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.

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.

Lesch-Nyhan syndrome due to a splice-site mutation in a 14-month-old boy presenting as acute renal failure.

Lesch-Nyhan disease (LND) is a rare X-linked recessive inherited disorder caused by mutations in HPRT1 gene resulting in deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT). LND is characterized by hyperuricemia and a spectrum of neurological and behavioral manifestations. We describe a rare case of a 14-month-old boy presenting with acute renal failure and hyperuricemia. The patient exhibited all features of LNS apart from self-injurious behavior. The enzymatic analysis demonstrated total inactivity of the HPRT, and the molecular analysis revealed a splice-site mutation in intron 3 leading to exon 4 exclusion. This splice-site mutation has been previously reported only twice.

Hypoxanthine phosphoribosyltransferase (HPRT)-deficiency is associated with impaired fertility in the female rat.

The purine hypoxanthine plays important role in regulating oocyte maturation and early embryonic development. The enzyme hypoxanthine phosphoribosyltransferase (HPRT) recycles hypoxanthine to generate substrates for nucleotide synthesis and key metabolites, and here we show that HPRT deficiency in the rat disrupts early embryonic development and causes infertility in females.

CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses.

BACKGROUND: Xanthine urinary stones are a rare entity that may occur in patients with Lesch-Nyhan syndrome receiving allopurinol. There is little literature describing imaging characteristics of these stones, and the most appropriate approach to imaging these stones is therefore unclear. We performed in-vitro and in-vivo analyses of xanthine stones using computed tomography (CT) at different energy levels, ultrasound (US), and magnetic resonance imaging (MRI). METHODS: Five pure xanthine stones from a child with Lesch-Nyhan were imaged in-vitro and in-vivo. CT of the stones was performed at 80 kVp, 100 kVp, 120 kVp and 140 kVp and CT numbers of the stones were recorded in Hounsfield units (HU). US of the stones was performed and echogenicity, acoustic shadowing and twinkle artifact were assessed. MRI of the stones was performed and included T2-weighted, ultrashort echo-time-weighted and T2/T1-weighted 3D bFFE sequences and signal was assessed. RESULTS: In-vitro analysis on CT demonstrated that xanthine stones were radiodense and the average attenuation coefficient did not differ with varying kVp, measuring 331.0 ± 51.7 HU at 80 kVp, 321.4 ± 63.4 HU at 100 kVp, 329.7 ± 54.2 HU at 120 kVp and 328.4 ± 61.1 HU at 140 kVp. In-vivo analysis on CT resulted in an average attenuation of 354 ± 35 HU. On US, xanthine stones where echogenic with acoustic shadowing and twinkle artifact. On MRI, stones lacked signal on all tested sequences. CONCLUSION: Xanthine stone analyses, both in-vitro and in-vivo, demonstrate imaging characteristics typical of most urinary stones: dense on CT, echogenic on US, and lacking signal on MRI. Therefore, the approach to imaging xanthine stones should be comparable to that of other urinary stones.

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.

Clinical, biochemical and genetic characteristics of a cohort of 101 French and Italian patients with HPRT deficiency.

BACKGROUND: HPRT deficiency is a rare disorder of purine metabolism whose natural history is not fully understood. No optimal management recommendations exist. The objective of the present study is to characterize a large cohort of patients with HPRT deficiency, comparing Lesch-Nyhan Disease (LND) and its attenuated variants, with the purpose of helping clinicians in disease management and prognostic definition. METHODS: Genetic and clinical features of French and Italian patients with a confirmed diagnosis of HPRT deficiency were collected. RESULTS: A hundred and one patients were studied, including 66 LND, 22 HND (HPRT-related Neurological Dysfunction) and 13 HRH (HPRT-Related Hyperuricemia) patients. The clinical manifestations at onset were not specific, but associated with an orange coloration of diapers in 22% of patients. The overall neurological involvement was more severe in LND than in HND patients. Behavioural disturbances were not limited to self-injuries and were not exclusive of LND. Median age of involuntary movements and self-injuries appearance in LND was 1.0 and 3 years, respectively. Renal manifestations (66.3% of patients) occurred at any age with a median onset age of 1.1 years, while gout (25.7% of patients) appeared later in disease course (median onset age 18 years) and was more frequent in attenuated variants than in LND. HPRT activity and genotype showed a significant correlation with the severity of the neurological disease. On the contrary, there were no significant differences in the development of nephropathy or gout. For the treatment of neurological aspects, botulinum toxin injections, oral or intrathecal baclofen and gabapentin were partially efficacious and well tolerated, while deep brain stimulation was associated to a worsening of patients' condition. CONCLUSIONS: The present study improves the knowledge of the natural history of HPRT deficiency and could represent a starting point for the development of future management guidelines.

Xanthine calculi in a patient with Lesch-Nyhan syndrome and factor V Leiden treated with allopurinol: case report.

BACKGROUND: Lesch-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 PRESENTATION: We 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. CONCLUSIONS: Pediatricians treating these children should be aware of these rare conditions and promptly manage the potential complications that may require medical or surgical intervention.

Treatment of self-injurious behaviors in Lesch-Nyhan syndrome with S-adenosylmethionine.

An 11-year-old boy with Lesch-Nyhan syndrome (LNS) had persistently injured himself by biting his lips and buccal mucosa since infancy. Risperidone was only partially effective in suppressing this behavior. Oral administration of S-adenosylmethionine (SAMe), involving increasing the dose from 400 mg to 1 g, resulted in the amelioration of self-injurious behavior and anxiety as well as marked improvement in his self-esteem, performance at school, and friendships. No adverse effects were noted. SAMe may have a favorable effect on symptoms of LNS by activating monoaminergic pathways and/or increasing the adenosine pool in the salvage pathway of guanosine monophosphate synthesis. Defects in these pathways have been essentially implicated in the neurological pathophysiology of LNS.

Fuzzy optimization for detecting enzyme targets of human uric acid metabolism.

MOTIVATION: Mathematical modeling and optimization have been used for detecting enzyme targets in human metabolic disorders. Such optimal drug design methods are generally differentiated as two stages, identification and decision-making, to find optimal targets. We developed a unified method named fuzzy equal metabolic adjustment to formulate an optimal enzyme target design problem for drug discovery. The optimization framework combines the identification of enzyme targets and a decision-making strategy simultaneously. The objectives of this algorithm include evaluations of the therapeutic effect of target enzymes, the adverse effects of drugs and the minimum effective dose (MED). RESULTS: An existing generalized mass action system model of human uric acid (UA) metabolism was used to formulate the fuzzy optimization method for detecting two types of enzymopathies: hyperuricemia caused by phosphoribosylpyrophosphate synthetase (PRPPS) overactivity and Lesch-Nyhan syndrome. The fuzzy objectives were set so that the concentrations of the metabolites were as close as possible to the healthy levels. The target design included a diet control of ribose-5-phospahate (R5P). The diet control of R5P served as an extra remedy to reduce phosphate uptake entering the purine metabolic pathway, so that we could obtain a more satisfactory treatment than obtained for those without a diet control. Moreover, enhancing UA excretion resulted in an effective treatment of hyperuricemia caused by PRPPS overactivity. This result correlates with using probenecid and benbromazone, which are uricosuric agents present in current clinical medications. By contrast, the Lesch-Nyhan syndrome required at least three enzyme targets to cure hyperuricemia.

Management of oral lesions in Lesch-Nyham syndrome.

Lesh-Nyhan Syndrome is a hereditary disorder that affects the way in which the body handles the production and breakdown of purines. One of its main characteristic is self-mutilation. We present a new appliance which allows healing to occur.

Urine alkalinization may be enough for the treatment of bilateral renal pelvis stones associated with Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is a rare sex-linked disorder of purine metabolism that is caused by a mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene which causes marked hyperuricemia and hyperuricosuria, with signs of gouty arthritis and uric acid stone disease in early childhood. We report a case of renal pelvis calculi which was dissolved within 10 days of urine alkalinization and hydration.

[Movement disorders and neurometabolic diseases]. / Mouvements anormaux et maladies neurométaboliques.

Movement disorders, especially dystonia, are a frequent manifestation of neurometabolic diseases. Proper characterization and classification of movement disorders is crucial but may be challenging in this setting. The diagnostic work-up should be focused first on treatable disease. Mixed movement disorders, marked orofacial involvement and associated neurological and extra-neurological features should prompt the clinician to consider the possibility of an underlying neurometabolic disorder. The diagnostic approach is based on the abrupt, paroxysmal or insidious nature of onset of the movement disorders, the clinical picture including neurological and systemic signs and symptoms, and the presence or absence of abnormalities on the brain MRI. In addition to specific treatment for the metabolic disease, when available, symptomatic treatment of the movement disorders can be proposed, remembering that these patients are particularly vulnerability to iatrogenesis.

Effective treatment of self-injurious oral trauma in Lesch-Nyhan syndrome: a case report.

Lesch-Nyhan syndrome (LNS) is an X-linked disorder originating from deficiency of the enzyme hypoxanthine guanine phosphoribosyl transferase. It is characterized by neurological manifestations, including the dramatic symptom of compulsive self-mutilation, which results in destruction of oral and perioral tissues. Several drug trials have been administered to improve the severe self-destructive behaviour, with questionable effectiveness. Invasive treatment approaches, such as extraction of teeth and orthognathic surgery, have been suggested with variable success. A conservative treatment with an intraoral appliance serving to prevent oral and peri-oral self-injury is presented in this report. The patient was a 14-year-old boy demonstrating the typical LNS behaviour, including compulsive self-biting, significant loss of lip and tongue tissue, spasticity and involuntary movements. An acrylic maxillary appliance was designed and constructed with an occlusal plate raising the bite. The appliance was retained by two Adams' clasps on the first premolars, along with three ball clasps between the incisors. Fabrication, insertion, and maintenance were uncomplicated and non-stressful to the patient. Periodic recall over 3-year period has confirmed the effective healing of the oral lesions and a high level of tolerance of the appliance.

Efficacy of rasburicase in hyperuricemia secondary to Lesch-Nyhan syndrome.

We report on a 16-day-old male with metabolic acidosis, hyperuricemia, hyperuricosuria, and nephrocalcinosis caused by Lesch-Nyhan syndrome. Activity of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme in lysed erythrocytes was undetectable, and molecular DNA analysis confirmed the presence of a 4-base pair deletion at the 5' end of intervening sequence 8 in the HPRT1 gene, a change that affects a 5' splice site consensus sequence. Rasburicase, a urate oxidase enzyme, was administered on day 26 of life, with an endovenous dose of 0.20 mg/kg/d for 3 days. Plasma urate concentrations normalized (2.96 mg/dL) at 38 days of life. Kidney function was preserved in our patient. In summary, rasburicase proved to be a safe and effective treatment in a patient with Lesch-Nyhan syndrome with uric acid nephropathy in the neonatal period.

Myelination disturbance in a patient with hyperuricemia and hyperserotoninemia combined with 18q deletion syndrome.

We previously reported a male patient with an 18q21.3 deletion, hyperuricemia and typical symptoms of the Lesch-Nyhan syndrome who lacked hypoxanthine-guanine-phosphoribosyl-transferase (HGPRT) deficiency. The patient developed progressive peripheral neuropathy in additon to his profound mental retardation and self-injurious behavior. At the age of 23 years MR imaging revealed globally delayed myelination with relative sparing of the corpus callosum and frontal lobes. They were focal hyperintensities suggestive of gliosis. Multimodality evoked potentials found evidence of impaired central and peripheral conduction. Single photon emission computed tomographic (SPECT) imaging demonstrated left frontal hyperperfusion and under it a temporoparietal hypoperfusion.

Animal Models of Self-Injurious Behavior: An Update.

Although self-injurious behavior is a common comorbid behavior problem among individuals with neurodevelopmental disorders, little is known about its etiology and underlying neurobiology. Interestingly, it shows up in various forms across patient groups with distinct genetic errors and diagnostic categories. This suggests that there may be shared neuropathology that confers vulnerability in these disparate groups. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key contributing factor. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury and highlights the convergence in findings between these models and expression of self-injury in humans.