Management of neurological symptoms in Lesch-Nyhan disease: A systematic review.

Lesch-Nyhan Disease (LND) is an X-linked recessive genetic disorder arising from hypoxanthine phosphoribosyltransferase 1 gene mutations, leading to a complete deficiency. LND presents a complex neurological profile characterized by generalized dystonia, motor dysfunctions and self-injurious behavior, which management is challenging. We conducted a systematic review of studies assessing the efficacy of pharmacological and non-pharmacological interventions in management of neurological symptoms in LND (PROSPERO registration number:CRD42023446513). Among 34 reviewed full-text papers; 22 studies were rated as having a high risk of bias. Considerable heterogeneity was found in studies regarding the timing of treatment implementation, adjunctive treatments and outcome assessment. Single-patient studies and clinical trials often showed contradictory results, while therapeutic failures were underreported. S-Adenosylmethionine and Deep Brain Stimulation were the most studied treatment methods and require further research to address inconsistencies. The evidence from levodopa studies underlines that optimal timing of treatment implementation should be thoroughly investigated. Standardized study design and reducing publication bias are crucial to overcome current limitations of assessing intervention efficacy in LND.

Recurrent Fevers, Dysautonomia, and Dehydration in a Patient With Lesch-Nyhan Syndrome.

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.

Establishment and characterization of Lesch-Nyhan syndrome rabbit model.

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.

Lesch-Nyhan syndrome: a case report.

Lesch-Nyhan syndrome (LNS) is a rare X-linked recessive disorder caused by a mutation in the hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene. This syndrome is characterized by excessive production of uric acid, mental retardation, self-mutilation, choreoathetosis, and spasticity. The most distinctive symptom is compulsive self-mutilation. For patients with LNS, different methods have been tried to reduce self-biting behaviors including restraints, behavioral treatment, medications, deep brain stimulation, tooth extraction and botulinum toxin A injection. In this report, we present a case of LNS undergoing cheiloplasty due to self-mutilation and tooth extraction of the left deciduous maxillary canine.

Single-Electrode Deep Brain Stimulation of Bilateral Posterolateral Globus Pallidus Internus in Patients With Medically Resistant Lesch-Nyhan Syndrome.

Deep brain stimulation (DBS) targeting various locations within the globus pallidus internus (GPi) is emerging as a therapeutic option for patients with medically resistant Lesch-Nyhan syndrome. We report our institutional experience with single-electrode DBS in the bilateral posterolateral GPi as an effective method for reduction of both dystonia and self-injurious behavior. Two pediatric patients aged six and 14 years underwent implantation of bilateral singular DBS leads in the posterolateral GPi and were followed postoperatively through the programming process and symptomatic improvements. Caregivers reported that after DBS in the posterolateral GPi, these patients experienced decreased self-mutilation behavior and decreased dystonia.

Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing.

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.

Deep brain stimulation in Lesch-Nyhan syndrome: a systematic review.

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.

Oral Self-Mutilation in Lesch-Nyhan Patients: A Cross-Sectional Study.

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.

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.

Ethical implications of early genetic diagnosis in an infant with Lesch-Nyhan syndrome.

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.

Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report.

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.

Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: Case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome.

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.

Paroxysmal hyperthermia, dysautonomia and rhabdomyolysis in a patient with Lesch-Nyhan syndrome.

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.

Cerebral Venous Sinus Thrombosis in a Child with Lesch-Nyhan Syndrome.

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.

Deep Brain Stimulation of the Internal Pallidum in Lesch-Nyhan Syndrome: Clinical Outcomes and Connectivity Analysis.

BACKGROUND: Lesch-Nyhan syndrome (LNS) is a rare genetic disorder characterized by a deficiency of hypoxanthine-guanine phosphoribosyltransferase enzyme. It manifests during infancy with compulsive self-mutilation behavior associated with disabling generalized dystonia and dyskinesia. Clinical management of these patients poses an enormous challenge for medical teams and carers. OBJECTIVES: We report our experience with bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the management of this complex disorder. MATERIALS AND METHODS: Preoperative and postoperative functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team, including imaging, neuropsychology, and neurophysiology evaluations were analyzed with regards to motor and behavioral control, goal achievement, and patient and caregivers' expectations. RESULTS: Four male patients (mean age 13 years) underwent DBS implantation between 2011 and 2018. Three patients received double bilateral DBS electrodes within the posteroventral GPi and the anteromedial GPi, whereas one patient had bilateral electrodes placed in the posteroventral GPi only. Median follow-up was 47.5 months (range 22-98 months). Functional improvement was observed in all patients and discussed in relation to previous reports. Analysis of structural connectivity revealed significant correlation between the involvement of specific cortical regions and clinical outcome. CONCLUSION: Combined bilateral stimulation of the anteromedial and posteroventral GPi may be considered as an option for managing refractory dystonia and self-harm behavior in LNS patients. A multidisciplinary team-based approach is essential for patient selection and management, to support children and families, to achieve functional improvement and alleviate the overall disease burden for patients and caregivers.

Analysis of diagnosis and treatment of Lesch-Nyhan syndrome / 中华泌尿外科杂志

Objective:To explore the etiology, clinical diagnosis and treatment strategy of Lesch Nyhan syndrome.Methods:We retrospectively analyzed 2 patients with severe dyskinesia, mental retardation and complicated renal calculi who were admitted to the first people's Hospital of Zhengzhou in August 2019. Case 1, male, 9 years old, had multiple urinary calculi for 1 year. The patient came to the local hospital because double multiple kidney stones and bladder stonesa year ago. The patient had been treated with transurethral holmium laser lithotripsy for bladder stones. The results of infrared spectrum showed that the bladder stone was anhydrous uric acid stone. A week ago, color Doppler ultrasound showed multiple kidney stones and bladder stones. The patient was underdeveloped, mentally retarded and had a full-term cesarean section. There was no history of hypoxia, asphyxia and rescue of the patient. He had the following clinical manifestations: In the waking state, he was no language response to any stimulation. The nasolabial fold on the right was shallow and the corner of the mouth was oblique to the left. He lost the large movements such as lifting head, sitting alone, standing. The trunk showed torsion spasticity, limb muscle strength 2-3, limbs showing spastic hypertonia, limb joints stiff, hands showing fist-like, no involuntary movement and muscle fasciculation. The biceps reflex and knee tendon reflex were not elicited, and the pathological reflex was positive. Serum uric acid was 517 μmol/L. The Case 2 came from the same family, male, 6 years old, had the similar symptoms to his elder brother case 1. The family members complained on behalf of the child about intermittent fever for more than 2 years. The imaging examination of case 2 revealed kidney stones. Serum uric acid was 373 μmol/L. Whole Exome Sequencing and Sanger Sequencing were used to find the genetic causes of the two siblings. The NCBI-Homologene database was used to find the homologous sequence of the human HPRT1 gene, and the human HPRT1 gene sequence was compared with other species to analyze the protein conservation. The online website PredictProtein (http: //www.predactprotein) was used to predict the two-dimensional structure of the HPRT1 gene. The reported cases were summarized and same with the treatment plan.Results:A De novo mutation [c.571T>G(p.Tyr191Asp)] was found in the HPRT1 gene of the child, which was inherited from the mother. Lesch Nyhan syndrome can be diagnosed by the results of gene examination combined with clinical manifestations. The amino acid Tyr at the 191 position and the amino acids before and after it were highly conserved. Amino acid 191 was involved in the β-strand of the protein. We treated the patients with the lowest dose of allopurinol and children's conventional dose of potassium sodium bicitrate granules, and low purine diet. After 3 months of treatment, the serum uric acid was decreased, and the urinary calculi did not increase significantly.Conclusions:Combining with the clinical manifestations of children, HPRT1 gene might be the cause of pediatric disease and the two siblings could be diagnosed as Lesch-Nyhan syndrome. For such patients, the lowest dose of allopurinol and children's conventional dose of potassium sodium hydrogen citrate granule combined with diet could be more effective.

Atypical Cadherin FAT3 Is a Novel Mediator for Morphological Changes of Microglia.

Microglia are resident macrophages that are critical for brain development and homeostasis. Microglial morphology is dynamically changed during postnatal stages, leading to regulating synaptogenesis and synapse pruning. Moreover, it has been well known that the shape of microglia is also altered in response to the detritus of the apoptotic cells and pathogens such as bacteria and viruses. Although the morphologic changes are crucial for acquiring microglial functions, the exact mechanism which controls their morphology is not fully understood. Here, we report that the FAT atypical cadherin family protein, FAT3, regulates the morphology of microglial cell line, BV2. We found that the shape of BV2 becomes elongated in a high-nutrient medium. Using microarray analysis, we identified that FAT3 expression is induced by culturing with a high-nutrient medium. In addition, we found that purinergic analog, hypoxanthine, promotes FAT3 expression in BV2 and mouse primary microglia. FAT3 expression induced by hypoxanthine extends the time of sustaining the elongated forms in BV2. These data suggest that the hypoxanthine-FAT3 axis is a novel pathway associated with microglial morphology. Our data provide a possibility that FAT3 may control microglial transitions involved in their morphologic changes during the postnatal stages in vivo.

HPRT-related hyperuricemia with a novel p.V35M mutation in HPRT1 presenting familial juvenile gout.

Unlike complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT) (i.e., Lesch-Nyhan syndrome), partial HPRT deficiency causes HPRT-related hyperuricemia without neurological symptoms. Herein, we describe a 22-year-old man without neurological symptoms that presented gout, hyperuricemia (serum urate level, 12.2 mg/dL), multiple renal microcalculi, and a family history of juvenile gout that was exhibited by his brother and grandfather. Genetic testing revealed a novel missense mutation, c.103G>A (p.V35M), in the HPRT1 gene, and biochemical testing (conducted using the patient's erythrocytes) showed that the patient retained only 12.4% HPRT enzymatic activity compared to that exhibited by a healthy control subject. We thus diagnosed the patient with HPRT-related hyperuricemia caused by partial HPRT deficiency. After his serum urate level was controlled via treatment with febuxostat, his gout did not recur. Thus, this study emphasizes that HPRT deficiency should be considered as a potential cause of familial juvenile gout, even in the absence of neurological symptoms.

Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report.

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.