Dystonia in Handcuffs: A Picture Typical of Lesch-Nyhan Syndrome.
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ABSTRACT:
SUBMITTER: Menozzi E
PROVIDER: S-EPMC6749813 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC10466019 | biostudies-literature
Project description:Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15-18 weeks' gestation, or chorionic villus cells obtained at about 10-12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments.
| S-EPMC2234399 | biostudies-literature
Project description:Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder of purine metabolism caused by a mutation in Xq26.2-q26.3 (OMIM 308000.0004). The presence of the diagnostic triad, i.e. signs of self-injurious behavior (SIB) and results of pedigree analysis and novel molecular biology & genetic testing, confirms the diagnosis of LNS. With a level of hypoxanthine guanine phosphoribosyl-transferase 1 (HPRT1) enzyme activity < 2%, patients develop neurological, neurocognitive, and neuromotor symptoms along with SIB. Described here is a case of 4-year-old boy who was diagnosed with LNS. The boy displayed SIB, i.e. biting of the lips and fingers, and he had cerebral venous sinus thrombosis caused by LNS.
| S-EPMC5359358 | biostudies-literature
Project description: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.
| S-EPMC9996127 | biostudies-literature
Project description:PURPOSE:Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was to describe macrocytic erythrocytes as another common aspect of the phenotype. METHODS:The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly. RESULTS:Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia. CONCLUSION:These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.
| S-EPMC6281870 | biostudies-literature
Project description:Patients with Lesch-Nyhan disease (LND) often engage in self-injurious biting. This problem requires difficult management choices, sometimes including removal of the teeth. Although many health care professionals are reluctant to remove teeth in a child because of the permanent negative cosmetic consequences of the edentulous state, disfigurement of the face and tongue from self-biting can be worse. We analyzed the records of 5 LND patients who used mouth guards to spare the teeth. Success was variable, and dental extraction ultimately was required in 4 cases. We also reviewed previously published cases on the use of dental devices to spare teeth in LND. Various devices have been recommended, but failure rates are high, and tooth extraction often is still needed. Although dental extraction is not required in all cases, it should not be delayed when biting is severe.
| S-EPMC4237204 | biostudies-other
Project description: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.
| S-EPMC8055678 | biostudies-literature
Project description:Lesch-Nyhan disease (LND) is characterized by dystonia, cognitive abnormalities, and self-injurious behavior. No effective therapies are available. LND is associated with a presynaptic dopaminergic deficit, but the reported effects of dopamine replacement therapy are conflicting. The current prospective open-label study assesses the effects of levodopa on both neurological and behavioral features of LND. All 6 study participants discontinued levodopa early, due to lack of effect and sometimes worsening of motor function. The results provide important clues for pathophysiological mechanisms and suggestions for future treatment options.
| S-EPMC3523804 | biostudies-literature
Project description:BackgroundLesch-Nyhan syndrome is a rare inborn error of purine metabolism marked by a complete deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Inherited as an X-linked recessive genetic disorder that primarily affects males, patients with Lesch-Nyhan syndrome exhibit severe neurological impairments, including choreoathetosis, ballismus, cognitive dysfunction, and self-injurious behavior. Uric acid levels are usually abnormally high, leading to kidney and bladder stones which often necessitate urological intervention. Factor V Leiden is an autosomal dominant disorder of blood clotting associated with hypercoagulability, thrombophilia, and renal disease.Case presentationWe present the first reported case of xanthine calculi in a patient with Lesch-Nyhan syndrome and Factor V Leiden who was treated with allopurinol. A renal ultrasound and CT scan demonstrated bilateral staghorn calculi in the kidneys as well as nephrocalcinosis. Two years earlier the patient underwent cystoscopy with bilateral ureteroscopy and laser lithotripsy, and he was stone free afterwards. The patient subsequently underwent bilateral percutaneous nephrolithotomy (PCNL) and was stone free following the procedure. Patients with endogenous overproduction of uric acid who are being treated with allopurinol have a higher chance of developing xanthine stones.ConclusionsPediatricians treating these children should be aware of these rare conditions and promptly manage the potential complications that may require medical or surgical intervention.
| S-EPMC6043999 | biostudies-literature
Project description:Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.
| S-EPMC3999711 | biostudies-literature