DeCure for X-linked hereditary sensory and autonomic neuropathy with hearing loss
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for X-linked hereditary sensory and autonomic neuropathy with hearing loss — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleX-linked hereditary sensory and autonomic neuropathy with hearing loss maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for x-linked hereditary sensory and autonomic neuropathy with hearing loss is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
apoptosis inducing factor mitochondria associated 1 (AIFM1) — AIFM1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet faddrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5KVI · 1.995 Å · ligand FLAVIN-ADENINE DINUCLEOTIDE (FAD). Experimental structure, not a prediction.
What the evidence adds up to
X-linked hereditary sensory and autonomic neuropathy with hearing loss is not directly described in these abstracts. The 2006 paper reports a five-generation Chinese family with X-linked recessive auditory neuropathy and progressive peripheral sensory neuropathy, onset at an average age of 13 years, with hearing impairment ranging from mild to severe and absent auditory brainstem responses from onset. Linkage analysis defined a novel locus, AUNX1, on Xq23–q27.3, a 42.09 cM region between markers DXS1220 and DXS8084, but mutation screening of the candidate gene SLC6A14 did not identify the causative variant. The 2017 review lists six loci (DFNX1-6) and five genes for X-linked non-syndromic hearing loss, including AIFM1 for DFNX5 and COL4A6 for DFNX6, and notes that some syndromic forms with large chromosomal deletions are associated with mental retardation. The 2020 case report describes a proband and his brother with prelingual non-syndromic sensorineural hearing loss grade IV–V, carrying a pathogenic variant c.907C>T (p.Pro303Ser) in POU3F4 (DFNX2), which predisposes to the Gusher effect during stapedoplasty; this variant was absent in a control sample of Nogai women.
The 2015 study from a tertiary hospital in South India found that 60% of patients with auditory neuropathy spectrum disorder had neurological involvement, including peripheral neuropathy, hereditary motor-sensory neuropathy, and spastic paresis, and 66% were born of consanguineous marriages. Neurological lesions did not appear simultaneously with hearing loss in most patients. The 2000 and 2014 reviews provide general background on monogenic hearing loss but do not address sensory neuropathy. No abstract reports a drug treatment, repurposed or otherwise, for any form of X-linked hearing loss or neuropathy.
What is missing: no clinical trial has tested any drug for X-linked hereditary sensory and autonomic neuropathy with hearing loss. The causative gene for the AUNX1 locus remains unidentified. Patient stratification by genotype is absent from all studies. Funding for functional studies and for trials of any candidate therapy has not been reported.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2000 · 202 citations
Genetic Causes of Hearing Loss
AbstractHearing loss is the most common sensory defect in humans, affecting normal communication in 10 percent of people aged 65 years or older. In most cases, hearing loss is a multifactorial disorder caused by both genetic and environmental factors. However, single-gene mutations can lead to hearing loss. In these cases, hearing loss is a monogenic disorder with an autosomal dominant, autosomal recessive, X-linked, or mitochondrial mode of inheritance. These monogenic forms of hearing loss can be syndromic (characterized by hearing loss in combination with other abnormalities) or nonsyndromic (with only hearing loss). This review focuses on nonsyndromic hearing loss, since . . .
Current Genomics · 2017 · 64 citations · open access
X-Linked Sensorineural Hearing Loss: A Literature Review
AbstractSensorineural hearing loss is a very diffuse pathology (about 1/1000 born) with several types of transmission. X-linked hearing loss accounts for approximately 1% - 2% of cases of non-syndromic forms, as well as for many syndromic forms. To date, six loci (DFNX1-6) and five genes (PRPS1 for DFNX1, POU3F4 for DFNX2, SMPX for DFNX4, AIFM1 for DFNX5 and COL4A6 for DFNX6) have been identified for X-linked non-syndromic hearing loss. For the syndromic forms, at least 15 genes have been identified, some of which are also implicated in non-syndromic forms. Moreover, some syndromic forms, presenting large chromosomal deletions, are associated with mental retardation too. This review presents an overview of the currently known genes related to X-linked hearing loss with the support of the most recent literature. It summarizes the genetics and clinical features of X-linked hearing loss to give information useful to realize a clear genetic counseling and an early diagnosis. It is important to get an early diagnosis of these diseases to decide the investigations to predict the evolution of the disease and the onset of any other future symptoms. This information will be clearly useful for choosing the best therapeutic strategy. In particular, regarding audiological aspects, this review highlights risks and benefits currently known in some cases for specific therapeutic intervention.
<i>AUNX1</i>, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23–27.3
AbstractBACKGROUND: We report here the genetic characterisation of a large five generation Chinese family with the phenotypic features of auditory neuropathy and progressive peripheral sensory neuropathy, and the genetic feature of X linked recessive inheritance. Disease onset was at adolescence (at an average age of 13 years for six affected subjects). The degree of hearing impairment varied from mild to severe, with decreased otoacoustic emissions; auditory brainstem responses were lacking from onset. METHODS: Two-point and multipoint model based linkage analysis using the MILNK and LINKMAP programs of the FASTLINK software package produced maximum two-point and multipoint LOD scores of 2.41 and 2.41, respectively. RESULTS: These findings define a novel X linked auditory neuropathy locus/region (AUNX1, Xq23-q27.3). This region is 42.09 cM long and contains a 28.07 Mb region with flanking markers DXS1220 and DXS8084, according to the Rutgers Combined Linkage-Physical Map, build 35. However, mutation screen of the candidate gene SLC6A14 within the region did not identify the causative genetic determinant for this large Chinese family.
The Journal of Laryngology & Otology · 2014 · 42 citations
Non-syndromic hereditary sensorineural hearing loss: review of the genes involved
AbstractBACKGROUND: Hereditary sensorineural hearing loss is the most frequently occurring birth defect. It has profound effects for the individual and is a substantial burden on society. Insight into disease mechanisms can help to broaden therapeutic options and considerably lower lifetime social costs. In the past few decades, the identification of genes that can cause this type of hearing loss has developed rapidly. OBJECTIVE: This paper provides a concise overview of the currently known genes involved in non-syndromic hereditary hearing loss and their function in the inner ear.
Russian Bulletin of Otorhinolaryngology · 2020 · 7 citations
Presentation of a rare case of hereditary hearing loss with X-linked recessive inheritance associated with the POU3F4 gene
Abstract<h3></h3> Врожденная потеря слуха — одна из самых частых наследственных патологий человека, она встречается у 1—2 из 1000 новорожденных. Тугоухость с Х-сцепленным типом наследования встречается в 1—5% случаев всех врожденных нарушений слуха. Обратившийся пробанд (мужчина) имеет больного брата, у обоих прелингвальная несиндромальная нейросенсорная тугоухость IV—V степени. Родители здоровы. Цель исследования — определение причины тугоухости в данной семье и оценка популяционной частоты найденного патогенного генетического варианта. Методом NGS обнаружен патогенный вариант c.907C>T (p.Pro303Ser) в гене <i>POU3F4</i> (Xq21.1)<i>.</i> Это второй случай Х-сцепленной тугоухости (DFNX2, OMIM 304400) в Европе, вызванный вариантом c.907C>T в гене <i>POU3F4</i>. DFNX2-тугоухость проявляется аномалиями развития внутреннего уха, предрасполагающими к явлению «эффект Gusher» — это обильная отоликворея при проведении стапедопластики. У брата был диагностирован вариант c.907C>T в гене <i>POU3F4</i> в гемизиготном состоянии, у матери — в гетерозиготном состоянии, у отца — не обнаружен. Молекулярно-генетический анализ показал, что генетический вариант c.907C>T в контрольной выборке здоровых индивидов женского пола из популяции ногайцев не выявлен, что предполагает его низкую частоту в популяции.
Annals of Indian Academy of Neurology · 2015 · 5 citations · open access
Neurological associations in auditory neuropathy spectrum disorder: Results from a tertiary hospital in South India
AbstractAIMS: To find out the prevalence and types of neurological abnormalities associated in auditory neuropathy spectrum disorder in a large tertiary referral center. SETTINGS AND DESIGN: A prospective clinical study was conducted on all patients diagnosed with auditory neuropathy spectrum disorder in the ear, nose, and throat (ENT) and neurology departments during a 17-month period. Patients with neurological abnormalities on history and examination were further assessed by a neurologist to determine the type of disorder present. RESULTS: The frequency of auditory neuropathy spectrum disorder was 1.12%. Sixty percent were found to have neurological involvement. This included cerebral palsy in children, peripheral neuropathy (PN), spinocerebellar ataxia, hereditary motor-sensory neuropathy, spastic paresis, and ponto-bulbar palsy. Neurological lesions did not present simultaneously with hearing loss in most patients. Sixty-six percent of patients with auditory neuropathy spectrum disorder were born of consanguineous marriages. CONCLUSIONS: There is a high prevalence of neurological lesions in auditory neuropathy spectrum disorder which has to be kept in mind while evaluating such patients. Follow-up and counselling regarding the appearance of neuropathies is therefore important in such patients. A hereditary etiology is indicated in a majority of cases of auditory neuropathy spectrum disorder.
Laryngo-Rhino-Otologie · 2022 · 0 citations · open access
A mutation in Atp11a causes autosomal dominant inherited auditory neuropathy type 2 (AUNA2).
AbstractIn 2017, Lang-Roth et al described a large German-born family with age-progressive nonsyndromic sensorineural hearing loss. Preserved otoacoustic emissions and abnormal or absent early auditory evoked potentials and stapedial reflexes suggested a primary disorder of sound coding in the auditory nerve. However, in contrast to other forms of auditory neuropathy, speech comprehension in noise was not significantly impaired beyond the expected level. Genetic linkage analysis revealed 12q24 or 13q34 as possible disease loci (Lang-Roth et al. 2017).
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
