMITTER: Liu XZ

PROVIDER: S-EPMC4511087 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.

Liu Xue Zhong XZ Xie Dinghua D Yuan Hui Jun HJ de Brouwer Arjan P M AP Christodoulou John J Yan Denise D

International journal of audiology 20121128 1

<h4>Objective</h4>The purpose of this review was to evaluate the current literature on phosphoribosylpyrophosphate synthetase 1 (PRPS1)-related diseases and their consequences on hearing function.<h4>Design</h4>A literature search of peer-reviewed, published journal articles was conducted in online bibliographic databases.<h4>Study sample</h4>Three databases for medical research were included in this review.<h4>Results</h4>Mutations in PRPS1 are associated with a spectrum of non-syndromic to syn ...[more]

PMID: 23190330

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Project description:Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation.Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation.A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency.These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts.

Dataset Information

Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.

Publications

Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.

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