Very early-onset retinal degeneration and sensorineural hearing loss in two unrelated female infants with PRS deficiency

Very early-onset retinal degeneration and sensorineural hearing loss in two unrelated female infants with PRS deficiency | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Very early-onset retinal degeneration and sensorineural hearing loss in two unrelated female infants with PRS deficiency David Zocche, Mariya Moosajee, Alpana M Kulkarni, Robert H Henderson, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6469359/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Phosphoribosyl pyrophosphate synthetase (PRS) deficiency, an X-linked condition caused by loss-of-function variants in PRPS1, manifests as a phenotypic continuum encompassing three previously distinct disorders: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked non-syndromic sensorineural hearing loss (DFNX1). Males are typically more severely affected, while females with the same variant often present with milder forms. We report two unrelated female patients with progressive sensorineural hearing loss and very early-onset retinal degeneration and PRPS1 c.640C>T p.(Arg214Trp) variant. Notably, these cases show retinal involvement earlier than previously reported, expanding the clinical spectrum of PRS deficiency. This report contributes to the growing understanding of the phenotypic variability and complexity of this condition, particularly regarding early ocular manifestations. PRPS1 retinal degeneration sensorineural hearing loss X-linked disorder Figures Figure 1 Figure 2 Figure 3 Introduction Phosphoribosyl pyrophosphate synthetase (PRS) deficiency is a rare X-linked metabolic disorder caused by mutations in the PRPS1 gene, which plays a critical role in nucleotide biosynthesis. 1 PRS deficiency is characterized by a broad phenotypic spectrum, ranging from mild neurological impairments to severe neurodevelopmental delays and multisystemic involvement. 2 Two major forms of PRS deficiency have been described: Arts syndrome, 3 associated with severe neurological symptoms including sensorineural hearing loss and peripheral neuropathy, and a milder form manifesting with isolated neurological abnormalities. 4 The PRPS1 gene encodes the enzyme phosphoribosyl pyrophosphate synthetase 1 (PRS-1), a crucial enzyme in cellular metabolism. It catalyses the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and ATP. This reaction is the first and essential step in pathways that synthesise purine and pyrimidine nucleotides, as well as pyridine nucleotides like NAD and NADP. Pathogenic variants in PRPS1 disrupt these pathways, affecting nucleotide synthesis, energy metabolism, and signalling. In this report, we describe two unrelated paediatric patients with PRPS1 deficiency from distinct families, both presenting with a unique combination of sensorineural hearing loss and early-onset, severe retinal dystrophy. Genetic analysis revealed that both children share the same pathogenic variant in PRPS1 , and no known familial relation. The occurrence of this shared variant in both cases, alongside the presence of early-onset retinal dystrophy, underscores the potential for genotype-phenotype variability in this condition. This case report highlights the need for further investigation into the molecular mechanisms underlying the retinal pathology and expands the clinical spectrum of PRS deficiency. Case presentation Patient 1: P1 is currently 2 years old. She is the second child of healthy, unrelated parents with no family history of hearing or vision loss. Mother reported raised blood pressure during this pregnancy and gestational diabetes. Antenatal scans were unremarkable. P1 was born at term after a delivery. Birth weight was 3kg. She had congenital nystagmus and failed her hearing screen in her left ear. P1 was diagnosed with left-sided mild sensorineural hearing loss at 4kHz (air conduction </=40dbeHL and bone conduction 25dbeHL) on diagnostic auditory brainstem testing (ABR), while hearing in the right ear was normal soon after birth. High frequency tympanometry revealed normal middle ear function bilaterally. Buccal swab for CMV DNA was negative. An MRI of the internal auditory meatus was unremarkable. Development at this stage was age appropriate. At 2 years of age her hearing loss progressed in the low frequency on the right to 30dbHL at 0.25kHz but was satisfactory at other frequencies (</=25dbHl). At age 3, there was further progression, and she now has left moderate and right mild sensorineural hearing loss ( Figure 1a ). She is not ready yet for masked bone conduction hence this could not be ascertained on the left. At 1 year, P1 was sitting with support but had not yet begun crawling. She began walking independently at 18 months. By 3 years of age, P1's gait was unsteady, and she had frequent falls when running. At 1 year of age, ophthalmic electrodiagnostic tests (EDTs) showed severe bilateral generalised retinal disfunction affecting the rod and cone systems at the level of the photoreceptors. There was no regression in motor skills, and her development has shown steady progress. At 2.5 years of age, she had a visual assessment 6/48 with Cardiff cards in the right eye, briefly fixing and following when assessing the left eye. Anterior segments were unremarkable. Fundus imaging on the right eye shows macular atrophy, images not obtainable on the left ( Figure 2 ). Optical coherence tomography (OCT) of both eyes revealed bilateral disruption of the ellipsoid zone with foveal atrophy, consistent with advanced macular involvement ( Figure 3 ). At 3 years, P1 responds to daily speech, though she requires louder vocalizations to gain her attention from another room. Her speech can be loud, and she is capable of joining 2-3 words in a phrase and following simple instructions. Ophthalmological examination at 3 years revealed no structural eye abnormalities. Her gait was broad-based, with normal reflexes and motor strength. Constant pendular horizontal nystagmus was observed in all positions of gaze, and smooth pursuit and saccades were interrupted by nystagmus. Cervical vestibular evoked myogenic potentials (VEMP) were absent bilaterally at 100 dBnHL. Trio whole genome sequencing with analysis of Genomics England virtual panel R32.2 Retinal disorders v3.0 showed heterozygous PRPS1 c.640C>T p.(Arg214Trp) pathogenic variant. This variant was not detected in her parents and deemed to be de novo . P1 was referred to Clinical Genetics for phenotypic assessment to exclude neurological manifestations in keeping with ataxia or CMT-related conditions. P1 had a normal neurological examination, and there were no concerns with motor development or regression of gross motor skills. Patient 2: P2 is a 22-month-old female, the second child of healthy, unrelated parents, with no significant family history of hearing loss or retinal degeneration. She was born at term after an uneventful pregnancy and delivery. Postnatally, there were no concerns, and she did not require admission to the neonatal unit. P2 failed the newborn hearing test and was diagnosed with bilateral sensorineural hearing loss (SNHL). Initially, her right ear exhibited moderate-to-severe SNHL, and her left ear had mild SNHL ( Figure 1b ). She was fitted with hearing aids at 3 months. At her 7-month review, P2 had good motor development, with appropriate head control and attempts to stand. She could sit with support and maintained good eye contact, indicating typical communicative development. However, abnormal eye movements, specifically nystagmus, were observed. Ophthalmology review at the age of 10 months revealed normal fundoscopy but suboptimal vision and bilateral rotatory nystagmus. Audiology testing using auditory brainstem response (ABR) indicated moderate-to-severe hearing loss, with responses around 60 dBeHL in her left ear. Further audiological assessments at 1, 2, and 3 months showed progressive hearing loss. Tympanometry indicated that there was no middle ear effusion. By 10 months, ABR testing revealed a profound sensorineural hearing loss in both ears. Bone conduction testing confirmed that her hearing loss was permanent in nature. She received bilateral cochlear implants at 15 months. MRI head and internal auditory meatus at 4 months showed no abnormalities of the inner ears. Genetic testing, undertaken via the Genomics England R67 monogenic hearing loss panel v3.0, revealed that P2 is heterozygous for the PRPS1 c.640C>T p.(Arg214Trp) likely pathogenic variant. At 13 months, electrodiagnostic testing revealed a non-detectable electroretinogram, and visual evoked potentials were present only for large check sizes, indicating the potential for rudimentary vision. Retinal imaging showed bilateral optic nerve pallor and widespread granular pigment changes at the level of the retinal pigment epithelium (RPE), with macular atrophy in the left eye ( Figure 2b ). These findings suggested severe retinal dystrophy, significantly impairing P2's ability to see fine detail or read. By 16 months, P2 was meeting her developmental milestones except for delayed speech and language skills. She had no seizures or dysmorphic features. Her growth parameters, including head circumference, height, and weight, were within the normal range for her age (64th, 83rd, and 67th percentiles, respectively). At 22 months, a follow-up ophthalmologic evaluation showed continued nystagmus with multiplanar rotary eye movements. Slit lamp and fundus exams indicated normal corneas, lenses, and anterior chambers, but persistent optic nerve pallor and retinal pigmentary changes. Discussion and Conclusions The two cases we describe provide further insight into the phenotypic variability associated with PRPS1 variants. Both children presented with sensorineural hearing loss and early-onset, severe retinal dystrophy, a novel finding in females with PRS deficiency. While progressive sensorineural hearing loss is a well-established feature across the spectrum, 5 ocular involvement is typically mild in females with a much later onset. Fiorentino et al 6 described a mean age of onset of 19 years for retinal degeneration in females, which included 2 female patients with the PRPS1 c.640C>T p.Arg214Trp variant and retinal dystrophy at 25 and 17 years old respectively. Rezende Filho et al 7 additional reported retinal degeneration in a female patient with a PRPS1 variant at 20 years of age, consistent with previous findings. In affected females, who predictably have less severe manifestations, the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome. 8 The severity of retinal dystrophy in our reported individuals is notable, given that both children harbour the same variant as other reported individuals with much later onset 6 In expanding the phenotypic understanding of PRPS1 syndromes, several studies emphasized that even within families carrying the same mutation, the presentation can range from isolated hearing loss to systemic disorders involving ataxia and optic atrophy. 4,9,10 The intricate relationship between hearing loss and retinal impairment highlights the shared molecular pathways and overlapping cellular vulnerabilities in sensory systems. Dual sensory impairment genetic conditions such as Usher syndrome, a sensory hereditary ciliopathy characterized by progressive vision and hearing loss, illustrate these mutual pathophysiological processes. 11 In Usher syndrome type II, pathogenic variants in ADGRV1 or USH2A genes affect proteins involved in the structural integrity of stereocilia in hair cells and photoreceptor ciliary function. 12 Similarly, in Usher syndrome type III, pathogenic variants in CLRN1 disrupt protein functions necessary for hair cell survival and retinal function. 13 A significant proportion of children with permanent childhood hearing impairment also have visual impairments. The British Association of Audiovestibular Physicians (BAAP) guidelines emphasize the importance of eye examinations in this population, noting that 20–60% of children with permanent childhood hearing impairment have undetected visual issues. 14 Comprehensive genomic testing has a high diagnostic yield in cases of dual sensory impairment, facilitating informed management strategies. For instance, Bahena et al reported a 92% diagnostic yield in individuals with dual sensory impairment without intellectual disability. 15 In PRS deficiency, disruptions in nucleotide metabolism and oxidative stress mechanisms may contribute to the simultaneous degeneration of auditory and visual functions, underscoring the importance of these pathways in maintaining sensory cell integrity. Emerging therapeutic strategies for nucleotide metabolism disorders, such as antioxidant therapies 16 and targeted nucleotide supplementation, 17 hold promise for addressing PRPS1 -related dysfunctions, although their efficacy remains to be evaluated in clinical trials. In severe forms of PRPS1 deficiency, supplementation of the purine and NAD pathways outside of PRPP-dependent reactions have been explored as potential treatments. Four reported individuals had stability or improvement of symptoms, suggesting that S-adenosylmethionine and nicotinamide riboside can be a treatment option in Arts syndrome. 18 As an example of antioxidant therapies, in mitochondrial disorders characterized by impaired energy production and increased reactive oxygen species, antioxidant supplementation has been utilized to enhance mitochondrial function and reduce oxidative damage. 19 These therapeutic approaches highlight the potential of antioxidant strategies in managing disorders associated with nucleotide metabolism and oxidative stress. The variability in PRPS1 -related phenotypes, combined with X-linked inheritance and potential skewed X-inactivation in females, presents unique challenges for genetic counselling, necessitating a tailored approach to family planning. However, the expanding understanding of the pathophysiological mechanisms and phenotypic spectrum of this condition, coupled with the increasing number of reported cases and initial therapeutic efforts, provides optimism for improved management and outcomes. Abbreviations No uncommon abbreviations were used in this manuscript. Declarations Ethics approval and consent to participate: Ethics approval not applicable. Consent as stated below. Consent for publication: The mother consented for publication, and the consent form has been submitted to the editor and reviewers. Availability of data and material: not applicable. Competing interests: the authors do not declare any competing interests. Funding: not applicable. Authors' contributions : DZ was responsible for writing the manuscript, EC and RI were responsible for compiling the clinical data, EC and RI were responsible for revising the paper. MM provided retinal images. AK provided audiogram and audiology clinical data for P1. Acknowledgements: We would like to acknowledge the families for their collaboration in this work. References Kim HJ, Sohn KM, Shy ME, et al. 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 . Sep 2007;81(3):552-8. doi:10.1086/519529 Mercati O, Abi Warde MT, Lina-Granade G, et al. PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review. Eur J Med Genet . Nov 2020;63(11):104033. doi:10.1016/j.ejmg.2020.104033 de Brouwer AP, Williams KL, Duley JA, et al. Arts syndrome is caused by loss-of-function mutations in PRPS1. Am J Hum Genet . Sep 2007;81(3):507-18. doi:10.1086/520706 Almoguera B, He S, Corton M, et al. Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy. Orphanet Journal of Rare Diseases . 2014/12/10 2014;9(1):190. doi:10.1186/s13023-014-0190-9 Mittal R, Patel K, Mittal J, et al. Association of PRPS1 Mutations with Disease Phenotypes. Dis Markers . 2015;2015:127013. doi:10.1155/2015/127013 Fiorentino A, Arno G, Pontikos N, et al. Mutations in the X-linked gene PRPS1 cause retinal degeneration in females. Investigative Ophthalmology & Visual Science . 2017;58(8):1243-1243. Rezende Filho FM, Palma MM, Pedroso JL, Barsottini OG, Sallum JM. PRPS1 Gene Mutation Causes Complex X-Linked Adult-Onset Cerebellar Ataxia in Women. Neurol Genet . Apr 2021;7(2):e563. doi:10.1212/nxg.0000000000000563 Synofzik M, Müller vom Hagen J, Haack TB, et al. X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation. Orphanet J Rare Dis . Feb 14 2014;9:24. doi:10.1186/1750-1172-9-24 Liu X, Han D, Li J, et al. Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2. Am J Hum Genet . Jan 2010;86(1):65-71. doi:10.1016/j.ajhg.2009.11.015 Robusto M, Fang M, Asselta R, et al. The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. European Journal of Human Genetics . 2015/06/01 2015;23(6):766-773. doi:10.1038/ejhg.2014.168 Ullah F, Zeeshan Ali M, Ahmad S, et al. Current updates on genetic spectrum of usher syndrome. Nucleosides Nucleotides Nucleic Acids . May 8 2024:1-24. doi:10.1080/15257770.2024.2344194 Koenekoop R, Arriaga M, Trzupek KM, Lentz J. Usher Syndrome Type II. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews(®) . University of Washington, Seattle Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. Ratnam K, Västinsalo H, Roorda A, Sankila EM, Duncan JL. Cone structure in patients with usher syndrome type III and mutations in the Clarin 1 gene. JAMA Ophthalmol . Jan 2013;131(1):67-74. doi:10.1001/2013.jamaophthalmol.2 Hollingsworth R, Ludlow AK, Wilkins A, Calver R, Allen PM. Visual performance and ocular abnormalities in deaf children and young adults: a literature review. Acta Ophthalmol . Jun 2014;92(4):305-10. doi:10.1111/aos.12302 Bahena P, Daftarian N, Maroofian R, et al. Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment. Hum Genet . Apr 2022;141(3-4):785-803. doi:10.1007/s00439-021-02303-1 Pinilla I, Maneu V, Campello L, et al. Inherited Retinal Dystrophies: Role of Oxidative Stress and Inflammation in Their Physiopathology and Therapeutic Implications. Antioxidants (Basel) . May 30 2022;11(6)doi:10.3390/antiox11061086 Martinez Velazquez LA, Ballios BG. The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease. Int J Mol Sci . Oct 26 2021;22(21)doi:10.3390/ijms222111542 Lee A, Knox R, Reynolds M, McRoy E, Nguyen H. S-adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review. JIMD Rep . © 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.; 2023:417-423. vol. 6. Lukashev AN, Skulachev MV, Ostapenko V, Savchenko AY, Pavshintsev VV, Skulachev VP. Advances in development of rechargeable mitochondrial antioxidants. Prog Mol Biol Transl Sci . 2014;127:251-65. doi:10.1016/b978-0-12-394625-6.00010-6 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6469359","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":446252969,"identity":"ddbbbc62-1779-4032-bca3-44ad9e3d5a81","order_by":0,"name":"David Zocche","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYDCCA0DEA2YByQ8gLklaGGdAtDA2ENLCANPCzEOMFr7jZwwPvGGok+NvP3vwse2OO/YM0s3HH+DTInkmx+DgHAY2Y4kzecnGuWeeJTbIHEvEa4vBgbSEwzwMPIkbJHjMpHPbDicwSOQY4tdy/hlIiwRIi/lvy7bD9gwS+R/xa7mRfACoxQBsCzNj22HGBokc/N6XvPH4wME5BglAv+QYS/a2HU5sk0gznIFPC9/5xOYPbypAIXbG8MNPoMP4JZIffMCnBeo8JDYbYeWjYBSMglEwCggBANTxTMrcVXizAAAAAElFTkSuQmCC","orcid":"","institution":"Northwick Park and St Mark's Hospitals","correspondingAuthor":true,"prefix":"","firstName":"David","middleName":"","lastName":"Zocche","suffix":""},{"id":446252970,"identity":"510ecee8-9fb6-4f9b-84d3-afee7662c883","order_by":1,"name":"Mariya Moosajee","email":"","orcid":"","institution":"Moorfields Eye Hospital NHS Foundation Trust","correspondingAuthor":false,"prefix":"","firstName":"Mariya","middleName":"","lastName":"Moosajee","suffix":""},{"id":446252971,"identity":"25e02f8d-5718-4373-9cc4-574646486d07","order_by":2,"name":"Alpana M Kulkarni","email":"","orcid":"","institution":"Hertfordshire Community NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Alpana","middleName":"M","lastName":"Kulkarni","suffix":""},{"id":446252972,"identity":"64c02da3-d4b9-46f6-add9-290ecc0e56dc","order_by":3,"name":"Robert H Henderson","email":"","orcid":"","institution":"UCL Great Ormond Street Institute of Child Health","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"H","lastName":"Henderson","suffix":""},{"id":446252973,"identity":"02e5b097-c0d3-4043-9274-8715a49bb1b2","order_by":4,"name":"Emma Clement","email":"","orcid":"","institution":"Great Ormond Street Hospital for Children","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Clement","suffix":""},{"id":446252974,"identity":"ea589ff4-df27-4c21-bca3-1b79f872adaa","order_by":5,"name":"Rita Ibitoye","email":"","orcid":"","institution":"Northwick Park and St Mark's Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Rita","middleName":"","lastName":"Ibitoye","suffix":""}],"badges":[],"createdAt":"2025-04-17 07:53:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6469359/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6469359/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81198752,"identity":"1f1277e2-9daf-46f7-a1ec-8223d203675d","added_by":"auto","created_at":"2025-04-23 10:52:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":133381,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Pure tone Audiogram of Case 1. This audiogram shows mild-to-moderate sensorineural hearing loss in the right ear (PTA-AC: 35 dBHL) and moderate-to-severe sensorineural hearing loss in the left ear (PTA-AC: 55 dBHL), with a sloping pattern indicating worse thresholds at higher frequencies. \u003cstrong\u003eb.\u003c/strong\u003e Bilateral audiogram of P2 demonstrating severe sensorineural hearing loss with thresholds ranging from 90–100 dB across all tested frequencies in both ears. The findings are symmetric and consistent with profound hearing impairment. AC Air Conduction, BC Bone Conduction, Hz- Hertz, db decibels\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6469359/v1/8a6f5b56882f155bb40ddd0b.png"},{"id":81198754,"identity":"f53dccf2-292f-4bf1-834c-0bee0afc7e18","added_by":"auto","created_at":"2025-04-23 10:52:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1067501,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e Retinal images of patient 1. The retinal image demonstrates atrophy of the retinal pigment epithelium with mottled pigmentation, macular changes suggestive of retinal dystrophy, and peripheral abnormalities consistent with advanced retinal degeneration. \u003cstrong\u003eb. \u003c/strong\u003eOptos pseudocolour fundus of both eyes of patient 2. The images demonstrate macular pigmentation in the right eye, and retinal/RPE atrophy in the left. Both eyes have disc pallor and vascular attenuation with granular pigmentation at the level of the RPE extending to the periphery. The Optos Fundus Autofluorescence imaging is significantly reduced in both eyes.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6469359/v1/e2bd987884154ef38a82ed84.png"},{"id":81198753,"identity":"1051e30c-c991-4512-a64a-9a121a6617aa","added_by":"auto","created_at":"2025-04-23 10:52:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":760402,"visible":true,"origin":"","legend":"\u003cp\u003eOcular CT images for both eyes in patient 1, left(L) and right(R), showing loss of the ellipsoid zone and foveal atrophy. No OCT imaging was possible in patient 2.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6469359/v1/c1c585202d53421c72876fd9.png"},{"id":81198755,"identity":"8a65712c-3c73-4b5d-a44c-19e51fbff406","added_by":"auto","created_at":"2025-04-23 10:53:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2346811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6469359/v1/20cd4c49-706f-4448-be8c-d36670ec606e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Very early-onset retinal degeneration and sensorineural hearing loss in two unrelated female infants with PRS deficiency","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePhosphoribosyl pyrophosphate synthetase (PRS) deficiency is a rare X-linked metabolic disorder caused by mutations in the \u003cem\u003ePRPS1\u003c/em\u003e gene, which plays a critical role in nucleotide biosynthesis.\u003csup\u003e1\u003c/sup\u003e PRS deficiency is characterized by a broad phenotypic spectrum, ranging from mild neurological impairments to severe neurodevelopmental delays and multisystemic involvement.\u003csup\u003e2\u003c/sup\u003e Two major forms of PRS deficiency have been described: Arts syndrome,\u003csup\u003e3\u003c/sup\u003e associated with severe neurological symptoms including sensorineural hearing loss and peripheral neuropathy, and a milder form manifesting with isolated neurological abnormalities.\u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe \u003cem\u003ePRPS1\u003c/em\u003e gene encodes the enzyme phosphoribosyl pyrophosphate synthetase 1 (PRS-1), a crucial enzyme in cellular metabolism. It catalyses the formation of phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and ATP. This reaction is the first and essential step in pathways that synthesise purine and pyrimidine nucleotides, as well as pyridine nucleotides like NAD and NADP. Pathogenic variants in \u003cem\u003ePRPS1\u003c/em\u003e disrupt these pathways, affecting nucleotide synthesis, energy metabolism, and signalling.\u003c/p\u003e\n\u003cp\u003eIn this report, we describe two unrelated paediatric patients with \u003cem\u003ePRPS1\u003c/em\u003e deficiency from distinct families, both presenting with a unique combination of sensorineural hearing loss and early-onset, severe retinal dystrophy. Genetic analysis revealed that both children share the same pathogenic variant in \u003cem\u003ePRPS1\u003c/em\u003e, and no known familial relation. The occurrence of this shared variant in both cases, alongside the presence of early-onset retinal dystrophy, underscores the potential for genotype-phenotype variability in this condition. This case report highlights the need for further investigation into the molecular mechanisms underlying the retinal pathology and expands the clinical spectrum of PRS deficiency.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003e\u003cstrong\u003ePatient 1:\u003c/strong\u003e P1 is currently 2 years old. She is the second child of healthy, unrelated parents with no family history of hearing or vision loss. Mother reported raised blood pressure during this pregnancy and gestational diabetes. Antenatal scans were unremarkable. P1 was born at term after a delivery. Birth weight was 3kg. She had congenital nystagmus and failed her hearing screen in her left ear.\u003c/p\u003e\n\u003cp\u003eP1 was diagnosed with left-sided mild sensorineural hearing loss at 4kHz (air conduction \u0026lt;/=40dbeHL and bone conduction \u0026nbsp;25dbeHL) on diagnostic auditory brainstem testing (ABR), while hearing in the right ear was normal \u0026nbsp;soon after birth. High frequency tympanometry revealed normal middle ear function bilaterally. Buccal swab for CMV DNA was \u0026nbsp;negative. An MRI of the internal auditory meatus was unremarkable. Development at this stage was age appropriate. \u0026nbsp;At 2 years of age her hearing loss progressed in the low frequency on the right to 30dbHL at 0.25kHz but was satisfactory at other frequencies (\u0026lt;/=25dbHl). At age 3, there was further progression, and she now has left moderate and right mild sensorineural hearing loss (\u003cstrong\u003eFigure 1a\u003c/strong\u003e). She is not ready yet for masked bone conduction hence this could not be ascertained on the left.\u003c/p\u003e\n\u003cp\u003eAt 1 year, P1 was sitting with support but had not yet begun crawling. She began walking independently at 18 months. By 3 years of age, P1\u0026apos;s gait was unsteady, and she had frequent falls when running. At 1 year of age, ophthalmic electrodiagnostic tests (EDTs) showed severe bilateral generalised retinal disfunction affecting the rod and cone systems at the level of the photoreceptors. There was no regression in motor skills, and her development has shown steady progress.\u003c/p\u003e\n\u003cp\u003eAt 2.5 years of age, she had a visual assessment 6/48 with Cardiff cards in the right eye, briefly fixing and following when assessing the left eye. Anterior segments were unremarkable. Fundus imaging on the right eye shows macular atrophy, images not obtainable on the left (\u003cstrong\u003eFigure 2\u003c/strong\u003e). Optical coherence tomography (OCT) of both eyes revealed bilateral disruption of the ellipsoid zone with foveal atrophy, consistent with advanced macular involvement (\u003cstrong\u003eFigure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAt 3 years, P1 responds to daily speech, though she requires louder vocalizations to gain her attention from another room. Her speech can be loud, and she is capable of joining 2-3 words in a phrase and following simple instructions.\u003c/p\u003e\n\u003cp\u003eOphthalmological examination at 3 years revealed no structural eye abnormalities. Her gait was broad-based, with normal reflexes and motor strength. Constant pendular horizontal nystagmus was observed in all positions of gaze, and smooth pursuit and saccades were interrupted by nystagmus. Cervical vestibular evoked myogenic potentials (VEMP) were absent bilaterally at 100 dBnHL.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTrio whole genome sequencing with analysis of Genomics England virtual panel R32.2 Retinal disorders v3.0 showed heterozygous \u003cem\u003ePRPS1\u003c/em\u003e c.640C\u0026gt;T p.(Arg214Trp) pathogenic variant. This variant was not detected in her parents and deemed to be \u003cem\u003ede novo\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003eP1 was referred to Clinical Genetics for phenotypic assessment to exclude neurological manifestations in keeping with ataxia or CMT-related conditions. P1 had a normal neurological examination, and there were no concerns with motor development or regression of gross motor skills.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient 2:\u003c/strong\u003e P2 is a 22-month-old female, the second child of healthy, unrelated parents, with no significant family history of hearing loss or retinal degeneration. She was born at term after an uneventful pregnancy and delivery. Postnatally, there were no concerns, and she did not require admission to the neonatal unit.\u003c/p\u003e\n\u003cp\u003eP2 failed the newborn hearing test and was diagnosed with bilateral sensorineural hearing loss (SNHL). Initially, her right ear exhibited moderate-to-severe SNHL, and her left ear had mild SNHL (\u003cstrong\u003eFigure 1b\u003c/strong\u003e). She was fitted with hearing aids at 3 months.\u003c/p\u003e\n\u003cp\u003eAt her 7-month review, P2 had good motor development, with appropriate head control and attempts to stand. She could sit with support and maintained good eye contact, indicating typical communicative development. However, abnormal eye movements, specifically nystagmus, were observed. Ophthalmology review at the age of 10 months revealed normal fundoscopy but suboptimal vision and bilateral rotatory nystagmus. Audiology testing using auditory brainstem response (ABR) indicated moderate-to-severe hearing loss, with responses around 60 dBeHL in her left ear.\u003c/p\u003e\n\u003cp\u003eFurther audiological assessments at 1, 2, and 3 months showed progressive hearing loss. Tympanometry indicated that there was no middle ear effusion. By 10 months, ABR testing revealed a profound sensorineural hearing loss in both ears. Bone conduction testing confirmed that her hearing loss was permanent in nature. She received bilateral cochlear implants at 15 months.\u003c/p\u003e\n\u003cp\u003eMRI head and internal auditory meatus at 4 months showed no abnormalities of the inner ears. Genetic testing, undertaken via the Genomics England R67 monogenic hearing loss panel v3.0, revealed that P2 is heterozygous for the \u003cem\u003ePRPS1\u003c/em\u003e c.640C\u0026gt;T p.(Arg214Trp) likely pathogenic variant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 13 months, electrodiagnostic testing revealed a non-detectable electroretinogram, and visual evoked potentials were present only for large check sizes, indicating the potential for rudimentary vision. Retinal imaging showed bilateral optic nerve pallor and widespread granular pigment changes at the level of the retinal pigment epithelium (RPE), with macular atrophy in the left eye (\u003cstrong\u003eFigure 2b\u003c/strong\u003e). These findings suggested severe retinal dystrophy, significantly impairing P2\u0026apos;s ability to see fine detail or read.\u003c/p\u003e\n\u003cp\u003eBy 16 months, P2 was meeting her developmental milestones except for delayed speech and language skills. She had no seizures or dysmorphic features. Her growth parameters, including head circumference, height, and weight, were within the normal range for her age (64th, 83rd, and 67th percentiles, respectively).\u003c/p\u003e\n\u003cp\u003eAt 22 months, a follow-up ophthalmologic evaluation showed continued nystagmus with multiplanar rotary eye movements. Slit lamp and fundus exams indicated normal corneas, lenses, and anterior chambers, but persistent optic nerve pallor and retinal pigmentary changes.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eThe two cases we describe provide further insight into the phenotypic variability associated with \u003cem\u003ePRPS1\u003c/em\u003e variants. Both children presented with sensorineural hearing loss and early-onset, severe retinal dystrophy, a novel finding in females with PRS deficiency. While progressive sensorineural \u0026nbsp;hearing loss is a well-established feature across the spectrum,\u003csup\u003e5\u003c/sup\u003e ocular involvement is typically mild in females with a much later onset. Fiorentino et al\u003csup\u003e6\u003c/sup\u003e described a mean age of onset of 19 years for retinal degeneration in females, which included 2 female patients with the \u003cem\u003ePRPS1\u003c/em\u003e c.640C\u0026gt;T p.Arg214Trp variant and retinal dystrophy at 25 and 17 years old respectively. Rezende Filho et al\u003csup\u003e7\u003c/sup\u003e additional reported retinal degeneration in a female patient with a \u003cem\u003ePRPS1\u003c/em\u003e variant at 20 years of age, consistent with previous findings.\u003c/p\u003e\n\u003cp\u003eIn affected females, who predictably have less severe manifestations, the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome.\u003csup\u003e8\u003c/sup\u003e The severity of retinal dystrophy in our reported individuals is notable, given that both children harbour the same variant as other reported individuals with much later onset\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn expanding the phenotypic understanding of \u003cem\u003ePRPS1\u003c/em\u003e syndromes, several studies emphasized that even within families carrying the same mutation, the presentation can range from isolated hearing loss to systemic disorders involving ataxia and optic atrophy.\u003csup\u003e4,9,10\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe intricate relationship between hearing loss and retinal impairment highlights the shared molecular pathways and overlapping cellular vulnerabilities in sensory systems. Dual sensory impairment genetic conditions such as Usher syndrome, a sensory hereditary ciliopathy characterized by progressive vision and hearing loss, illustrate these mutual pathophysiological processes.\u003csup\u003e11\u003c/sup\u003e In Usher syndrome type II, pathogenic variants in \u003cem\u003eADGRV1\u003c/em\u003e or \u003cem\u003eUSH2A\u003c/em\u003e genes affect proteins involved in the structural integrity of stereocilia in hair cells and photoreceptor ciliary function.\u003csup\u003e12\u003c/sup\u003e Similarly, in Usher syndrome type III, pathogenic variants in \u003cem\u003eCLRN1\u003c/em\u003e disrupt protein functions necessary for hair cell survival and retinal function.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eA significant proportion of children with permanent childhood hearing impairment also have visual impairments. The British Association of Audiovestibular Physicians (BAAP) guidelines emphasize the importance of eye examinations in this population, noting that 20\u0026ndash;60% of children with permanent childhood hearing impairment have undetected visual issues.\u003csup\u003e14\u003c/sup\u003e Comprehensive genomic testing has a high diagnostic yield in cases of dual sensory impairment, facilitating informed management strategies. For instance, Bahena et al reported a 92% diagnostic yield in individuals with dual sensory impairment without intellectual disability.\u003csup\u003e15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn PRS deficiency, disruptions in nucleotide metabolism and oxidative stress mechanisms may contribute to the simultaneous degeneration of auditory and visual functions, underscoring the importance of these pathways in maintaining sensory cell integrity.\u003c/p\u003e\n\u003cp\u003eEmerging therapeutic strategies for nucleotide metabolism disorders, such as antioxidant therapies\u003csup\u003e16\u003c/sup\u003e and targeted nucleotide supplementation,\u003csup\u003e17\u003c/sup\u003e hold promise for addressing \u003cem\u003ePRPS1\u003c/em\u003e-related dysfunctions, although their efficacy remains to be evaluated in clinical trials.\u003c/p\u003e\n\u003cp\u003eIn severe forms of \u003cem\u003ePRPS1\u003c/em\u003e deficiency, supplementation of the purine and NAD pathways outside of PRPP-dependent reactions have been explored as potential treatments. Four reported individuals had stability or improvement of symptoms, suggesting that S-adenosylmethionine and nicotinamide riboside can be a treatment option in Arts syndrome.\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAs an example of antioxidant therapies, in mitochondrial disorders characterized by impaired energy production and increased reactive oxygen species, antioxidant supplementation has been utilized to enhance mitochondrial function and reduce oxidative damage.\u003csup\u003e19\u003c/sup\u003e These therapeutic approaches highlight the potential of antioxidant strategies in managing disorders associated with nucleotide metabolism and oxidative stress.\u003c/p\u003e\n\u003cp\u003eThe variability in \u003cem\u003ePRPS1\u003c/em\u003e-related phenotypes, combined with X-linked inheritance and potential skewed X-inactivation in females, presents unique challenges for genetic counselling, necessitating a tailored approach to family planning. However, the expanding understanding of the pathophysiological mechanisms and phenotypic spectrum of this condition, coupled with the increasing number of reported cases and initial therapeutic efforts, provides optimism for improved management and outcomes.\u003c/p\u003e"},{"header":"Abbreviations ","content":"\u003cp\u003eNo uncommon abbreviations were used in this manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Ethics approval not applicable. Consent as stated below.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e The mother consented for publication, and the consent form has been submitted to the editor and reviewers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003enot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e the authors do not declare any competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e: DZ was responsible for writing the manuscript, EC and RI were responsible for compiling the clinical data, EC and RI were responsible for revising the paper. MM provided retinal images. AK provided audiogram and audiology clinical data for P1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eWe would like to acknowledge the families for their collaboration in this work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKim HJ, Sohn KM, Shy ME, et al. 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). \u003cem\u003eAm J Hum Genet\u003c/em\u003e. Sep 2007;81(3):552-8. doi:10.1086/519529\u003c/li\u003e\n\u003cli\u003eMercati O, Abi Warde MT, Lina-Granade G, et al. PRPS1 loss-of-function variants, from isolated hearing loss to severe congenital encephalopathy: New cases and literature review. \u003cem\u003eEur J Med Genet\u003c/em\u003e. Nov 2020;63(11):104033. doi:10.1016/j.ejmg.2020.104033\u003c/li\u003e\n\u003cli\u003ede Brouwer AP, Williams KL, Duley JA, et al. Arts syndrome is caused by loss-of-function mutations in PRPS1. \u003cem\u003eAm J Hum Genet\u003c/em\u003e. Sep 2007;81(3):507-18. doi:10.1086/520706\u003c/li\u003e\n\u003cli\u003eAlmoguera B, He S, Corton M, et al. Expanding the phenotype of PRPS1 syndromes in females: neuropathy, hearing loss and retinopathy. \u003cem\u003eOrphanet Journal of Rare Diseases\u003c/em\u003e. 2014/12/10 2014;9(1):190. doi:10.1186/s13023-014-0190-9\u003c/li\u003e\n\u003cli\u003eMittal R, Patel K, Mittal J, et al. Association of PRPS1 Mutations with Disease Phenotypes. \u003cem\u003eDis Markers\u003c/em\u003e. 2015;2015:127013. doi:10.1155/2015/127013\u003c/li\u003e\n\u003cli\u003eFiorentino A, Arno G, Pontikos N, et al. Mutations in the X-linked gene PRPS1 cause retinal degeneration in females. \u003cem\u003eInvestigative Ophthalmology \u0026amp; Visual Science\u003c/em\u003e. 2017;58(8):1243-1243.\u003c/li\u003e\n\u003cli\u003eRezende Filho FM, Palma MM, Pedroso JL, Barsottini OG, Sallum JM. PRPS1 Gene Mutation Causes Complex X-Linked Adult-Onset Cerebellar Ataxia in Women. \u003cem\u003eNeurol Genet\u003c/em\u003e. Apr 2021;7(2):e563. doi:10.1212/nxg.0000000000000563\u003c/li\u003e\n\u003cli\u003eSynofzik M, M\u0026uuml;ller vom Hagen J, Haack TB, et al. X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation. \u003cem\u003eOrphanet J Rare Dis\u003c/em\u003e. Feb 14 2014;9:24. doi:10.1186/1750-1172-9-24\u003c/li\u003e\n\u003cli\u003eLiu X, Han D, Li J, et al. 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In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. \u003cem\u003eGeneReviews(\u0026reg;)\u003c/em\u003e. University of Washington, Seattle Copyright \u0026copy; 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.\u003c/li\u003e\n\u003cli\u003eRatnam K, V\u0026auml;stinsalo H, Roorda A, Sankila EM, Duncan JL. Cone structure in patients with usher syndrome type III and mutations in the Clarin 1 gene. \u003cem\u003eJAMA Ophthalmol\u003c/em\u003e. Jan 2013;131(1):67-74. doi:10.1001/2013.jamaophthalmol.2\u003c/li\u003e\n\u003cli\u003eHollingsworth R, Ludlow AK, Wilkins A, Calver R, Allen PM. Visual performance and ocular abnormalities in deaf children and young adults: a literature review. \u003cem\u003eActa Ophthalmol\u003c/em\u003e. Jun 2014;92(4):305-10. doi:10.1111/aos.12302\u003c/li\u003e\n\u003cli\u003eBahena P, Daftarian N, Maroofian R, et al. 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JIMD Reports published by John Wiley \u0026amp; Sons Ltd on behalf of SSIEM.; 2023:417-423. vol. 6.\u003c/li\u003e\n\u003cli\u003eLukashev AN, Skulachev MV, Ostapenko V, Savchenko AY, Pavshintsev VV, Skulachev VP. Advances in development of rechargeable mitochondrial antioxidants. \u003cem\u003eProg Mol Biol Transl Sci\u003c/em\u003e. 2014;127:251-65. doi:10.1016/b978-0-12-394625-6.00010-6\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"PRPS1, retinal degeneration, sensorineural hearing loss, X-linked disorder","lastPublishedDoi":"10.21203/rs.3.rs-6469359/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6469359/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Phosphoribosyl pyrophosphate synthetase (PRS) deficiency, an X-linked condition caused by loss-of-function variants in PRPS1, manifests as a phenotypic continuum encompassing three previously distinct disorders: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked non-syndromic sensorineural hearing loss (DFNX1). Males are typically more severely affected, while females with the same variant often present with milder forms. We report two unrelated female patients with progressive sensorineural hearing loss and very early-onset retinal degeneration and PRPS1 c.640C\u003eT p.(Arg214Trp) variant. Notably, these cases show retinal involvement earlier than previously reported, expanding the clinical spectrum of PRS deficiency. This report contributes to the growing understanding of the phenotypic variability and complexity of this condition, particularly regarding early ocular manifestations.","manuscriptTitle":"Very early-onset retinal degeneration and sensorineural hearing loss in two unrelated female infants with PRS deficiency","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-23 10:52:52","doi":"10.21203/rs.3.rs-6469359/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8085de34-ac04-44ac-b473-9c5f23304db2","owner":[],"postedDate":"April 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-23T10:52:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-23 10:52:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6469359","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6469359","identity":"rs-6469359","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}