RARE DISEASE
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome
Lesch-Nyhan syndrome
Synonyms: HPRT complete deficiency, HPRT deficiency grade IV, Hypoxanthine guanine phosphoribosyltransferase complete deficiency, Hypoxanthine guanine phosphoribosyltransferase deficiency, grade IV
Synonyms: HPRT complete deficiency, HPRT deficiency grade IV, Hypoxanthine guanine phosphoribosyltransferase complete deficiency, Hypoxanthine guanine phosphoribosyltransferase deficiency, grade IV
Synonyms: HPRT complete deficiency, HPRT deficiency grade IV, Hypoxanthine guanine phosphoribosyltransferase complete deficiency, Hypoxanthine guanine phosphoribosyltransferase deficiency, grade IV
Drug discovery
5
drugs
With orphan designations
Overview
Lesch-Nyhan syndrome is an X-linked recessive disorder caused by HPRT1 gene mutations, leading to deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). This results in hyperuricemia, progressive neurological dysfunction (dystonia, choreoathetosis), and compulsive self-injurious behaviors. Renal complications (nephrolithiasis) and gout arise from uric acid overproduction, while dopaminergic dysfunction underlies neurobehavioral manifestations [1][2][6][10].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
256 drug discovery papers about Lesch-Nyhan syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
256 drug discovery papers about Lesch-Nyhan syndrome, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-13 | Bioinformatic analysis of gene networks and molecular pathways in Lesch-Nyhan Syndrome: A comprehensive enrichment study
Aim: Lesch–Nyhan syndrome (LNS) is a rare X-linked recessive disorder caused by hypoxanthine-guanine phosphoribosyl transferase deficiency, resulting in neurological dysfunction, cognitive impairment, and self-injurious behaviour. Despite longstanding clinical characterisation, molecular networks linking purine metabolism defects to systemic manifestations remain poorly understood. This study aimed to define the functional characteristics, pathway associations, transcriptional regulation, and tissue-specific expression patterns of LNS-associated genes. Methodology: Ten LNS-implicated genes retrieved from GeneCards were analysed via Enrichr. Gene Ontology (GO) 2025 characterised biological processes, molecular functions, and cellular components. Reactome 2024 identified pathway interactions, ChEA predicted transcription factor regulation, HMDB mapped metabolite associations, and GTEx assessed tissue-specific expression. A significance threshold of p < 0.05 was applied. Results: Enrichment analyses highlighted the key roles in purine metabolism, urate transport, dopamine regulation, and nucleotide biosynthesis. Implicated genes were associated with metabolic enzymes, neurotransmitter balance, and lipoprotein particle components. Transcription factor analysis identified regulatory elements governing gene expression, whilst tissue-specific patterns indicated neurological and metabolic involvement. Interpretation: This integrative analysis connects purine metabolic dysregulation with the complex neurological and systemic features of LNS, proposing potential molecular targets warranting further preclinical investigation for therapeutic development. Key words: Bioinformatics, Gene enrichment analysis, HPRT1 deficiency, Lesch-Nyhan syndrome, Purine metabolism
2026-05-01 | Learning and memory disorders in impaired striatum lack sufficient HGPRTI on exposure to caffeine and KBr03, whereas its chemotherapeutic treatment with naringenin-7-O-neohesperidoside was elicited via NOS/cAMP/PKA and BDNF/TrkB signaling responses
• Mixture of caffeine and KBrO 3 causes vasoconstriction injury. • It also promotes striatum limbic neurotransmitter enzymes. • It also exerts the symptoms of Lesch-Nyhan-Syndrome (LNS) • Naringenin-7-O-neohesperidoside inhibits vasoconstriction injury. • It depletes the indicators of LNS in an in-vivo model. This study investigated the chemotherapeutic efficacy of naringenin-7-O-neohesperidoside (NAR) against Lesch-Nyhan syndrome and neurobehavioral abnormalities in rat models. Ninety male Wistar rats were grouped into nine groups (n = 10). Group I: control rats, Group II was exposed to 100 mg/kg KBrO 3 , Group III was exposed to 250 mg/kg CAF, Group IV was exposed to 100 mg/kg KBrO 3 + 250 mg/kg CAF. Group V was administered with 100 mg/kg KBrO 3 + 100 mg/kg HAL. Group VI was administered with 100 mg/kg KBrO 3 + 50 mg/kg NAR. Group VII was administered with 250 mg/kg CAF + 50 mg/kg NAR. Group VIII was treated with 100 mg/kg KBrO 3 + 250 mg/kg CAF + 50 mg/kg NAR. Finally, group IX was treated with 50 mg/kg NAR. The study lasted for five weeks. The result showed that striatal hypoxanthine–guanine-phosphoribosyl transferase-1 (HGPRT1) was suppressed on exposure to KBrO 3 only, CAF only and KBrO 3 + CAF by 52.5% when compared with the control. The post-administration with NAR remarkably elevated the expression of striatal HGPRT1 in relation to the corresponding exposed groups by 22.8%, 31.6%, 40.4% and 14.0%, respectively. NAR also inhibited the activities of arginase and phosphodiesterase-5 1 (PDE-5 1 ) with corresponding up-regulation of dopamine and cAMP-regulated-phosphoprotein (DARPP), brain-derived neurotrophic factor (BDNF), and tropomyosin-receptor-kinase-B (TrkB). Similarly, the gene coding for B-cell lymphoma/leukaemia 11b (Bcl11b) was down-regulated. Additionally, NAR remarkably reduced the activities of AChE, BuChE, MAO-A and enzymes of ATP hydrolysis (ATPase, AMPase and ADA) with consequential increase in NO level. Also, locomotion, coordination, and memory were improved upon post-treatment with NAR, followed by repression of self-mutilation, anxiety and depression. Also, vascular congestion of nigrostriatal tracts, cellular degeneration of striatum, plasma uric-acid and malonaldehyde (MDA) contents were essentially lowered. This study proposes that NAR could be a viable therapeutic agent for the up-regulation of striatal-HGPRTI-gene to inhibit Lesch-Nyhan Syndrome and neurobehavioral abnormalities through NOS/cAMP/PKA and BDNF/TrkB signalling cascades in a rat model
2025-12-01 | Mitochondrial Dysfunction in Primary Mixed Culture of Hippocampal Neurons in the Hprt1del8Val Mouse Model
Biochemical processes in the brain are closely linked to purine metabolism. Cells synthesize purines de novo or by recycling decay products with the participation of the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT), which catalyzes the recycling of purines via the salvage pathway. Deficiency of HGPRT leads to changes in mitochondrial respiration. The aim of the work was to study the mitochondrial bioenergetics of the primary mixed culture of hippocampal neurons on a strain of mice with a patient-specific mutation in the Hprt1 del8Val gene. The study established a violation of the mitochondrial bioenergetics of the primary mixed culture of hippocampal neurons both at the stage of embryonic and postnatal development. A bioenergetic index of cellular health was calculated based on data obtained during a mitochondrial stress test, during which known inhibitors of cellular respiration were sequentially added to the cell culture to assess the mitochondrial profile and the cell’s ability to produce energy. The Bioenergetic Index of Cellular Health combines mitochondrial functional parameters such as ATP-coupled respiration, maximum respiratory capacity, proton leak and non-mitochondrial respiration into a single value. This study impaired mitochondrial bioenergetics in a primary mixed culture of hippocampal neurons during both embryonic and postnatal development. A decrease in mitochondrial respiratory reserve in the embryonic period in mice with a mutation in the Hprt1 del8Val gene was accompanied by a decrease in ATP production. In the culture of postnatal neurons ATP production decreased while non-mitochondrial respiration increased. The bioenergetic index of cellular health in the P2 culture is reduced compared to the E18 culture. The dysfunctions in mitochondrial bioenergetics reveal new mechanisms in understanding the molecular nature underlying the development of severe neurological phenotypes associated with impaired purine metabolism in the brain. Mice with a patient-specific mutation in the Hprt1 del8Val gene are a unique model with altered energy homeostasis making them a reliable tool for finding therapeutic targets aimed at correcting metabolic disorders in Lesch–Nyhan syndrome.
2025-07-28 | Epigenetic modulation of human neurobiological disorders: Lesch-Nyhan disease as a model disorder.
Epigenetics is the study of how cells control gene activity without changing the DNA sequence. Epigenetic changes affect how genes are turned on and off or expressed, and thus help regulate how cells in different parts of the body use the same genetic code. Errors in the epigenetic process can not only lead to abnormal gene activity or inactivity, but can also influence alternative splicing (AS) and could cause human diseases. Understanding of how epigenetic defects can affect human health, especially for neurological disorders, could suggest targets for therapeutic interventions. For such a purpose, the Lesch-Nyhan disease (LND) has been selected as a valuable model to study the genetic-epigenetic interplay, especially to explore the epistasis between the housekeeping hypoxanthine phosphoribosyltransferase 1 (HPRT1) and β-amyloid precursor protein (APP) genes. This review is structured as follows: we begin with an overview about the monogenetic neurological disorders associated with epigenetic changes; next, the current knowledge on HPRT1 and APP genes is provided; then, the epistasis between HPRT1 and APP genes related to the neurobehavioral syndrome in LND is described; and finally, we present the construction of expression vectors to study intermolecular interactions between the hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and APP in LND. Information obtained from such expression vectors would be useful for future directions to design therapies through epigenetic interventions.
2025-03-03 | Purine Metabolism and Dystonia: Perspectives of a Long-Promised Relationship.
Dystonia research focuses on the identification of converging biological pathways, allowing to define molecular drivers that serve as treatment targets. We summarize evidence supporting the concept that aberrations in purine metabolism intersect with dystonia pathogenesis. The recent discovery of IMPDH2-related dystonia introduced a gain-of-function paradigm in purinergic system defects, offering new perspectives to understand purine-pool imbalances in brain diseases. We discuss commonalities between known dystonia-linked mechanisms and mechanisms emerging from studies of purine metabolism disorders including Lesch-Nyhan disease. Together, we hypothesize that a greater appreciation of the relevance of purine perturbances in dystonia can offer fresh avenues for therapeutic intervention. ANN NEUROL 2025;97:809-825.
cell therapies
2025-12-19 | Umbilical Cord Blood Transplantation in Lesch-Nyhan Syndrome: A Case Report and Literature Review.
Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene mutations, leading to HPRT1 deficiency, hyperuricemia, and severe neurological dysfunction, including self-injurious behavior. Hematopoietic stem cell transplantation (HSCT) has been applied to some inborn errors of metabolism (IEM), yet only a few cases with limited success in LNS have been reported. This case was diagnosed with LNS at nine months of age due to developmental delays. He subsequently received 5/6 human leukocyte antigen-matched umbilical cord blood transplantation (UCBT) at 14 months of age. Myeloablative conditioning included fludarabine, busulfan, and antithymocyte globulin. This patient achieved complete donor chimerism on day 32 after UCBT. Before UCBT, the patient's HPRT1 protein was lower than his parents, but the levels increased after UCBT. At 36 months of age, no self-mutilation was noted, and neurological improvement was found. HSCT is more effective in preventing disease progression in IEM than in reversing established manifestations, making early diagnosis critical. In this case, LNS was diagnosed early, allowing prompt HSCT. To our knowledge, this is the youngest LNS patient to receive HSCT. We propose that early HSCT may contribute to neurological improvements. Early UCBT is feasible and may prevent self-mutilation and promote neurological recovery in LNS. Further studies are needed.
2025-08-03 | Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.
Induced pluripotent stem cells (iPSCs) are widely used to model human genetic diseases. The most common strategy involves collecting cells from relevant individuals and then reprogramming them into iPSCs. This strategy is very powerful, but finding enough individuals with a specific genetic disease can be challenging, especially since most are rare. In addition, making numerous iPSC lines is time-consuming and expensive. As a result, most studies have included relatively small numbers of iPSC lines, sometimes from the same individual. Considering the experimental variability obtained using different iPSC lines, there has been great interest in delineating the most efficient number of lines needed to achieve a robust and reproducible result. Several recommendations have been published, although most conclusions have been based on methods where experimental variance from individual cases is difficult to separate from technical issues related to the preparation of iPSCs. The current study used gene expression profiles determined by RNA sequencing (RNAseq) to empirically evaluate the impact of the number of unique individuals and the number of replicate iPSC lines from each individual for modeling Lesch-Nyhan disease (LND). This disease is caused by mutations in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase. Results for detecting disease-relevant changes in gene expression depended on the analytical method employed, and whether or not statistical procedures were used to address multiple iPSC lines from the same individual. In keeping with prior studies, the best results were obtained with iPSC lines from 3-4 unique individuals per group. In contrast to prior studies, results were improved with 2 lines per individual, without statistical corrections for duplicate lines from the same individual. In the current study where all lines were produced in parallel using the same methods, most variance in gene expression came from technical factors unrelated to the individual from whom the iPSC lines were prepared.
2024-11-04 | Unleashing the Power of Induced Pluripotent stem Cells in in vitro Modelling of Lesch-Nyhan Disease.
Lesch-Nyhan disease (LND) is a monogenic rare neurodevelopmental disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT), the key enzyme of the purines salvage pathway. Beyond its well-documented metabolic consequences, HPRT deficiency leads to a distinctive neurobehavioral syndrome characterized by motor disabilities, cognitive deficits, and self-injurious behavior. Although various cell and animal models have been developed to investigate LND pathology, none have adequately elucidated the underlying mechanisms of its neurological alterations. Recent advances in human pluripotent stem cell research and in vitro differentiation techniques have ushered in a new era in rare neurodevelopmental disorders research. Pluripotent stem cells, with their ability to propagate indefinitely and to differentiate into virtually any cell type, offer a valuable alternative for modeling rare diseases, allowing for the detection of pathological events from the earliest stages of neuronal network development. Furthermore, the generation of patient-derived induced pluripotent stem cells using reprogramming technology provides an opportunity to develop a disease-relevant model within the context of a patient-specific genome. In this review, we examine current stem cell-based models of LND and assess their potential as optimal models for exploring key pathological molecular events during neurogenesis and for the discovering novel treatment options. We also address the limitations, challenges, and future prospects for improving the use of iPSCs in LND research.
2021-08-31 | Infectious Endocarditis Derived from a Tongue Ulcer Caused by Self-injurious Behavior in Lesch-Nyhan Syndrome Which Required Total Teeth Extraction and Glossectomy
Introduction: Self-injurious behavior is one of the characteristic symptoms of Lesch-Nyhan syndrome. In severe cases, the patient's lips or tongue are often injured, but there are no reports of cases leading to infective endocarditis via bacteremia. There are non-invasive treatments for self-injurious behavior, but surgery is occasionally needed. Herein, we report a case of Lesch-Nyhan syndrome that required surgery to control self-injurious behavior.Case presentation: A 21-year-old boy with Lesch-Nyhan syndrome exhibited uncontrollable self-injurious behavior. He visited our hospital with a high fever. Physical examination revealed ulcerations on both his lips and tongue, and there was also a defect on his tongue. All blood cultures that were taken were positive. Vegetations were found on the heart valves through echocardiography, revealing that he has infective endocarditis. To prevent recurrence of ulceration, we performed total tooth extraction and glossectomy. After four months, there is no recurrence of ulcerations or infective endocarditis.Discussion: Although total tooth extraction is irreversible, invasive, and has a significant impact on the patient's appearance, it is a definite way not only to prevent ulcerations caused by self-injurious behavior but also to protect his life.
2015-01-23 | Pluripotent Stem Cells and Gene Therapy
Over the past decade, our understanding of stem cell biology has rapidly expanded with the discovery that any mammalian somatic cells can be genetically reprogrammed into a pluripotent state with the potential to differentiate into any cell lineage. Induced pluripotent stem cells (iPSCs) have revolutionized current experimental approaches for understanding the pathophysiological underpinnings of diseases with genetic etiologies. While the translational potential of human iPSCs to correct genetic diseases is great, there is yet no consensus on how to maximize human iPSC production while minimizing negative off-target effects, such as tumorigenesis or immunogenicity of transplanted cells. In this chapter, we will summarize the various reprogramming factor requirements and gene delivery methodologies that have been employed in generating human pluripotent stem cells. We will further focus on the clinical translation of human iPSC technology by discussing how it can be used to model disease as a cell-source for drug discovery and as a direct therapy for reversing phenotypes caused by genetic diseases.
gene therapies
2025-12-22 | Understanding Lesch-Nyhan Syndrome: Overview and Pharmacotherapeutic Strategies
Lesch-Nyhan Syndrome is a rare genetic disorder related to chromosome X and characterized by a mutation in the HGPRT1 gene. This mutation leads to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT). The lack of HGPRT results in the accumulation of uric acid in all body fluids, which in turn causes severe neurological and behavioral symptoms.Self-mutilating behavior, characterized by lip and finger biting, is a hallmark feature of this syndrome. High uric acid levels result in the accumulation of sodium urate crystals in joints, kidneys, the Central Nervous System, and other parts of the body, resulting in swelling of the joints, severe kidney problems, and neurological features. Symptom control is the mainstay of the treatment. Allopurinol can prevent excessive amounts of uric acid accumulation in joints. Kidney stones in Lesch-Nyhan 102Syndrome can be treated with lithotripsy, while physiotherapy is recommended to prevent contractures. However, no standard treatment currently exists to address the neurological symptoms of Lesh-Nyhan Syndrome. A variety of patients can benefit from drugs like diazepam, phenobarbital, haloperidol, levodopa, or carbidopa. Further research into more options, such as targeted gene therapy for the definitive management of the condition, is required to develop a standard treatment.
2025-07-01 | Neurogenetic and inborn errors of metabolism in pediatrics: A case series highlighting phenotypic diversity and treatable presentations
Background: Neurogenetic and inborn errors of metabolism (IEMs) are rare but treatable causes of childhood neuroregression, seizures, and movement disorders. Timely diagnosis using metabolic and genetic tools can reverse or mitigate progression. Methods: We present four pediatric cases with varied neurogenetic and metabolic disorders: Glutaric Aciduria Type I, Biotinidase Deficiency, KCTD7-related Progressive Myoclonus Epilepsy, and Lesch-Nyhan Syndrome. Results: Despite overlapping neurological phenotypes, distinct biochemical and genetic profiles were observed. Early initiation of targeted therapy led to significant clinical improvement in all cases. Conclusion: These cases emphasize the need for early suspicion and investigation of neurogenetic disorders in children with unexplained regression, seizures, or movement abnormalities. Early diagnosis can dramatically alter outcomes in these otherwise devastating conditions.
2023-09-08 | CRISPR/Cas9-mediated generation of human embryonic stem cell sub-lines with HPRT1 gene knockout to model Lesch Nyhan disease.
Lesch-Nyhan disease (LND) is a X-linked genetic disease affecting boys characterized by complex neurological and neuropsychiatric symptoms. LND is caused by loss of function mutations in the HPRT1 gene leading to decrease activity of hypoxanthine-guanine phosphoribosyl transferase enzyme (HGPRT) and altered purine salvage pathway (Lesch and Nyhan, 1964). This study describes the generation of isogenic clones with deletions in HPRT1 produced from one male human embryonic stem cell line using CRISPR/Cas9 strategy. Differentiation of these cells into different neuronal subtypes will help elucidating the neurodevelopmental events leading to LND and develop therapeutic strategies for this devastating neurodevelopmental disorder.
2022-03-02 | Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
2021-03-20 | De novo assembly and delivery to mouse cells of a 101 kb functional human gene.
Design and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here, we describe a workflow for de novo DNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kilobase pairs (kb). The DNA assembly step is supported by an integrated robotic workcell. We demonstrate assembly of the 101 kb human HPRT1 gene in yeast from 3 kb building blocks, precision delivery of the resulting construct to mouse embryonic stem cells, and subsequent expression of the human protein from its full-length human gene in mouse cells. This workflow provides a framework for mammalian genome writing. We envision utility in producing designer variants of human genes linked to disease and their delivery and functional analysis in cell culture or animal models.
proteins
2026-01-17 | Conservative management of oral self-mutilation in Lesch–Nyhan syndrome enhanced by a digital workflow: a case report
Abstract Introduction Lesch-Nyhan Syndrome (LNS) is a rare X-linked disorder characterized by the triad of hyperuricemia, neurological dysfunction, and compulsive self-injurious behavior, often involving oral self-mutilation. Objective This report describes the conservative, multidisciplinary management of severe oral self-mutilation in a hospitalized child with LNS, combining botulinum toxin and a digitally fabricated customized bite plate. Case Report A 10-year-old male with LNS was admitted to the Intensive Care Unit due to gastrostomy-related perforation and sepsis. Oral examination revealed complete permanent dentition, generalized dental calculus and gingivitis, cicatricial lesions on the tongue, and partial loss of the lower lip due to chronic self-biting. Previous provisional bite plates had proven ineffective. Methods The patient underwent periodontal treatment, botulinum toxin application to the bilateral masseter and orbicularis oris muscles, and placement of a customized bite plate fabricated via digital intraoral scanning and 3D printing. Patients with additional neurological conditions might potentially benefit from it. Results Post-intervention, parafunctional movements decreased, soft tissue lesions partially healed, and oral function was preserved without adverse effects. Conclusion This case report reveals that combining tailored care, botulinum toxin therapy, and digital splint manufacture creates a realistic and patient-centered alternative to extreme interventions, preserving oral function and contributing to enhanced quality of life.
2025-12-16 | Uncovering Proteomic and Biochemical Alterations in Plasma from Lesch-Nyhan Disease Patients.
Lesch-Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch-Nyhan variants - LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.
2022-08-11 | Oral Self-Mutilation in Lesch-Nyhan Syndrome: A Case Report
Lesch-Nyhan syndrome (LNS) is an inherited recessive X-related disorder caused by a deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase. It is characterized by dystonia and compulsive self-mutilation, in particular, biting behavior on the oral mucosa, tongue, lips, fingers, and shoulders, typically before one year of age. The majority of these patients require several procedures, including dental extractions, to prevent significant secondary lesions. This article aims to report a clinical case of a 12-year-old boy with an LNS diagnosis who was referred to the Paediatric Stomatology Department of Central Lisbon University Hospital. Since the age of eight, the patient had displayed self-harm behavior, with arm and oral injuries. On evaluation, he presented with deep ulcerated lesions on the lips and tongue, with substance loss associated with a significant decrease in food intake and consequent weight loss. The management included conservative therapy with gabapentin, lorazepam, and botulinum toxin injections. A successful reduction of self-mutilation with no signs of new lesions in the oral cavity and an improvement in nutritional status were reported. The therapeutic approach is essential to provide the best quality of life for patients and their caregivers. To delay radical treatments, multiple therapeutic options can be used. The oral pathology team considered that the most appropriate therapy was botulinum toxin A injections along with therapeutic adjustment, which was effective in wound healing and self-mutilation behavior ceasing at the two-month follow-up.
2022-02-18 | Safety and Efficacy of Botulinum Toxin in the Treatment of Self-Biting Behavior in Lesch-Nyhan Disease.
Lesch-Nyhan disease (LND) is a disease of purine metabolism linked to chromosome X due to the absence or near-absence of enzyme hypoxanthine-guanine phosphoribosyltransferase. Patients with LND have a compulsive autoaggressive behavior that consists of self-mutilation by biting. The objective of this study was to explore the safety and efficacy of botulinum toxin (BoNT) injected into the masticatory muscles and biceps brachii to reduce self-mutilation in patients with LND. We retrospectively analyzed six patients with LND who were treated with BoNT to prevent automutilatory behavior. The patient ages when started on treatment with BoNT were 4, 4.5, 6.6, 7.9, 13.9, and 32.3 years. Patients received a mean number of injections of 20, ranging from 3 to 29, over a period that ranged from 1.5 to 7.1 years. The maximum total dose of Botox was 21.3 units/kg mean and the maximum total dose of Dysport was 37.5 units/kg mean. A total of 119 injections were performed. Of these 113 (95%) were partially or completely effective. Only three of 119 injections (2.5%) produced adverse effects. Botulinum toxin is useful and safe for the treatment of self-biting behavior in patients with LND.
2020-06-24 | Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis.
The nucleotide salvage pathway is used to recycle degraded nucleotides (purines and pyrimidines); one of the enzymes that helps to recycle purines is hypoxanthine guanine phosphoribosyl transferase 1 (HGPRT1). Therefore, defects in this enzyme lead to the accumulation of DNA and nucleotide lesions and hence replication errors and genetic disorders. Missense mutations in hypoxanthine phosphoribosyl transferase 1 (HPRT1) are associated with deficiencies such as Lesch-Nyhan disease and chronic gout, which have manifestations such as arthritis, neurodegeneration, and cognitive disorders. In the present study, we collected 88 non-synonymous single nucleotide polymorphisms (nsSNPs) from the UniProt, dbSNP, ExAC, and ClinVar databases. We used a series of sequence-based and structure-based in silico tools to prioritize and characterize the most pathogenic and stabilizing or destabilizing nsSNPs. Moreover, to obtain the structural impact of the pathogenic mutations, we mapped the mutations to the crystal structure of the HPRT protein. We further subjected these mutant proteins to a 50 ns molecular dynamics simulation (MDS). The MDS trajectory showed that all mutant proteins altered the structural conformation and dynamic behavior of the HPRT protein and corroborated its association with LND and gout. This study provides essential information regarding the use of HPRT protein mutants as potential targets for therapeutic development.
small molecules
2026-07-13 | Bioinformatic analysis of gene networks and molecular pathways in Lesch-Nyhan Syndrome: A comprehensive enrichment study
Aim: Lesch–Nyhan syndrome (LNS) is a rare X-linked recessive disorder caused by hypoxanthine-guanine phosphoribosyl transferase deficiency, resulting in neurological dysfunction, cognitive impairment, and self-injurious behaviour. Despite longstanding clinical characterisation, molecular networks linking purine metabolism defects to systemic manifestations remain poorly understood. This study aimed to define the functional characteristics, pathway associations, transcriptional regulation, and tissue-specific expression patterns of LNS-associated genes. Methodology: Ten LNS-implicated genes retrieved from GeneCards were analysed via Enrichr. Gene Ontology (GO) 2025 characterised biological processes, molecular functions, and cellular components. Reactome 2024 identified pathway interactions, ChEA predicted transcription factor regulation, HMDB mapped metabolite associations, and GTEx assessed tissue-specific expression. A significance threshold of p < 0.05 was applied. Results: Enrichment analyses highlighted the key roles in purine metabolism, urate transport, dopamine regulation, and nucleotide biosynthesis. Implicated genes were associated with metabolic enzymes, neurotransmitter balance, and lipoprotein particle components. Transcription factor analysis identified regulatory elements governing gene expression, whilst tissue-specific patterns indicated neurological and metabolic involvement. Interpretation: This integrative analysis connects purine metabolic dysregulation with the complex neurological and systemic features of LNS, proposing potential molecular targets warranting further preclinical investigation for therapeutic development. Key words: Bioinformatics, Gene enrichment analysis, HPRT1 deficiency, Lesch-Nyhan syndrome, Purine metabolism
2026-05-01 | Learning and memory disorders in impaired striatum lack sufficient HGPRTI on exposure to caffeine and KBr03, whereas its chemotherapeutic treatment with naringenin-7-O-neohesperidoside was elicited via NOS/cAMP/PKA and BDNF/TrkB signaling responses
• Mixture of caffeine and KBrO 3 causes vasoconstriction injury. • It also promotes striatum limbic neurotransmitter enzymes. • It also exerts the symptoms of Lesch-Nyhan-Syndrome (LNS) • Naringenin-7-O-neohesperidoside inhibits vasoconstriction injury. • It depletes the indicators of LNS in an in-vivo model. This study investigated the chemotherapeutic efficacy of naringenin-7-O-neohesperidoside (NAR) against Lesch-Nyhan syndrome and neurobehavioral abnormalities in rat models. Ninety male Wistar rats were grouped into nine groups (n = 10). Group I: control rats, Group II was exposed to 100 mg/kg KBrO 3 , Group III was exposed to 250 mg/kg CAF, Group IV was exposed to 100 mg/kg KBrO 3 + 250 mg/kg CAF. Group V was administered with 100 mg/kg KBrO 3 + 100 mg/kg HAL. Group VI was administered with 100 mg/kg KBrO 3 + 50 mg/kg NAR. Group VII was administered with 250 mg/kg CAF + 50 mg/kg NAR. Group VIII was treated with 100 mg/kg KBrO 3 + 250 mg/kg CAF + 50 mg/kg NAR. Finally, group IX was treated with 50 mg/kg NAR. The study lasted for five weeks. The result showed that striatal hypoxanthine–guanine-phosphoribosyl transferase-1 (HGPRT1) was suppressed on exposure to KBrO 3 only, CAF only and KBrO 3 + CAF by 52.5% when compared with the control. The post-administration with NAR remarkably elevated the expression of striatal HGPRT1 in relation to the corresponding exposed groups by 22.8%, 31.6%, 40.4% and 14.0%, respectively. NAR also inhibited the activities of arginase and phosphodiesterase-5 1 (PDE-5 1 ) with corresponding up-regulation of dopamine and cAMP-regulated-phosphoprotein (DARPP), brain-derived neurotrophic factor (BDNF), and tropomyosin-receptor-kinase-B (TrkB). Similarly, the gene coding for B-cell lymphoma/leukaemia 11b (Bcl11b) was down-regulated. Additionally, NAR remarkably reduced the activities of AChE, BuChE, MAO-A and enzymes of ATP hydrolysis (ATPase, AMPase and ADA) with consequential increase in NO level. Also, locomotion, coordination, and memory were improved upon post-treatment with NAR, followed by repression of self-mutilation, anxiety and depression. Also, vascular congestion of nigrostriatal tracts, cellular degeneration of striatum, plasma uric-acid and malonaldehyde (MDA) contents were essentially lowered. This study proposes that NAR could be a viable therapeutic agent for the up-regulation of striatal-HGPRTI-gene to inhibit Lesch-Nyhan Syndrome and neurobehavioral abnormalities through NOS/cAMP/PKA and BDNF/TrkB signalling cascades in a rat model
2025-12-01 | Mitochondrial Dysfunction in Primary Mixed Culture of Hippocampal Neurons in the Hprt1del8Val Mouse Model
Biochemical processes in the brain are closely linked to purine metabolism. Cells synthesize purines de novo or by recycling decay products with the participation of the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT), which catalyzes the recycling of purines via the salvage pathway. Deficiency of HGPRT leads to changes in mitochondrial respiration. The aim of the work was to study the mitochondrial bioenergetics of the primary mixed culture of hippocampal neurons on a strain of mice with a patient-specific mutation in the Hprt1 del8Val gene. The study established a violation of the mitochondrial bioenergetics of the primary mixed culture of hippocampal neurons both at the stage of embryonic and postnatal development. A bioenergetic index of cellular health was calculated based on data obtained during a mitochondrial stress test, during which known inhibitors of cellular respiration were sequentially added to the cell culture to assess the mitochondrial profile and the cell’s ability to produce energy. The Bioenergetic Index of Cellular Health combines mitochondrial functional parameters such as ATP-coupled respiration, maximum respiratory capacity, proton leak and non-mitochondrial respiration into a single value. This study impaired mitochondrial bioenergetics in a primary mixed culture of hippocampal neurons during both embryonic and postnatal development. A decrease in mitochondrial respiratory reserve in the embryonic period in mice with a mutation in the Hprt1 del8Val gene was accompanied by a decrease in ATP production. In the culture of postnatal neurons ATP production decreased while non-mitochondrial respiration increased. The bioenergetic index of cellular health in the P2 culture is reduced compared to the E18 culture. The dysfunctions in mitochondrial bioenergetics reveal new mechanisms in understanding the molecular nature underlying the development of severe neurological phenotypes associated with impaired purine metabolism in the brain. Mice with a patient-specific mutation in the Hprt1 del8Val gene are a unique model with altered energy homeostasis making them a reliable tool for finding therapeutic targets aimed at correcting metabolic disorders in Lesch–Nyhan syndrome.
2025-07-28 | Epigenetic modulation of human neurobiological disorders: Lesch-Nyhan disease as a model disorder.
Epigenetics is the study of how cells control gene activity without changing the DNA sequence. Epigenetic changes affect how genes are turned on and off or expressed, and thus help regulate how cells in different parts of the body use the same genetic code. Errors in the epigenetic process can not only lead to abnormal gene activity or inactivity, but can also influence alternative splicing (AS) and could cause human diseases. Understanding of how epigenetic defects can affect human health, especially for neurological disorders, could suggest targets for therapeutic interventions. For such a purpose, the Lesch-Nyhan disease (LND) has been selected as a valuable model to study the genetic-epigenetic interplay, especially to explore the epistasis between the housekeeping hypoxanthine phosphoribosyltransferase 1 (HPRT1) and β-amyloid precursor protein (APP) genes. This review is structured as follows: we begin with an overview about the monogenetic neurological disorders associated with epigenetic changes; next, the current knowledge on HPRT1 and APP genes is provided; then, the epistasis between HPRT1 and APP genes related to the neurobehavioral syndrome in LND is described; and finally, we present the construction of expression vectors to study intermolecular interactions between the hypoxanthine-guanine phosphoribosyltransferase (HGprt) enzyme and APP in LND. Information obtained from such expression vectors would be useful for future directions to design therapies through epigenetic interventions.
2025-03-03 | Purine Metabolism and Dystonia: Perspectives of a Long-Promised Relationship.
Dystonia research focuses on the identification of converging biological pathways, allowing to define molecular drivers that serve as treatment targets. We summarize evidence supporting the concept that aberrations in purine metabolism intersect with dystonia pathogenesis. The recent discovery of IMPDH2-related dystonia introduced a gain-of-function paradigm in purinergic system defects, offering new perspectives to understand purine-pool imbalances in brain diseases. We discuss commonalities between known dystonia-linked mechanisms and mechanisms emerging from studies of purine metabolism disorders including Lesch-Nyhan disease. Together, we hypothesize that a greater appreciation of the relevance of purine perturbances in dystonia can offer fresh avenues for therapeutic intervention. ANN NEUROL 2025;97:809-825.
cell therapies
2025-12-19 | Umbilical Cord Blood Transplantation in Lesch-Nyhan Syndrome: A Case Report and Literature Review.
Lesch-Nyhan syndrome (LNS) is a rare X-linked disorder caused by hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene mutations, leading to HPRT1 deficiency, hyperuricemia, and severe neurological dysfunction, including self-injurious behavior. Hematopoietic stem cell transplantation (HSCT) has been applied to some inborn errors of metabolism (IEM), yet only a few cases with limited success in LNS have been reported. This case was diagnosed with LNS at nine months of age due to developmental delays. He subsequently received 5/6 human leukocyte antigen-matched umbilical cord blood transplantation (UCBT) at 14 months of age. Myeloablative conditioning included fludarabine, busulfan, and antithymocyte globulin. This patient achieved complete donor chimerism on day 32 after UCBT. Before UCBT, the patient's HPRT1 protein was lower than his parents, but the levels increased after UCBT. At 36 months of age, no self-mutilation was noted, and neurological improvement was found. HSCT is more effective in preventing disease progression in IEM than in reversing established manifestations, making early diagnosis critical. In this case, LNS was diagnosed early, allowing prompt HSCT. To our knowledge, this is the youngest LNS patient to receive HSCT. We propose that early HSCT may contribute to neurological improvements. Early UCBT is feasible and may prevent self-mutilation and promote neurological recovery in LNS. Further studies are needed.
2025-08-03 | Modeling rare genetic disease with patient-derived induced pluripotent stem cells: reassessment of the minimum numbers of lines needed.
Induced pluripotent stem cells (iPSCs) are widely used to model human genetic diseases. The most common strategy involves collecting cells from relevant individuals and then reprogramming them into iPSCs. This strategy is very powerful, but finding enough individuals with a specific genetic disease can be challenging, especially since most are rare. In addition, making numerous iPSC lines is time-consuming and expensive. As a result, most studies have included relatively small numbers of iPSC lines, sometimes from the same individual. Considering the experimental variability obtained using different iPSC lines, there has been great interest in delineating the most efficient number of lines needed to achieve a robust and reproducible result. Several recommendations have been published, although most conclusions have been based on methods where experimental variance from individual cases is difficult to separate from technical issues related to the preparation of iPSCs. The current study used gene expression profiles determined by RNA sequencing (RNAseq) to empirically evaluate the impact of the number of unique individuals and the number of replicate iPSC lines from each individual for modeling Lesch-Nyhan disease (LND). This disease is caused by mutations in the HPRT1 gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase. Results for detecting disease-relevant changes in gene expression depended on the analytical method employed, and whether or not statistical procedures were used to address multiple iPSC lines from the same individual. In keeping with prior studies, the best results were obtained with iPSC lines from 3-4 unique individuals per group. In contrast to prior studies, results were improved with 2 lines per individual, without statistical corrections for duplicate lines from the same individual. In the current study where all lines were produced in parallel using the same methods, most variance in gene expression came from technical factors unrelated to the individual from whom the iPSC lines were prepared.
2024-11-04 | Unleashing the Power of Induced Pluripotent stem Cells in in vitro Modelling of Lesch-Nyhan Disease.
Lesch-Nyhan disease (LND) is a monogenic rare neurodevelopmental disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT), the key enzyme of the purines salvage pathway. Beyond its well-documented metabolic consequences, HPRT deficiency leads to a distinctive neurobehavioral syndrome characterized by motor disabilities, cognitive deficits, and self-injurious behavior. Although various cell and animal models have been developed to investigate LND pathology, none have adequately elucidated the underlying mechanisms of its neurological alterations. Recent advances in human pluripotent stem cell research and in vitro differentiation techniques have ushered in a new era in rare neurodevelopmental disorders research. Pluripotent stem cells, with their ability to propagate indefinitely and to differentiate into virtually any cell type, offer a valuable alternative for modeling rare diseases, allowing for the detection of pathological events from the earliest stages of neuronal network development. Furthermore, the generation of patient-derived induced pluripotent stem cells using reprogramming technology provides an opportunity to develop a disease-relevant model within the context of a patient-specific genome. In this review, we examine current stem cell-based models of LND and assess their potential as optimal models for exploring key pathological molecular events during neurogenesis and for the discovering novel treatment options. We also address the limitations, challenges, and future prospects for improving the use of iPSCs in LND research.
2021-08-31 | Infectious Endocarditis Derived from a Tongue Ulcer Caused by Self-injurious Behavior in Lesch-Nyhan Syndrome Which Required Total Teeth Extraction and Glossectomy
Introduction: Self-injurious behavior is one of the characteristic symptoms of Lesch-Nyhan syndrome. In severe cases, the patient's lips or tongue are often injured, but there are no reports of cases leading to infective endocarditis via bacteremia. There are non-invasive treatments for self-injurious behavior, but surgery is occasionally needed. Herein, we report a case of Lesch-Nyhan syndrome that required surgery to control self-injurious behavior.Case presentation: A 21-year-old boy with Lesch-Nyhan syndrome exhibited uncontrollable self-injurious behavior. He visited our hospital with a high fever. Physical examination revealed ulcerations on both his lips and tongue, and there was also a defect on his tongue. All blood cultures that were taken were positive. Vegetations were found on the heart valves through echocardiography, revealing that he has infective endocarditis. To prevent recurrence of ulceration, we performed total tooth extraction and glossectomy. After four months, there is no recurrence of ulcerations or infective endocarditis.Discussion: Although total tooth extraction is irreversible, invasive, and has a significant impact on the patient's appearance, it is a definite way not only to prevent ulcerations caused by self-injurious behavior but also to protect his life.
2015-01-23 | Pluripotent Stem Cells and Gene Therapy
Over the past decade, our understanding of stem cell biology has rapidly expanded with the discovery that any mammalian somatic cells can be genetically reprogrammed into a pluripotent state with the potential to differentiate into any cell lineage. Induced pluripotent stem cells (iPSCs) have revolutionized current experimental approaches for understanding the pathophysiological underpinnings of diseases with genetic etiologies. While the translational potential of human iPSCs to correct genetic diseases is great, there is yet no consensus on how to maximize human iPSC production while minimizing negative off-target effects, such as tumorigenesis or immunogenicity of transplanted cells. In this chapter, we will summarize the various reprogramming factor requirements and gene delivery methodologies that have been employed in generating human pluripotent stem cells. We will further focus on the clinical translation of human iPSC technology by discussing how it can be used to model disease as a cell-source for drug discovery and as a direct therapy for reversing phenotypes caused by genetic diseases.
gene therapies
2025-12-22 | Understanding Lesch-Nyhan Syndrome: Overview and Pharmacotherapeutic Strategies
Lesch-Nyhan Syndrome is a rare genetic disorder related to chromosome X and characterized by a mutation in the HGPRT1 gene. This mutation leads to a deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT). The lack of HGPRT results in the accumulation of uric acid in all body fluids, which in turn causes severe neurological and behavioral symptoms.Self-mutilating behavior, characterized by lip and finger biting, is a hallmark feature of this syndrome. High uric acid levels result in the accumulation of sodium urate crystals in joints, kidneys, the Central Nervous System, and other parts of the body, resulting in swelling of the joints, severe kidney problems, and neurological features. Symptom control is the mainstay of the treatment. Allopurinol can prevent excessive amounts of uric acid accumulation in joints. Kidney stones in Lesch-Nyhan 102Syndrome can be treated with lithotripsy, while physiotherapy is recommended to prevent contractures. However, no standard treatment currently exists to address the neurological symptoms of Lesh-Nyhan Syndrome. A variety of patients can benefit from drugs like diazepam, phenobarbital, haloperidol, levodopa, or carbidopa. Further research into more options, such as targeted gene therapy for the definitive management of the condition, is required to develop a standard treatment.
2025-07-01 | Neurogenetic and inborn errors of metabolism in pediatrics: A case series highlighting phenotypic diversity and treatable presentations
Background: Neurogenetic and inborn errors of metabolism (IEMs) are rare but treatable causes of childhood neuroregression, seizures, and movement disorders. Timely diagnosis using metabolic and genetic tools can reverse or mitigate progression. Methods: We present four pediatric cases with varied neurogenetic and metabolic disorders: Glutaric Aciduria Type I, Biotinidase Deficiency, KCTD7-related Progressive Myoclonus Epilepsy, and Lesch-Nyhan Syndrome. Results: Despite overlapping neurological phenotypes, distinct biochemical and genetic profiles were observed. Early initiation of targeted therapy led to significant clinical improvement in all cases. Conclusion: These cases emphasize the need for early suspicion and investigation of neurogenetic disorders in children with unexplained regression, seizures, or movement abnormalities. Early diagnosis can dramatically alter outcomes in these otherwise devastating conditions.
2023-09-08 | CRISPR/Cas9-mediated generation of human embryonic stem cell sub-lines with HPRT1 gene knockout to model Lesch Nyhan disease.
Lesch-Nyhan disease (LND) is a X-linked genetic disease affecting boys characterized by complex neurological and neuropsychiatric symptoms. LND is caused by loss of function mutations in the HPRT1 gene leading to decrease activity of hypoxanthine-guanine phosphoribosyl transferase enzyme (HGPRT) and altered purine salvage pathway (Lesch and Nyhan, 1964). This study describes the generation of isogenic clones with deletions in HPRT1 produced from one male human embryonic stem cell line using CRISPR/Cas9 strategy. Differentiation of these cells into different neuronal subtypes will help elucidating the neurodevelopmental events leading to LND and develop therapeutic strategies for this devastating neurodevelopmental disorder.
2022-03-02 | Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.
Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
2021-03-20 | De novo assembly and delivery to mouse cells of a 101 kb functional human gene.
Design and large-scale synthesis of DNA has been applied to the functional study of viral and microbial genomes. New and expanded technology development is required to unlock the transformative potential of such bottom-up approaches to the study of larger mammalian genomes. Two major challenges include assembling and delivering long DNA sequences. Here, we describe a workflow for de novo DNA assembly and delivery that enables functional evaluation of mammalian genes on the length scale of 100 kilobase pairs (kb). The DNA assembly step is supported by an integrated robotic workcell. We demonstrate assembly of the 101 kb human HPRT1 gene in yeast from 3 kb building blocks, precision delivery of the resulting construct to mouse embryonic stem cells, and subsequent expression of the human protein from its full-length human gene in mouse cells. This workflow provides a framework for mammalian genome writing. We envision utility in producing designer variants of human genes linked to disease and their delivery and functional analysis in cell culture or animal models.
proteins
2026-01-17 | Conservative management of oral self-mutilation in Lesch–Nyhan syndrome enhanced by a digital workflow: a case report
Abstract Introduction Lesch-Nyhan Syndrome (LNS) is a rare X-linked disorder characterized by the triad of hyperuricemia, neurological dysfunction, and compulsive self-injurious behavior, often involving oral self-mutilation. Objective This report describes the conservative, multidisciplinary management of severe oral self-mutilation in a hospitalized child with LNS, combining botulinum toxin and a digitally fabricated customized bite plate. Case Report A 10-year-old male with LNS was admitted to the Intensive Care Unit due to gastrostomy-related perforation and sepsis. Oral examination revealed complete permanent dentition, generalized dental calculus and gingivitis, cicatricial lesions on the tongue, and partial loss of the lower lip due to chronic self-biting. Previous provisional bite plates had proven ineffective. Methods The patient underwent periodontal treatment, botulinum toxin application to the bilateral masseter and orbicularis oris muscles, and placement of a customized bite plate fabricated via digital intraoral scanning and 3D printing. Patients with additional neurological conditions might potentially benefit from it. Results Post-intervention, parafunctional movements decreased, soft tissue lesions partially healed, and oral function was preserved without adverse effects. Conclusion This case report reveals that combining tailored care, botulinum toxin therapy, and digital splint manufacture creates a realistic and patient-centered alternative to extreme interventions, preserving oral function and contributing to enhanced quality of life.
2025-12-16 | Uncovering Proteomic and Biochemical Alterations in Plasma from Lesch-Nyhan Disease Patients.
Lesch-Nyhan disease (LND) is an ultra-rare X-linked inborn error of metabolism caused by complete or partial deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), a key enzyme in the purine salvage pathway. This defect leads to uric acid overproduction and a broad spectrum of neurological and behavioral manifestations, whose severity depends on the degree of residual enzymatic activity. Although emerging evidence implicates HPRT deficiency in widespread cellular dysfunctions, particularly within midbrain dopaminergic neurons, the molecular mechanisms underlying the neurobehavioral phenotype of HPRT deficiency remain poorly understood and are not adequately explained by purine metabolism dysfunctions alone. Although proteomics represents a powerful approach for elucidating molecular alterations underlying disease, it has so far found only limited application in LND research. To address this gap, we provide here the first proteomic study combined with clinical biochemistry data and pro-inflammatory cytokines profiling of plasma samples from 29 HPRT deficient individuals (21 with classic LND and 8 with Lesch-Nyhan variants - LNV). We suggest that plasma proteomics might be a potential tool in LND for monitoring disease progression and therapeutic response, potentially paving the way for targeted treatment strategies that extend beyond the purine salvage pathway to address the currently unmet clinical needs of LND patients.
2022-08-11 | Oral Self-Mutilation in Lesch-Nyhan Syndrome: A Case Report
Lesch-Nyhan syndrome (LNS) is an inherited recessive X-related disorder caused by a deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase. It is characterized by dystonia and compulsive self-mutilation, in particular, biting behavior on the oral mucosa, tongue, lips, fingers, and shoulders, typically before one year of age. The majority of these patients require several procedures, including dental extractions, to prevent significant secondary lesions. This article aims to report a clinical case of a 12-year-old boy with an LNS diagnosis who was referred to the Paediatric Stomatology Department of Central Lisbon University Hospital. Since the age of eight, the patient had displayed self-harm behavior, with arm and oral injuries. On evaluation, he presented with deep ulcerated lesions on the lips and tongue, with substance loss associated with a significant decrease in food intake and consequent weight loss. The management included conservative therapy with gabapentin, lorazepam, and botulinum toxin injections. A successful reduction of self-mutilation with no signs of new lesions in the oral cavity and an improvement in nutritional status were reported. The therapeutic approach is essential to provide the best quality of life for patients and their caregivers. To delay radical treatments, multiple therapeutic options can be used. The oral pathology team considered that the most appropriate therapy was botulinum toxin A injections along with therapeutic adjustment, which was effective in wound healing and self-mutilation behavior ceasing at the two-month follow-up.
2022-02-18 | Safety and Efficacy of Botulinum Toxin in the Treatment of Self-Biting Behavior in Lesch-Nyhan Disease.
Lesch-Nyhan disease (LND) is a disease of purine metabolism linked to chromosome X due to the absence or near-absence of enzyme hypoxanthine-guanine phosphoribosyltransferase. Patients with LND have a compulsive autoaggressive behavior that consists of self-mutilation by biting. The objective of this study was to explore the safety and efficacy of botulinum toxin (BoNT) injected into the masticatory muscles and biceps brachii to reduce self-mutilation in patients with LND. We retrospectively analyzed six patients with LND who were treated with BoNT to prevent automutilatory behavior. The patient ages when started on treatment with BoNT were 4, 4.5, 6.6, 7.9, 13.9, and 32.3 years. Patients received a mean number of injections of 20, ranging from 3 to 29, over a period that ranged from 1.5 to 7.1 years. The maximum total dose of Botox was 21.3 units/kg mean and the maximum total dose of Dysport was 37.5 units/kg mean. A total of 119 injections were performed. Of these 113 (95%) were partially or completely effective. Only three of 119 injections (2.5%) produced adverse effects. Botulinum toxin is useful and safe for the treatment of self-biting behavior in patients with LND.
2020-06-24 | Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis.
The nucleotide salvage pathway is used to recycle degraded nucleotides (purines and pyrimidines); one of the enzymes that helps to recycle purines is hypoxanthine guanine phosphoribosyl transferase 1 (HGPRT1). Therefore, defects in this enzyme lead to the accumulation of DNA and nucleotide lesions and hence replication errors and genetic disorders. Missense mutations in hypoxanthine phosphoribosyl transferase 1 (HPRT1) are associated with deficiencies such as Lesch-Nyhan disease and chronic gout, which have manifestations such as arthritis, neurodegeneration, and cognitive disorders. In the present study, we collected 88 non-synonymous single nucleotide polymorphisms (nsSNPs) from the UniProt, dbSNP, ExAC, and ClinVar databases. We used a series of sequence-based and structure-based in silico tools to prioritize and characterize the most pathogenic and stabilizing or destabilizing nsSNPs. Moreover, to obtain the structural impact of the pathogenic mutations, we mapped the mutations to the crystal structure of the HPRT protein. We further subjected these mutant proteins to a 50 ns molecular dynamics simulation (MDS). The MDS trajectory showed that all mutant proteins altered the structural conformation and dynamic behavior of the HPRT protein and corroborated its association with LND and gout. This study provides essential information regarding the use of HPRT protein mutants as potential targets for therapeutic development.
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Drug Discovery Landscape
5 orphan drug designations for Lesch-Nyhan syndrome.
5 orphan drug designations for Lesch-Nyhan syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine | small molecules | FDA | — | Advanced Imaging Projects, LLC |
Ecopipam | small molecules | EMA | Dr Alain Munoz | |
pegsitacase | proteins | FDA | — | Swedish Orphan Biovitrum AB |
ecopipam hydrochloride | small molecules | FDA | Emalex Biosciences, Inc. | |
pramipexole | — | FDA | Boehringer-Ingelheim Pharmaceuticals, Inc. |
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