DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Lichtenstein-Knorr syndrome — 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 moduleLichtenstein-Knorr syndrome 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 lichtenstein-knorr syndrome 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
solute carrier family 9 member A1 (SLC9A1) — SLC9A1 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 azanyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 23XK · 3.1 Å · ligand N-[bis(azanyl)methylidene]-3-methylsulfonyl-4-propan-2-yl-benzamide (HG0). Experimental structure, not a prediction.
What the evidence adds up to
Lichtenstein-Knorr syndrome is an autosomal recessive condition that pairs sensorineural hearing loss with cerebellar ataxia. In 2014, a homozygous p.Gly305Arg missense mutation in SLC9A1, encoding the Na+/H+ exchanger NHE1, was identified in a large consanguineous family. That mutation caused near complete de-glycosylation, mis-targeting, and loss of proton pumping activity of NHE1. The authors concluded that the ataxia and hearing loss resulted from complete or near complete loss of NHE1 function and altered pH regulation in the central nervous system.
A 2022 case report described a 17-year-old boy from a consanguineous marriage who carried a novel homozygous splice site variant c.1573C>T in SLC9A1, leading to a premature stop codon at p.Gln525Ter. He had delayed milestones, progressive gait ataxia from age three, seizures from age eight, and progressive bilateral hearing loss from age ten. MRI showed cerebellar atrophy. He had received vitamin E supplements for about a year with no response, and vitamin B12 supplements. The report notes that only five cases with two variants causing Lichtenstein-Knorr syndrome had been described in the literature up to that point. The authors state that further studies of SLC9A1 in ataxia and hearing loss patients are needed to uncover the full spectrum of the disorder.
Two abstracts retrieved by the search do not concern Lichtenstein-Knorr syndrome. One is a systematic review comparing Desarda versus Lichtenstein technique for primary inguinal hernia repair, involving 1014 patients. It found no significant difference between the two techniques in operating time, return to normal gait, pain score, wound infection, hematoma, foreign body sensation, seroma, or recurrence rate. The other is a Russian study of 100 patients describing a modified Lichtenstein hernia repair that reported lower pain scores and fewer seromas in the modified group. Neither abstract mentions SLC9A1, ataxia, or hearing loss.
What is still missing is any clinical trial of a drug for Lichtenstein-Knorr syndrome. No pharmacological intervention has been tested in patients with SLC9A1 mutations. The only reported treatments are vitamin E and B12, which produced no response. The natural history is progressive, and the underlying mechanism — loss of NHE1 proton pumping — is well described, but no compound has been brought forward to correct it. The field lacks a patient registry, a natural history study with quantitative endpoints, and any funding for preclinical drug screening or repurposing.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 2014 · 47 citations · open access
Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein-Knorr syndrome
AbstractLichtenstein-Knorr syndrome is an autosomal recessive condition that associates sensorineural hearing loss and cerebellar ataxia. Here, we report the first identification of a gene involved in Lichtenstein-Knorr syndrome. By using a combination of homozygosity mapping and whole-exome sequencing, we identified the homozygous p.Gly305Arg missense mutation in SLC9A1 that segregates with the disease in a large consanguineous family. Mutant glycine 305 is a highly conserved amino acid present in the eighth transmembrane segment of all metazoan orthologues of NHE1, the Na(+)/H(+) exchanger 1, encoded by SLC9A1. We demonstrate that the p.Gly305Arg mutation causes the near complete de-glycosylation, mis-targeting and loss of proton pumping activity of NHE1. The comparison of our family with the phenotypes of spontaneous and knockout Slc9a1 murine models demonstrates that the association between ataxia and hearing loss is caused by complete or near complete loss of function of NHE1 and altered regulation of pHi in the central nervous system.
International Journal of Surgery · 2017 · 37 citations
Desarda versus Lichtenstein technique for the treatment of primary inguinal hernia: A systematic review
AbstractBACKGROUND: The aim of this study was to compare the effectiveness between Desarda and Lichtenstein inguinal hernia repair. METHODS: An electronic search for articles about Desarda and Lichtenstein technique published between 2001 and July 2017 was conducted in PubMed, Cochrane Library, Web of Science and EMBASE database. Meta-analysis was performed on surgical time, postoperative recovery, complications and recurrence rate. RESULTS: Eight primary studies identified a total of 1014 patients, of whom 500 and 514 underwent Desarda herniorrhaphy and Lichtenstein herniorrhaphy, respectively. There was no significant difference in terms of operating time, return to normal gait, pain score, wound infection, hematoma, foreinbody sensation, seroma and recurrence rate. CONCLUSIONS: Current evidence suggests that there is no difference between Desarda and Lichtenstein technique in short-term effectiveness. Further high-quality, long follow-up randomized controlled trials are needed to provide more reliable evidence.
Annals of Indian Academy of Neurology · 2022 · 1 citations · open access
Lichtenstein–Knorr Syndrome
AbstractSir, Lichtenstein–Knorr syndrome is a juvenile-onset form of cerebellar ataxia and sensorineural hearing loss. It was first described in 1930 by Lichtenstein and Knorr.[1] To date, only five cases with two variants causing Lichtenstein and Knorr phenotype have been described (literature search in PubMed, Google Scholar, OMIM database). Here, we describe a novel homozygous solute carrier family (SLC9A1) mutation in a 17-year-old boy who presented with ataxia and hearing loss leading to a diagnosis of Lichtenstein–Knorr syndrome. A 17-year-old boy, born out of consanguineous marriage, presented with a history of mental sub-normality, difficulty in walking from three years of age, and seizures from eight years of age. The child had an uneventful perinatal period. He had a delay in milestones involving all domains. The child started walking at the age of three years. However, the mother noticed swaying to either side, recurrent falls, and incoordination of both upper limbs. It was progressive in nature, associated with explosive quality of speech. Subsequently, from the age of eight years, child developed recurrent seizures. Semiology was unresponsiveness that lasted for a few seconds. He was initiated on carbamazepine, following which seizures were controlled. The patient remained seizure-free for one year. However, he started having recurrent episodes despite being on medications. Hence, phenytoin and clobazam were added outside. At the age of 10 years, he developed progressive hearing impairment in both ears. The other siblings were normal. The difficulty in walking and speech disturbances increased from the age of 16 years. There was no significant family history. No history of visual disturbances, weakness of limbs. On examination, child was conscious and following simple commands. Orbito-frontal circumference was 51 cm. Formal cognitive assessment could not be done. He had low set ears, notched incisors, malaligned teeth, and wide epicanthic fold. Parents and siblings did not have dysmorphism. Fundus examination was normal. Eye movements assessment showed multi-directional nystagmus. Bilateral sensorineural hearing loss was present. He had hypotonia of all limbs, deformities of right elbow and wrist in the form of flexion deformity, power of 5/5, areflexia, and flexor plantar response. There was bilateral incoordination of limbs, dysdiadochokinesia, and gait ataxia. Laboratory parameters showed hemoglobin of 11.6 gm%, total leucocyte count of 4700/mm3. He had low serum B12 levels (180 ng/L). His serum ammonia, lactate, and copper levels were within normal limits. Renal function test, liver function test, thyroid function test, and lipid profile were normal. Urine screening for abnormal metabolites and saline dilutional test for acanthocytes were negative. Magnetic resonance imaging (MRI) of brain revealed cerebellar atrophy [Figure 1 and Table 1]. Nerve conduction studies showed a mild decrease in conduction velocities. Brainstem auditory evoked response showed absent waveforms. Visual evoked potential (VEP) of both eyes was normal. He had received vitamin E supplements outside for about a year with no response. He received vitamin B12 supplements. In view of these clinical and investigation findings, a diagnosis of autosomal recessive cerebellar ataxia (ARCA) with sensorineural hearing loss and seizures was considered. ARCA can be sub-classified into congenital like Joubert syndrome, metabolic, that is, Ataxia with vitamin E deficiency, Abetalipoproteinemia, Refsum's disease, deoxyribonucleic acid repair defects, and degenerative types. Most of them have infantile-onset. Few manifest symptoms from adolescence. The clinical clue in our patient was SNHL. Deafness is a feature of Refsum's disease. However, our patient did not have retinitis pigmentosa and other features of Refsum disease. Hence, commonly described ARCAs were ruled out clinically.[2] We proceeded to genetic testing after counseling the family.Figure 1: MRI T1 (a) and T2 FLAIR axial (b) show normal cerebral parenchyma; reveals cerebellar atrophy in T2 FLAIR axial (c) and T1 sagittal image (d)Table 1: Clinical, imaging, and genetic findings of cases reportedOn clinical exome sequencing, a novel homozygous splice site proximal variant c. 1573C>T in exon 6 of the SLC9A1(chr1:27429716G>A) that results in a stop codon and premature truncation of the protein at codon 525 (p.Gln525Ter; ENST00000263980.3) was detected [Figure 2]. The p.Gln525Ter variant has not been reported in the 1000 genomes, ExAC, gnomAD, and NHLBI ESP databases. The insilico prediction of the variant on Variant Effect Predictor, Ensembl release 87 (SIFT version - 5.2.2; PolyPhen - 2.2.2); LRT version - November, 2009 release from dbNSFPv3.1 and Mutation Taster2 based on build NCBI 37/Ensembl 69 predicted this variant as pathogenic. The reference genome is conserved across species. Based on the above evidence and according to American College of Medical Genetics (ACMG) guidelines the SLC9A1 variation is classified as a pathogenic variant. Segregation analysis was performed in the unaffected parents and sibling by Sanger sequencing. The variant was in a heterozygous state in the unaffected parents and unaffected sister Figure 2. The phenotype of the proband is matching with the phenotype caused by pathogenic variants in the gene.Figure 2: Pedigree chart and segregation analysis of sister and parentsLichtenstein–Knorr syndrome is an autosomal recessive neurologic disorder characterized by severe progressive sensorineural hearing loss and progressive cerebellar ataxia. The onset of symptoms is usually in childhood or young adulthood.[3] To date, recessive SLC9A1 related pathogenic variants causing Lichtenstein–Knorr syndrome has been reported in five patients from two families [Table 1]. Our patient developed ataxia and hearing loss beginning in early childhood and progressed till the age of 17 years, like patient 3 of Guissart, Claire et al.[3] 2015. He also had seizures with developmental delay and mental retardation unlike other reported cases. The SLC9A1 is responsible for Na+/H+exchange transport (NHE1).[45] NHE1 is a ubiquitous protein that transports one Na+ into the cell in exchange for one H + against its electrochemical gradient.[56] In the spontaneous mouse mutant, analysis of mutant mouse tissues revealed progressive neuronal degeneration in three regions: vestibular nuclei, cochlear nuclei, and most prominently deep cerebellar nuclei. These sites of pathology correlate with the clinical presentation of our patients, similar to the three patients of family C in Guissart et al.[3] Despite the fact that the SLC9A1 mouse models did not present hearing loss, NHE1 was shown to have an important role in the inner ear by regulating the pH of the endo-lymphatic sac, which is essential for the normal hearing function. It has been shown that changes in the pH of the endolymph cause hearing loss.[7] This is the first detailed explanation of recessive SLC9A1 related Lichtenstein–Knorr Syndrome from South Asia. Further studies of SLC9A1 in ataxia/hearing loss patients will uncover the full spectrum of this unique disorder. In patients with suspected autosomal recessive ataxia, sensorineural hearing loss, and neuropathy are clues for diagnosis. Clinical phenotyping helps us curtail investigations, do specific genetic analysis, and prognosticate the illness. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Pirogov Russian Journal of Surgery · 2022 · 0 citations
New approaches for prevention of complications after Lichtenstein surgery
Abstract<h3>ВВЕДЕНИЕ</h3> Применение синтетических имплантатов в хирургии грыж сопровождается низкой частотой рецидива, но способно вызвать ряд осложнений, таких как длительный болевой синдром и образование хронических сером. <h3>МАТЕРИАЛ И МЕТОДЫ</h3> С целью профилактики осложнений после операции Лихтенштейна нами предложен способ комбинированной герниопластики, включающий 2 новых технических приема. Проведен анализ результатов 100 операций, выполненных за 5 лет по поводу косых паховых грыж в период с 2017 по 2021 г. Больные разделены на две группы по 50 человек в зависимости от выполненного оперативного вмешательства. Проведено сравнение частоты и тяжести хирургических осложнений и длительности стационарного лечения. <h3>РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ</h3> При оценке уровня боли по визуально-аналоговой шкале спустя 1 ч после операции интенсивность боли в зоне вмешательства в основной группе была в 1,3 раза меньше, чем в контрольной, через 1 сут после операции — практически в 2 раза меньше, через 5 дней — в 1,7 раза меньше. Через 3 мес после операции у 1 (2%) пациента в контрольной группе сохранялись жалобы на боли в зоне операции. Среди пациентов основной группы случаев хронической боли не зарегистрировано (<i>p</i><0,05). По данным УЗИ области послеоперационной раны наличие серозной жидкости в области сетки к 6-му дню после операции отмечено у 36 (60%) больных контрольной группы. В основной группе к этому сроку УЗИ-признаков серомы области операции не было ни у кого. Частота осложнений в основной группе достоверно ниже, чем в контрольной (<i>p</i><0,05). Средний срок госпитализации в основной группе был меньше, чем в контрольной (6,2±1,1 и 7,1±1,2 койко-дня соответственно) (<i>p</i><0,05). Таким образом, применение новой модификации операции Лихтенштейна является эффективным методом профилактики наиболее часто встречающихся осложнений после этой операции.
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.
