OBJECTIVE: To explore the clinical, genetic, therapeutic and prognostic characteristics of two children with Lesch-Nyhan syndrome (LNS) in order to enhance understanding of this disease and formulate more effective therapeutic strategies. METHODS: Clinical data were collected from two children clinically diagnosed with LNS who were treated at Anhui Provincial Children's Hospital from April 2023 to January 2024. Data were retrospectively collected and included clinical manifestations (symptoms, signs, laboratory and imaging findings), treatment course, and results of follow-up. Peripheral venous blood samples were obtained from child 1 and his parents. Whole-exome sequencing (WES) was performed. Candidate variants were validated by Sanger sequencing. Standard bioinformatic analysis of the raw WES data was conducted, including quality control, alignment, variant calling, and annotation. Candidate pathogenic variants were filtered using population frequency databases (e.g., gnomAD), disease databases (e.g., OMIM, ClinVar), and multiple in silico pathogenicity prediction tools (e.g., SIFT, PolyPhen-2, CADD). Phenotype matching was integrated using Human Phenotype Ontology (HPO) terms. Pathogenicity classification of variants was performed according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants (2015). This study was approved by the Medical Ethics Committee of Anhui Children's Hospital, Children's Hospital of Fudan University (Ethics No.: EYLL-2014-027). RESULTS: Child 1, a 4-year-old boy, had presented with developmental delay for over 3 years, accompanied by abnormal postures and involuntary lip-biting. Physical examination revealed limb dystonia, anxious expression, lower lip damage, and communication difficulties. Laboratory tests showed hyperuricemia and renal stones. Genetic testing identified a hemizygote variant of the HPRT1 gene, c.135G>T (p.Arg45Ser), inherited from an asymptomatic carrier mother, which confirmed the diagnosis of LNS. This variant was absent from population databases (gnomAD, 1000 Genomes, dbSNP). Protein function prediction tools consistently indicated it as a pathogenic or likely pathogenic variant (SIFT, PolyPhen-2, CADD, and REVEL scores all reached pathogenic thresholds). Protein structural modeling revealed that the variant may disrupt the hydrogen-bonding network compromising the tetramer stability. ACMG classification designated it as likely pathogenic (PM1+PM2_Supporting+PM5+PP3). The patient was treated with benhaxol hydrochloride, baclofen, and clonazepam to improve his neurological symptoms, in addition with treatment with febuxostat from the Nephrology Department to manage his purine metabolism. After one year of follow-up, the patient's abnormal posture showed slight improvement, self-injurious behavior persisted but was managed with protective gloves, blood uric acid levels normalized, and renal stones decreased. Case 2, a 13-year-old boy, was hospitalized to the Nephrology Department due to urinary tract infection. Following successful control of the infection, his limb dystonia has worsened, leading to his transfer to the Neurology Ward. The patient had a history of delayed motor and language development, abnormal postures, and lip-biting self-injurious behavior, with elevated blood uric acid levels, leading to the diagnosis of LNS. His parents had declined genetic testing due to financial constraints. Following discharge, the patient did not adhere to the prescribed medication regimen or attend scheduled outpatient visits. The patient had died by the time of the 4-month follow-up contact. CONCLUSION Variants of the HPRT1 gene probably underlay the LNS in the two children, and the HPRT1 is the only known pathogenic gene for LNS. Early genetic diagnosis, strict adherence to multidisciplinary comprehensive treatment, and intensive intervention for self-injurious behaviors are crucial for improving the quality of life and prolonging the survival of children with LNS.
Humans ; Male ; Lesch-Nyhan Syndrome/diagnosis* ; Exome Sequencing ; Child, Preschool ; Phenotype ; Infant ; Child ; Female ; Retrospective Studies ; Mutation

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome (LNS) but no specimen from the affected probands. METHODS: All affected individuals in this pedigrees were male and had deceased during childhood, with no biological specimen left. Based on their typical neurological dysfunction and tendency for self-mutilation, the diagnosis of LNS was suspected. Sanger sequencing was carried out to detect potential variant of the HPRT1 gene among female members from the pedigree. Following the identification of the pathogenic variant, prenatal diagnosis was provided for a high-risk fetus. RESULTS: The proband's mother and three other females were found to harbor heterozygous c.500_501delGGinsC (p.Arg167fs*23) variant of the HPRT1 gene, which was unreported previously. Prenatal diagnosis showed that the fetus was a male and had inherited the same pathogenic variant. CONCLUSION The c.500_501delGGinsC variant of the HPRT1 gene probably underlay the LNS in this pedigree. Above finding has provided a basis for prenatal diagnosis and genetic counseling for this pedigree.
Male ; Female ; Humans ; Pregnancy ; Lesch-Nyhan Syndrome/genetics* ; Pedigree ; Hypoxanthine Phosphoribosyltransferase/genetics* ; Prenatal Diagnosis ; China ; Mutation

Lesch-Nyhan syndrome is a rare X-linked recessive metabolic disorder characterized by developmental delay, hyperuricemia, choreoathetosis, spasticity, mental retardation, and compulsive self-injurious behavior. This disorder results from a complete deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This syndrome is often misdiagnosed to cerebral palsy and clinical manifestations are usually related to the degree of enzyme deficiency. Complete HGPRT deficiency presents with severe specific neurologic manifestation and nephrolithiasis leading to fatal kidney damage. This report highlighted the importance of clinical awareness leading to early diagnosis and therapy for prevention of the self mutilation and renal failure, even if we couldn't inhibit the progression of neuro-psychotic symptoms.
Cerebral Palsy ; Early Diagnosis ; Hyperuricemia ; Hypoxanthine Phosphoribosyltransferase ; Intellectual Disability ; Kidney ; Lesch-Nyhan Syndrome* ; Muscle Spasticity ; Nephrolithiasis ; Neurologic Manifestations ; Renal Insufficiency ; Self Mutilation ; Self-Injurious Behavior

An 8-month-old male infant presented with persistent, gross, orange-colored crystals in his urine. His physical and neurological development was normal. Laboratory study showed hyperuricemia, hyperuricosuria and urate crystaluria. He was determined to have partial hypoxanthine-guanine phosphoribosyl transferase(HPRT) deficiency. The molecular genetic analysis revealed a missense mutation in the patient's HPRT gene. By sequencing the patient's cDNA, we identified an A-to-G transition at nucleotide 239, resulting in the replacement of Aspartate with Glycine at amino acid 80 in the HPRT. To our knowledge, this mutation has not previously been reported. Our patient is now being placed on allopurinol therapy, and has had no problem since. Partial HPRT deficiency has been known to cause recurrent acute renal failure without the phenotypic features of Lesch-Nyhan syndrome. Therefore, we think that early diagnosis and treatment are very crucial in preventing acute renal failure.
Acute Kidney Injury ; Allopurinol ; Aspartic Acid ; DNA, Complementary ; Early Diagnosis ; Glycine ; Humans ; Hyperuricemia ; Hypoxanthine Phosphoribosyltransferase* ; Infant ; Lesch-Nyhan Syndrome ; Male ; Molecular Biology ; Mutation, Missense* ; Uric Acid

The Lesch-Nyhan syndrome which is caused by the deficiency of hypoxanthine guanine phosphoribosyltransferase is an X-linked recessive disorder characterized by hyperuricemia, choreoathetosis, mental retardation and compulsive self-injurious behavior. Clinical management of the patients with the Lesch-Nyhan syndrome is frustrating and requires burdensome medical treatment since it cripples the patient and shortens the life span by progression of neurological symptoms, but there are no cures or measures for relieving relentless natural course of the disease yet. Therefore, prenatal diagnosis of the affected fetus is important in genetic counselling for the family at high risk. In this study, four different mutations in the HPRT gene of four probands have been identified in four unrelated families; K215X, Q109X, nt.631 A, and nt.289 GT. Two mutations among them altered restriction enzyme sites; SpeI for Q109X and MaeI for nt.289 GT. Based on their molecular defects, prenatal diagnoses of 3 the fetuses were successfully made between ninth and eleventh week of gestation by polymerase chain reaction(PCR), restriction digestion and DNA sequencing using cDNA obtained from chorionic villus samples (CVS). We predicted the outcome of all fetuses prenatally. Among the three fetuses two were male and one was female according to the identification made by PCR amplification of the sex determining region of the Y chromosome(SRY) gene. Each carried a wild type allele for the corresponding mutant allele. They were also tested postnatally for the mutations to be unaffected.
Alleles ; Chorionic Villi ; Digestion ; DNA, Complementary ; Female ; Fetus* ; Humans ; Hyperuricemia ; Hypoxanthine Phosphoribosyltransferase ; Intellectual Disability ; Lesch-Nyhan Syndrome* ; Male ; Polymerase Chain Reaction ; Pregnancy ; Prenatal Diagnosis ; Self-Injurious Behavior ; Sequence Analysis, DNA