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Background: Lesch–Nyhan syndrome (LNS) is a rare X-linked recessive metabolic disorder caused by mutations in the HPRT1 gene, resulting in hypoxanthine–guanine phosphoribosyltransferase (HPRT) deficiency. Early diagnosis is critical for optimizing management and improving outcomes. This study presents a case series of three Taiwanese patients diagnosed at a single medical center. Methods: Exome sequencing and biochemical testing were used to confirm the diagnoses. Early clinical manifestations, including hyperuricemia, hypotonia, and developmental delay, were documented during the initial stages of the disease. Results: All three patients had hyperuricemia, hypotonia, spasticity, and motor developmental delay. Pathogenic variants in the HPRT1 gene were identified in two patients, while the third was confirmed by biochemical testing. Two patients had orange-colored crystalline deposits in their diapers, indicative of hyperuricosuria. Self-injurious behavior had not yet developed in two patients due to their young age. Conclusions: Early clinical features such as hyperuricemia, hypotonia, and motor delay may suggest LNS in infancy. Molecular genetic testing, particularly whole exome sequencing, can facilitate an early diagnosis before specific manifestations occur, enabling timely interventions and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background The current gold standard for extraperitoneal locally advanced rectal cancer is total neoadjuvant therapy (TNT) followed by total mesorectal excision. This research explored the number of lymph nodes in patients with locally advanced rectal cancer after TNT and its correlation with survival. Materials and Methods This is a post-hoc analysis based on the STELLAR trial, including patients with locally advanced rectal cancer from 16 tertiary centres who were randomized for short-term radiotherapy followed by chemotherapy (TNT group) or long-term concurrent chemotherapy group followed by total mesorectal excision between 2015 and 2018. This lymph node-related analysis is based on the TNT group. Subgroups were differentiated based on the lymph node harvest (below the median number: limited lymphadenectomy group, and greater than/equal to the median number: extended lymphadenectomy group). The primary outcomes were overall survival and disease-free survival (DFS). Correlations with clinical/pathological variables, lymphadenectomy categories and use of adjuvant chemotherapy were explored. Results Among the 451 patients enrolled in the STELLAR trial, 227 patients (50.3%) were assigned to the TNT group, including 29.5% females. The median number of lymph nodes retrieved in the TNT group was 11.0. Patients in the limited lymphadenectomy subgroup exhibited worse overall survival than those with extended lymphadenectomy (HR 2.95 (95% c.i. 1.47 to 5.92), P = 0.001). The overall survival was similar in the ypN0-limited and ypN1-extended subgroups (HR 0.38 (95% c.i. 0.11 to 1.30), P = 0.109). Adjuvant chemotherapy was associated with better overall survival and DFS than no adjuvant chemotherapy overall (P < 0.001) and in the limited lymphadenectomy subgroup (P < 0.001). However, there was no significant difference in overall survival or DFS with or without adjuvant chemotherapy in the extended lymphadenectomy subgroup (P = 0.887 and P = 0.192, respectively). Conclusion In the STELLAR trial, the median number of lymph nodes harvested was 11. In patients with limited lymphadenectomy, the use of adjuvant therapy after TNT was beneficial and correlated with better prognosis compared with patients who did not receive adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Introduction Lesch–Nyhan syndrome (LNS) is an X-linked disorder affecting the metabolism of the purine salvage pathway leading to excessive serum uric acid production. Treatment of hyperuricemia with Allopurinol is usually effective to lower serum uric acid concentration to acceptable levels. Allopurinol blocks the conversion of hypoxanthine and xanthine to serum uric acid in the purine degradation pathway. The effect of Allopurinol may result in excessive buildup of xanthine, potentially resulting in urolithiasis composed of xanthine. This rare occurrence poses a unique challenge maintaining a balance between lowering hyperuricemia and preventing the development of xanthine urolithiasis. This case report includes two siblings with LNS treated with Allopurinol who developed xanthine urolithiasis. Case description Patients are siblings, a 22-year-old male and a 21-year-old female, with LNS diagnosed in early childhood. They both share similar manifestations of the disease and were treated with Allopurinol with an intended therapeutic window of serum uric acid levels since diagnosis. Both were prone to developing urolithiasis and nephrolithiasis, the male more than the female, regardless of the medical regimen. Uric acid and calcium levels were normal in the serum and urine. Chemical analysis of calculi eliminated by both siblings revealed xanthine stones. Conclusions Patients with LNS tend to develop stones composed of urate. Rarely, they can also precipitate stones composed of xanthine resulting from its buildup in serum and urine by Allopurinol. This complication should be considered in all patients undergoing treatment with Allopurinol. Careful clinical monitoring and dose adjustments of Allopurinol must balance the need to control hyperuricemia with avoiding excessive blockade of hypoxanthine.

Introduction: Lesch–Nyhan syndrome (LNS) is an X-linked disorder affecting the metabolism of the purine salvage pathway leading to excessive serum uric acid production. Treatment of hyperuricemia with Allopurinol is usually effective to lower serum uric acid concentration to acceptable levels. Allopurinol blocks the conversion of hypoxanthine and xanthine to serum uric acid in the purine degradation pathway. The effect of Allopurinol may result in excessive buildup of xanthine, potentially resulting in urolithiasis composed of xanthine. This rare occurrence poses a unique challenge maintaining a balance between lowering hyperuricemia and preventing the development of xanthine urolithiasis. This case report includes two siblings with LNS treated with Allopurinol who developed xanthine urolithiasis. Case description: Patients are siblings, a 22-year-old male and a 21-year-old female, with LNS diagnosed in early childhood. They both share similar manifestations of the disease and were treated with Allopurinol with an intended therapeutic window of serum uric acid levels since diagnosis. Both were prone to developing urolithiasis and nephrolithiasis, the male more than the female, regardless of the medical regimen. Uric acid and calcium levels were normal in the serum and urine. Chemical analysis of calculi eliminated by both siblings revealed xanthine stones. Conclusions: Patients with LNS tend to develop stones composed of urate. Rarely, they can also precipitate stones composed of xanthine resulting from its buildup in serum and urine by Allopurinol. This complication should be considered in all patients undergoing treatment with Allopurinol. Careful clinical monitoring and dose adjustments of Allopurinol must balance the need to control hyperuricemia with avoiding excessive blockade of hypoxanthine. [ABSTRACT FROM AUTHOR]

Background: Lesch–Nyhan syndrome (LNS) is a rare X-linked recessive metabolic disorder caused by mutations in the HPRT1 gene, resulting in hypoxanthine–guanine phosphoribosyltransferase (HPRT) deficiency. Early diagnosis is critical for optimizing management and improving outcomes. This study presents a case series of three Taiwanese patients diagnosed at a single medical center. Methods: Exome sequencing and biochemical testing were used to confirm the diagnoses. Early clinical manifestations, including hyperuricemia, hypotonia, and developmental delay, were documented during the initial stages of the disease. Results: All three patients had hyperuricemia, hypotonia, spasticity, and motor developmental delay. Pathogenic variants in the HPRT1 gene were identified in two patients, while the third was confirmed by biochemical testing. Two patients had orange-colored crystalline deposits in their diapers, indicative of hyperuricosuria. Self-injurious behavior had not yet developed in two patients due to their young age. Conclusions: Early clinical features such as hyperuricemia, hypotonia, and motor delay may suggest LNS in infancy. Molecular genetic testing, particularly whole exome sequencing, can facilitate an early diagnosis before specific manifestations occur, enabling timely interventions and improving patient outcomes.

Given the good results of deep brain stimulation (DBS) in the treatment of movement disorders, DBS was initially tried to treat Lesch-Nyhan syndrome (LNS) with the aim to alleviate LNS-related dystonia. Some cases have reported clinical results of DBS in LNS thus far. This systematic review was conducted to comprehensively summarize cases of LNS treated with DBS and evaluate the efficacy and safety of DBS in LNS. Eight publications covering 12 LNS patients were included in this review. DBS improved dystonia of the LNS to varying degrees. All the included cases achieved partial or complete control of self-injurious behavior (SIB). Overall, DBS is a promising treatment for both motor and behavior disorders of LNS patients, but the results reported thus far have varied widely, especially for motor outcomes. The ultimate clinical benefits in LNS patients were still unpredictable. DBS-related complications were rather common, which raised questions about the safety of the procedure in LNS. More research is needed to further clarify the safety and effectiveness of this treatment. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333_334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease.

Defects in the gene HPRT1, which are inherited in a Xlinked recessive pattern, lead to metabolic disorders with a wide spectrum of severity. The most severe form is LeschNyhan syndrome which manifests when residual levels of the encoded enzyme - hypoxanthine-guanine phosphoribosyl-transferase, are under 2%. It is characterized by overproduction of uric acid and as result nephrolithiasis and tophi as well as neurologic symptoms - most commonly dyskinesia, and behavioural problems, typically self-injury. When residual enzyme levels are between 2 and 8%, patients have HPRT1-related neurologic dysfunction and lack behavioural abnormalities and when those are over 8 - 10% they have HPRT1-related hyperuricemia with only elevated uric acid levels. Hereby we present the clinical case of two twin brothers with a novel mutation in the gene HPRT1 which is associated with Lesch-Nyhan syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Lesch-Nyhan syndrome (LNS) is a rare genetic disease secondary to a HPRT1 mutation on chromosome X. It is characterized by dystonia, developmental delay, hyperuricemia and self-harming behaviours. The HPRT enzyme is implicated in the purine salvage pathway. The deficiency of HPRT results in accumulation of uric acid. There have been some cases associated with epilepsy, but it still remains a rare occurrence in LNS patients. Case presentation: We describe the case of a 20-month-old male patient with a heterozygous HPRT1 mutation c11_17del.p (Arg4Leufs*4) associated with LNS. The child associated epileptic seizures mistaken by his parents as non-epileptic sleep events associated with apnea. Seizures were discovered secondary to a polygraphic long-time sleep video-electroencephalography (EEG) monitoring. The dystonic movements and epileptic seizures responded to Levetiracetam, but the management of the behavioural disorder remained a challenge. Conclusions: Lesch-Nyhan syndrome is a rare inherited metabolic disease and its pathogenesis is not fully known, which makes the treatment management very difficult. Despite the fact that epilepsy is uncommon in LNS children, it should always be considered as part of the differential diagnosis in movement disorders. Therefore, long-term video-EEG monitoring is recommended as well as a detailed patient history to identify possible clinical/subclinical epileptic seizures that require treatment. [ABSTRACT FROM AUTHOR]

We introduce the application of alternative and augmentative communication aids in children with combined disabilities and symptomatic speech disorders. We will briefly introduce and compare alternative routes of communication in two boys with developmental anarthria. The first case study is devoted to a child with Lesch-Nyhan syndrome, the second to a boy with a developmental disorder of the central nervous system. Our goal is to map the avenues for functional communication and the development of a child unable to speak.

Abstract Background Riga–Fede disease is a rare begnin disorder of the oral tissues, it can be associated with congenital anomalies and neurological disturbances. Lesch–Nyhan syndrome is a rare X-linked recessive disorder characterized by neurological and behavioral manifestations. A patient can rarely be diagnosed with both diseases in a lifetime. Therefore, reporting manifestations from such disorders is important to avoid misdiagnosis and help in timely intervention. Case presentation This case report presents an 8-months-old male infant with traumatic oral ulcers from deciduous teeth. A diagnosis of Riga–Fede disease was made. Teeth grinding was performed and the oral lesions were healed. At the age of 2.5 years, the patient presented with neurological manifestations as well as facial tissue and premature teeth loss from self mutilation. Genetic sequencing revealed a variant of uncertain significance in the Hypoxanthine Phosphoribosyltransferase 1 gene. He was diagnosed with Lesch–Nyhan syndrome. Cleft palate, ventricular septal defect, congenitally undescended testis and ectopic left iliac kidney were also reported. The patient was scheduled on psychiatric treatment and after about six months of follow-up, both the behavioral and neurological symptoms were improved. Conclusions Riga–Fede disease can be an early manifestation of Lesch–Nyhan syndrome. To the best of our knowledge, this is the first reported case with the incidence of all the mentioned entities in one pediatric patient.

Background: Hypoxanthine-guanine phosphoribosyltransferase (HPRT1) deficiency is an inborn error of purine metabolism responsible for Lesch–Nyhan syndrome (LNS). The disease is inherited in an X-linked recessive manner and predominantly affects male individuals. Female individuals can carry a mutation as heterozygotes, but typically, they are asymptomatic because of the random inactivation of the affected allele. Nevertheless, although rare, heterozygote female individuals may manifest LNS with full characteristics. Herein, we describe a female patient from Saudi Arabia with LNS. Results: The patient (a 4-year-old girl) presented with typical characteristics of the disease, which include global developmental delay, self-mutilation, hyperuricemia, hypotonia, speech delay, spasticity, and seizures. Her general biochemical laboratory results were normal except for high levels of uric acid. The abdominal MRI\MRS, mostly unremarkable, showed bilateral echogenic foci within the renal collecting system. Genetic testing (whole-exome sequencing, iterative variant filtering, segregation analysis, and Sanger sequencing) pointed a novel de novo frameshift variant in HPRT1. X-inactivation assay using HpaII showed the presence of a 100% skewed X chromosome carrying the affected allele. RT-PCR of the cDNA indicated complete loss of the expression of the normal allele. Conclusion: Our study presents a female patient who has a severe case of LNSand found to be the 15th female patient with the disease in the world. The study emphasizethe need for a streamlined protocol that will help an early and accurate diagnosis of female LNS patients to avoid unnecessary interventions that lead to costly patient care. [ABSTRACT FROM AUTHOR]

Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine‐guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch–Nyhan syndrome (LNS) and is inherited in an X‐linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self‐mutilating behaviors. Here, we present the case of a male infant who was diagnosed with LNS at 3 weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally inherited deletion of at least 1.3 Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents' values that guided the decision‐making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity of discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family toward making an informed decision. [ABSTRACT FROM AUTHOR]

Abstract Lesch–Nyhan syndrome is an x‐linked genetic disorder of purine metabolism that results in the overproduction of uric acid and neurologic deficits manifesting as intellectual disability, dystonia, other movement disorders and self‐mutilation. We describe a 12‐year‐old patient with a history of Lesch–Nyhan syndrome, G6PD deficiency and central diabetes insipidus and multiple admissions for fever, acute kidney injury and transaminitis in the setting of rhabdomyolysis. The patient's temperature dysregulation and dysautonomia is likely attributable to abnormal neurotransmitter release, particularly that of dopamine, in the central nervous system. Our patient presented similarly to that of a patient with neuroleptic malignant syndrome (NMS), with symptoms including altered mental status, fever, dysautonomia and renal failure, and laboratory findings including elevated serum creatinine kinase, leukocytosis, transaminitis, hypernatremia and metabolic acidosis. Similar to NMS, disruption of dopamine neurotransmission results in dysregulated sympathetic activity and hyperthermia.

Background: Hypoxanthine-guanine phosphoribosyltransferase (HPRT1) deficiency is an inborn error of purine metabolism responsible for Lesch–Nyhan syndrome (LNS). The disease is inherited in an X-linked recessive manner and predominantly affects male individuals. Female individuals can carry a mutation as heterozygotes, but typically, they are asymptomatic because of the random inactivation of the affected allele. Nevertheless, although rare, heterozygote female individuals may manifest LNS with full characteristics. Herein, we describe a female patient from Saudi Arabia with LNS.Results: The patient (a 4-year-old girl) presented with typical characteristics of the disease, which include global developmental delay, self-mutilation, hyperuricemia, hypotonia, speech delay, spasticity, and seizures. Her general biochemical laboratory results were normal except for high levels of uric acid. The abdominal MRI\MRS, mostly unremarkable, showed bilateral echogenic foci within the renal collecting system. Genetic testing (whole-exome sequencing, iterative variant filtering, segregation analysis, and Sanger sequencing) pointed a novel de novo frameshift variant in HPRT1. X-inactivation assay using HpaII showed the presence of a 100% skewed X chromosome carrying the affected allele. RT-PCR of the cDNA indicated complete loss of the expression of the normal allele.Conclusion: Our study presents a female patient who has a severe case of LNSand found to be the 15th female patient with the disease in the world. The study emphasizethe need for a streamlined protocol that will help an early and accurate diagnosis of female LNS patients to avoid unnecessary interventions that lead to costly patient care.

Lesch–Nyhan syndrome (LNS) is a rare genetic condition resulting from an inherited disorder of purine metabolism. It is characterized by the lack of one enzyme, hypoxanthine-guanine phos-phoribosyltransferase (HGPRT), which is responsible for purine salvage. The main manifestations of this syndrome are hyperuricaemia, reduction in cognitive abilities, self-aggressive behavior, choreoathetosis, spasticity, and retarded development. The aim of the study was to investigate the means of treatment and efficacy of prevention of oral self-injury behavior (SIB) in patients with LNS. Information regarding the type and treatment of oral SIB in 19 LSN Italian patients (mean age 23.3 years) was gathered via a structured telephone interview of their parents. A total of 84% of the patients showed some form of self-injury behavior; the first form to manifest itself was finger biting (37%), followed by lip biting (25%), and then tongue biting (18%). Furthermore, 74% of cases featured oral SIB, and tooth extraction was found to be the most frequent form of treatment practiced (71%). This study has revealed the great difficulty parents and carers face in managing forms of oral SIB; dental extraction was the most common choice, despite its invasive nature and far-reaching consequences in regard to the psychosocial status of the patients. [ABSTRACT FROM AUTHOR]

Objective To analyze the genetic testing results of children with Lesch-Nyhan syndrome and their par⁃ ents/sisters，and to summarize their genetic characteristics. Methods The subjects were Case 1，Case 2 and their par⁃ ents（Case 1 and Case 2 were brothers），Case 3（male），the parents of Case 3 and his two sisters. The peripheral venous blood of the subjects was collected for high-throughput gene whole-exome sequencing，and the genetic status of the chil⁃ dren and their parents/sisters was analyzed. Results Cases 1 and 2 were brothers，and both had the hypoxanthine-gua⁃ nine phosphoribosyltransferase gene chrX：exon3 c. 236T>C，p. L79P mutation on the X chromosome，and the ACMG pathogenic variant was classified as possible pathogenic；the mother of the child had a heterozygous mutation at this locus， and the father had a wild-type gene at this locus. Case 3 had the X chromosome HPRT1 gene chrX exon3c. 197G>A，p. C66Y mutation，and the pathogenic variant was classified as possible pathogenic；the mother and eldest sister of the child had heterozygous for this locus，while these loci of the father and the second sister were wild-type. Conclusions The main clinical manifestations of children with Lesch-Nyhan syndrome are developmental delay，abnormal muscle tone and self-injury behavior. The mutation in exon 3 of HPRT1 gene may be the cause of Lesch-Nyhan syndrome，and the mu⁃ tation gene is inherited from the mother. [ABSTRACT FROM AUTHOR]

Background. Lesch-Nyhan syndrome is inherent X-linked recessive genetic disorder with decreased activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). The disease is characterized by presence of the classical triad: hyperuricemia, neurological and behavioral changes. In the article we present a clinical case of Lesch-Nyhan syndrome first diagnosed only at 16 years old despite the fact that the clinical clues were already found at the patient`s early age. Case presentation. An 18-year-old Caucasian man was admitted to the rheumatology department because of gouty arthritis. In neonatal period he was diagnosed with mild intrauterine growth restriction by hypoplastic type. Uric acid crystals were found in our patient`s urine at 6-month-old. In the first year of life, delayed motor development was noted together with permanent neurological changes which were referred to rickets. During school years, severe dysgraphia, dyslexia, dysarthria, logoneurosis warranted observation by a speech therapist. At his 12 he had been diagnosed with nephrocalcinosis, at 14 – with chronic kidney disease and symptomatic arterial hypertension. The family history was remarkable for gout in grandmother and great-grandmother, chronic pyelonephritis – in mother, urate nephropathy – in both brothers. In physical examination hyperemia and edema of the left first metatarsophalangeal joint, left ankle defiguration, funnel chest, gynecomastia, tophi on the ears were noted. On examination, some neurological disorders and mild cognitive impairment were found. In investigations hyperuricemia, arthritis of the first metatarsophalangeal joint, diffuse changes in the renal parenchyma with impaired renal excretory function were detected. Despite the clues in patient`s anamnesis, objective examination and additional investigation, as well as the presence of a family anamnesis suggesting the hereditary nature of hyperuricemia, the diagnosis of HGPRT deficiency was not made until the age of 16 years. Conclusion. The presence of Lesch-Nyhan syndrome can be assumed with the progression of muscle tone impairment and movement disorders in a child after the first six months of life in combination with high plasma uric acid concentration and its increased urinary excretion. Difficulties in the syndrome diagnosis are associated not only with a rare occurrence, but with a slight or moderate degree of central nervous system impairment that is often related by doctors to rickets or delivery trauma, as well as low accessibility of molecular genetic testing.

Background Lesch–Nyhan disease (LND) is a rare X-linked recessive inborn error of purine metabolism. Late diagnosis of LND may cause significant morbidity. LND cases have never been reported in Indonesia. Case report A 15-year-old male who had been diagnosed with cerebral palsy was referred to our hospital due to renal failure requiring emergency dialysis. The patient presented with three classic manifestations of LND: increased uric acid levels, neurological disorders, and self-injurious behaviors. LND was suspected because of an abscess-like lump on the left ankle that was confirmed to be a tophus, which had burst and discharged thick masses containing blood, debris, and white crystal materials. The diagnosis of LND was confirmed by the presence of a deletion to exon 1 of the HPRT1 gene. The patient received oral allopurinol daily and treatment for end-stage renal disease (ESRD), which included regular dialysis and subcutaneous administration of erythropoietin. At a 2-month follow-up, he improved clinically with a 71% decrease in uric acid levels after regular dialysis and allopurinol treatment. Conclusion In developed countries, LND can be diagnosed as early as 3 days after birth. However, diagnosis in the present case was delayed due to the rarity of the disease and the limited number of facilities in Indonesia that offer genetic counseling. Late diagnosis of LND leads to ESRD and irreversible abnormalities. This is the first case of LND presenting with a unique clinical presentation of tophus burst reported in Indonesia.

Lesch-Nyhan syndrome (LNS) is characterized by frequent oral self-mutilation (OSM). Although various treatments have been suggested, our limited knowledge regarding the exact pathogenic mechanism of self-mutilation in LNS makes it difficult to manage self-injurious behavior and there is a need for novel treatments. Herein, we describe the case of a 11-year-old boy with LNS and OSM who was conservatively treated using S-adenosylmethionine (SAM) and a mouthguard. This resulted in significant improvement in OSM, and the patient remains stable at 16 years old. This case demonstrates that combination treatment with SAM and a mouthguard should be considered for the management of OSM in LNS, as it can maintain the functionality and health of the oral cavity and improve a patient's quality of life. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine–guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome (LNS) is a disease characterized by a reduced ability to recycle purines, leading to increased de novo purine synthesis and uric acid production. Patients classically present with an array of hyperuricemic, neurologic, and behavioral symptoms. In this report, we describe a 26-year-old male with a history of LNS and recurrent fevers of unknown origin who presented to the emergency department (ED) with a fever, hypotension, and hypernatremia. We suspect that our patient's presentation was caused by autonomic instability in the setting of LNS leading to excessive free water loss. This report highlights a rare but life-threatening manifestation of LNS., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Pan et al.)

Lesch-Nyhan syndrome (LNS) is a congenital defect disease that results in defective purine metabolism. It is caused by pathogenic variants of the HPRT gene. Its clinical symptoms mainly include high uric acid levels, gout, and kidney stones and damage. The mechanism of LNS has not been fully elucidated, and no cure exists. Animal models have always played an important role in exploring causative mechanisms and new therapies. This study combined CRISPR/Cas9 and microinjection to knock out the HPRT gene to create an LNS rabbit model. A sgRNA targeting exon 3 of HPRT gene was designed. Subsequently, Cas9 mRNA and sgRNA were injected into rabbit zygotes, and injected embryos were transferred to the uterus. The genotype and phenotype of rabbits were analyzed after birth. Four infant rabbits (named R1, R2, R3 and R4), which showed varying levels of gene modification, were born. The gene-editing efficiency was 100%. No wild-type sequences at the target HPRT gene were detected in R4 rabbit. Next, 6-thioguanine drug testing confirmed that HPRT enzymatic activity was deficient in R4 infant rabbit. HE staining revealed kidney abnormalities in all infant rabbits. Overall, an sgRNA capable of knocking out the HPRT gene in rabbits was successfully designed, and HPRT gene-modified rabbits were successfully constructed by using CRISPR/Cas9 technology and microinjection. This study provides a new nonrodent animal model for studying LNS syndrome.

Real-time quantitative PCR (qRT-PCR) is often used as an effective experimental method for analyzing gene expression. In this method, normalization of target gene expression levels must be performed using housekeeping genes (HKGs). HKGs are used to compensate for difference between samples due to diverse quality and quality of RNAs and different reverse transcription yield. For an ideal reference gene, constant expression levels across different samples of one experiment is necessary. In the current study, expression stability of four candidate references genes including Beta actin (ACTB), glyceraldeyde-3-phosphate dehydrogenase (GAPDH), hypoxanthine guanine phosphoribosyl transferase (HPRT1) and Beta-2-Microglobulin (β2M) following retinoic acid (RA) treatment in embryonal carcinoma NCCIT cells were evaluated. NCCIT cells were exposed to RA (10 µM) for 14 days to induce differentiation. RT-qPCR for candidate references genes was performed and normalization between untreated and RA-treated cells was performed using identical sample input amounts. Expression of OCT4, SOX2, NANOG during RA-induced differentiation was assessed by quantitative real-time PCR. RT-qPCR results indicated significant difference in expression level of GAPDH between untreated (Ct mean: 19.36667± 0.28) and RA-treated (Ct mean: 28.94± 0.18) NCCIT cells. However, transcriptional level of ACTB, HPRT and β2M remained unchanged after RA treatment. qRT-PCR analysis using ACTB, HPRT and β2M showed treatment of NCCIT cells with RA lead to significant down regulation of OCT4 (79%), NANOG (71%) and SOX2 (96%) transcript. ACTB, HPRT and β2M were recognized as valid reference genes for analysis of gene expression during RA-induced differentiation of NCCIT cells, while GAPDH was not suitable. [ABSTRACT FROM AUTHOR]

Lesch–Nyhan disease (LND) is a rare X-linked recessive inborn error of purine metabolism. Late diagnosis of LND may cause significant morbidity. LND cases have never been reported in Indonesia. A 15-year-old male who had been diagnosed with cerebral palsy was referred to our hospital due to renal failure requiring emergency dialysis. The patient presented with three classic manifestations of LND: increased uric acid levels, neurological disorders, and self-injurious behaviors. LND was suspected because of an abscess-like lump on the left ankle that was confirmed to be a tophus, which had burst and discharged thick masses containing blood, debris, and white crystal materials. The diagnosis of LND was confirmed by the presence of a deletion to exon 1 of the HPRT1 gene. The patient received oral allopurinol daily and treatment for end-stage renal disease (ESRD), which included regular dialysis and subcutaneous administration of erythropoietin. At a 2-month follow-up, he improved clinically with a 71% decrease in uric acid levels after regular dialysis and allopurinol treatment. In developed countries, LND can be diagnosed as early as 3 days after birth. However, diagnosis in the present case was delayed due to the rarity of the disease and the limited number of facilities in Indonesia that offer genetic counseling. Late diagnosis of LND leads to ESRD and irreversible abnormalities. This is the first case of LND presenting with a unique clinical presentation of tophus burst reported in Indonesia. [ABSTRACT FROM AUTHOR]

To better understand the cancer risk posed by radiation and the development of radiation therapy resistant cancer cells, we investigated the involvement of the cancer risk factor, APOBEC3B, in the generation of radiation-induced mutations. Expression of APOBEC3B in response to irradiation was determined in three human cancer cell lines by real-time quantitative PCR. Using the hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation assay, mutations in the HPRT gene caused by irradiation were compared between APOBEC3B-deficient human hepatocellular carcinoma (HepG2) cells [APOBEC3B knocked out (KO) using CRISPR-Cas9 genome editing] and the parent cell line. Then, HPRT -mutated cells were individually cultured to perform PCR and DNA sequencing of HPRT exons. X-Irradiation induced APOBEC3B expression in HepG2, human cervical cancer epithelial carcinoma (HeLa) and human oral squamous cell carcinoma (SAS) cells. Forced expression of APOBEC3B increased spontaneous mutations. By contrast, APOBEC3B KO not only decreased the spontaneous mutation rate, but also strongly suppressed the increase in mutation frequency after irradiation in the parent cell line. Although forced expression of APOBEC3B in the nucleus caused DNA damage, higher levels of APOBEC3B tended to reduce APOBEC3B-induced γ-H2AX foci formation (a measure of DNA damage repair). Further, the number of γ-H2AX foci in cells stably expressing APOBEC3B was not much higher than that in controls before and after irradiation, suggesting that a DNA repair pathway may be activated. This study demonstrates that irradiation induces sustained expression of APOBEC3B in HepG2, HeLa and SAS cells, and that APOBEC3B enhances radiation-induced partial deletions. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome is a condition characterized by neurological and behavioral abnormalities and the overproduction of uric acid in the body. According to one estimate, the disorder occurs at a rate of approximately 1 in 400,000 births in the world. It occurs almost exclusively in males due to being an X-linked recessive disorder. Excess uric acid production and Neurological disorders with characteristic self-mutilating behaviors are major symptoms of LNS. LNS is a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthineguanine phosphoribosyltransferase (HPRT), Mutations in the HPRT1 gene cause LNS. Treatment for LNS is symptomatic, Gout treated with allopurinol; Kidney stones with lithotripsy; No standard treatment for the neurological symptoms of LNS. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome (LNS) is a serious form of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, a hereditary purine metabolism disorder. The prevalence reported in the literature is 1/380,000 to 235,000 births. Males are affected and females are heterozygous carriers. LNS patients present a combination of hypotonia, spasticity, and neurological and behavioral disorders. They also show an obsessive-compulsive self-injurious behavior with bites and injuries to the lips, tongue, cheeks and fingers. The literature offers little scientific contribution related to the management of this problem. The authors describe their experience with a 4-year-old LNS patient and present a viable solution to control and avoid bite injuries, namely a specifically modified bite. The patient was treated at the Pediatric Dentistry Department of "Sapienza" University of Rome with a modified bite with the internal surface, in contact with the teeth, realized in 2-mm-thick soft silicone, and the exterior part consisting of a transparent resin shell with front and rear shields to separate lips and cheeks from the dental arches. At a 12-month follow-up visit, compliance was excellent: the child wore the device with regularity and without discomfort, even during soft-food feeding. No intraoral bite injuries were found, with a general improvement of the young patient's quality of life. [ABSTRACT FROM AUTHOR]

Objectives: In patients with lung cancer undergoing mediastinal staging through endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), decisions are based on rapid on-site evaluation (ROSE) findings. We aimed to analyze the concordance rate between ROSE diagnosis and final diagnosis.Methods: A prospective study was carried out in patients undergoing EBUS-TBNA for lung cancer staging. Diagnosis concordance was defined as cases where lymph nodes (LNs) presented the same diagnosis in ROSE and final diagnosis. Determinants of concordance were analyzed.Results: Sixty-four patients were included and 637 LNs sampled. ROSE diagnosis was concordant with final diagnosis in 612 (96.1%) LNs and nonconcordant in 25 (3.9%). Differences in the concordance rate were found between pathologists, ROSE diagnoses, presence of cell block, number of passes, and number of slides. The staging status was changed between ROSE and the final diagnosis in three (4.6%) patients.Conclusions: ROSE diagnosis has a high concordance with the final diagnosis. [ABSTRACT FROM AUTHOR]

This paper summarizes a conference held at the National Institute of Child Health and Human Development on December 6-7, 1999, on self-injurious behavior [SIB] in developmental disabilities. Twenty-six of the top researchers in the U.S. from this field representing 13 different disciplines discussed environmental mechanisms, epidemiology, behavioral and pharmacological intervention strategies, neurochemical substrates, genetic syndromes in which SIB is a prominent behavioral phenotype, neurobiological and neurodevelopmental factors affecting SIB in humans as well as a variety of animal models of SIB. Findings over the last decade, especially new discoveries since 1995, were emphasized. SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities.

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by mutations in the HPRT1 gene. The clinical features and mutation spectrum of 26 Korean LNS patients from 23 unrelated families were retrospectively reviewed. The HPRT1 gene was analyzed by direct sequencing of genomic DNA. The median age at diagnosis was 2.3 years (range, 4 months–22.6 years) and the initial presenting features included developmental delay, orange colored urine, and self-injurious behaviors. Most patients were wheelchair-bound and suffered from urinary complications and neurologic problems such as self-mutilation and developmental delay. Twenty different mutations in HPRT1 were identified among 23 independent pedigrees, including six novel mutations. The most common mutation type was truncating mutations including nonsense and frameshift mutations (45%). Large deletions in the HPRT1 gene were identified in exon 1, exons 5–6, exons 1–9, and at chr X:134,459,540–134,467,241 (7702 bp) including the 5′-untranslated region, exon 1, and a portion of intron 1. In conclusion, this study describes the phenotypic spectrum of LNS and has identified 20 mutations from 23 Korean families, including six novel mutations in Korean patients with LNS. [ABSTRACT FROM AUTHOR]

Background: The secondary lymphoid tissues (LTs), lymph nodes (LNs) and gut-associated lymphoid tissue (GALT) are considered reservoirs for HIV. Antiretrovirals (ARVs) have lower penetration into LT. In vitro models predictive of ARV LT penetration have not been established.Objectives: To develop an in vitro model of LT bioavailability using human lymphoid endothelial cells (HLECs) and investigate its predictability with in vivo pharmacokinetic (PK) studies in mice.Methods: ARV bioavailability in HLECs was evaluated at the maximum plasma concentration (Cmax) observed in HIV-infected patients. ARVs were: abacavir, atazanavir, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, maraviroc, raltegravir, rilpivirine, ritonavir, tenofovir disoproxil fumarate and the PK booster cobicistat. The LT PK of representative drugs showing high (efavirenz), intermediate (dolutegravir) and low (emtricitabine) HLEC bioavailability was investigated in BALB/c mice given 50/10/30 mg/kg efavirenz/dolutegravir/emtricitabine orally, daily for 3 days. The concordance of in vitro and in vivo ARV bioavailability was examined.Results: ARVs showed high (>67th percentile; rilpivirine, efavirenz, elvitegravir and cobicistat), intermediate (67th-33rd percentile; ritonavir, tenofovir disoproxil fumarate, dolutegravir and maraviroc) and low (<33rd percentile; atazanavir, darunavir, raltegravir, emtricitabine and abacavir) HLEC bioavailability. The hierarchy of efavirenz, dolutegravir and emtricitabine bioavailability in LN, gut and brain tissues of mice was: efavirenz>dolutegravir>emtricitabine.Conclusions: ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan disease (LND) is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase. Patients with LND experience involuntary movements, including dystonia, choreoathetosis, opisthotonos, ballismus, and self-injury. Alleviating these involuntary movements is important to improve the quality of life in patients with LND. Many clinicians have difficulty controlling these involuntary movements in their patients, and there are no established and effective treatments. A 6-month-old boy with LND presented with generalized dystonia and self-injury behavior that was alleviated after receiving S-adenosylmethionine (SAMe). His self-injury behavior completely resolved after he received SAMe and risperidone. Although he had often experienced inspiratory stridor because of laryngeal dystonia and frequently developed aspiration pneumonitis and bronchitis, no inspiratory stridor was noted after SAMe treatment. The patient is continuing to receive SAMe and risperidone. SAMe treatment alleviates dystonic movements and improves quality of life in pediatric patients with LND. Additional research is needed to determine the long-term safety and efficacy of SAMe and its appropriate dosage. [ABSTRACT FROM AUTHOR]

Lesch-Nyhan syndrome is a rare neurometabolic condition characterized by progressive choreoathetosis, intellectual disability, and peculiar manifestations like self-mutilation. Occasional case reports in adults have suggested an association between Lesch-Nyhan syndrome and hypercoagulability; however, no such report of either a venous or arterial stroke in children with Lesch-Nyhan Syndrome exists in literature. We present a 3-year-old boy with global developmental delay, dystonic posturing, choreoathetoid movements, and self-mutilation involving fingers and lips. He had acute worsening of sensorium, recurrent seizures, and opisthotonous posturing. A diagnosis of Lesch-Nyhan Syndrome was confirmed by extremely low hypoxanthine-guanine phosphoribosyltransferase enzyme levels. In view of an acute neurological deterioration, magnetic resonance imaging brain and magnetic resonance venogram were done that showed sagittal and left transverse venous sinus thrombosis. This case is the first case report of cerebral venous sinus thrombosis in a child with Lesch-Nyhan Syndrome. It further strengthens the association between hypercoagulability and Lesch-Nyhan syndrome. [ABSTRACT FROM AUTHOR]