PUS7 deficiency in human patients causes profound neurodevelopmental phenotype by dysregulating protein translation.

Protein translation is a highly regulated process involving the interaction of numerous genes on every component of the protein translation machinery. Upregulated protein translation is a hallmark of cancer and is implicated in autism spectrum disorder, but the risks of developing each disease do not appear to be correlated with one another. In this study we identified two siblings from the NIH Undiagnosed Diseases Program with loss of function variants in PUS7, a gene previously implicated in the regulation of total protein translation. These patients exhibited a neurodevelopmental phenotype including autism spectrum disorder in the proband. Both patients also had features of Lesch-Nyhan syndrome, including hyperuricemia and self-injurious behavior, but without pathogenic variants in HPRT1. Patient fibroblasts demonstrated upregulation of protein synthesis, including elevated MYC protein, but did not exhibit increased rates of cell proliferation. Interestingly, the dysregulation of protein translation also resulted in mildly decreased levels of HPRT1 protein suggesting an association between dysregulated protein translation and the LNS-like phenotypic findings. These findings strengthen the correlation between neurodevelopmental disease, particularly autism spectrum disorders, and the rate of protein translation.

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.

[Analysis of HPRT1 gene variant and prenatal diagnosis for a Chinese pedigree with Lesch-Nyhan syndrome but no specimen from affected probands].

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.

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.

Clinical and molecular findings in a Turkish family with an ultra-rare condition, ELP2-related neurodevelopmental disorder.

Elongator is a multi-subunit protein complex bearing six different protein subunits, Elp1 to -6, that are highly conserved among eukaryotes. Elp2 is the second major subunit of Elongator and, together with Elp1 and Elp3, form the catalytic core of this essential complex. Pathogenic variants that affect the structure and function of the Elongator complex may cause neurodevelopmental disorders. Here, we report on a new family with three children affected with a severe form of intellectual disability along with spastic tetraparesis, choreoathetosis, and self injury. Molecular genetic analyses reveal a homozygous missense variant in the ELP2 gene (NM_018255.4 (ELP2): c.1385G > A (p.Arg462Gln)), while in silico studies suggest a loss of electrostatic interactions that may contribute to the overall stability of the encoded protein. We also include a comparison of the patients with ELP2-related neurodevelopmental disorder to those previously reported in the literature. Apart from being affected with intellectual disability, we have extremely limited clinical knowledge about patients harboring ELP2 variants. Besides providing support to the causal role of p.Arg462Gln in ELP2-related neurodevelopmental disorder, we add self-injurious behavior to the clinical phenotypic repertoire of the disease.

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.

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.

Genetic mimics of cerebral palsy.

The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have specific disease-modifying treatment. In this article, we discuss clinical features that should alert the clinician to the possibility of a cerebral palsy mimic, provide a practical framework for selecting and interpreting neuroimaging, biochemical, and genetic investigations, and highlight selected conditions that may present with predominant spasticity, dystonia/chorea, and ataxia. Making a precise diagnosis of a genetic disorder has important implications for treatment, and for advising the family regarding prognosis and genetic counseling. © 2019 International Parkinson and Movement Disorder Society.

Phenotypic and molecular spectrum of Korean patients with Lesch-Nyhan syndrome and attenuated clinical variants.

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.

Lesch-Nyhan Syndrome in a Chinese Family with Mutation in the Hypoxanthine-Guanine Phosphoribosyltransferase Gene.

BACKGROUND: Lesch-Nyhan syndrome (LNS) is a congenital X-linked recessive neurogenetic disorder caused by mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene. The main clinical manifestation includes hyperuricemia, juvenile-onset gouty arthritis, and neurological developmental disorders. Studies have reported more than 400 HPRT gene mutation sites, but the incidence of LNS in the Chinese population is extremely low. METHODS: Here we report a 16-year-old male patient who suffered neurological dysfunction at an early age and gouty arthritis in his youth. RESULTS: No activity of the HPRT enzyme was detected in the erythrocytes. Furthermore, we found a mutation on exon 3 of the HPRT gene in the patient and his mother (exon 3: c.143G>A), which resulted in arginine to histidine (p.R48H) substitution in the encoded protein. The same mutation was reported in several European families, but was found for the first time in a Chinese family. CONCLUSIONS: Clinicians in China have poor experience in diagnosing LNS cases due to the low incidence in China. Therefore, LNS screening for infants or adolescents with hyperuricemia, gouty arthritis, and neurological dysfunction should be performed.

A clinical trial of safety and tolerability for the selective dopamine D1 receptor antagonist ecopipam in patients with Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is an inherited metabolic disorder characterized by the overproduction of uric acid and distinct behavioral, cognitive, and motor abnormalities. The most challenging clinical problem is self-injurious behavior (SIB), which includes self-biting, self-hitting, self-abrasion, and other features. Currently, these behaviors are managed by behavioral extinction, sedatives, physical restraints, and removal of teeth. More effective treatments are needed. Pre-clinical studies have led to the hypothesis that D1-dopamine receptor antagonists may provide useful treatments for SIB in LND. Ecopipam is one such selective D1-dopamine receptor antagonist. This report summarizes results of a dose-escalation study of the safety and tolerability of ecopipam in 5 subjects with LND. The results suggest that ecopipam is well tolerated, with sedation being the most common dose-limiting event. Several exploratory measures also suggest ecopipam might reduce SIB in this population. These results support the hypothesis that D1-dopamine receptor antagonists may be useful for suppressing SIB in LND, and encourage further studies of efficacy.

HPRTYale proposed as a pathogenic variant for Lesch-Nyhan syndrome: a case report.

Lesch-Nyhan syndrome (LNS) is an X-linked recessive disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme encoded by the HPRT1 gene. The classic disease phenotype described by Lesch and Nyhan in 1964 includes hyperuricemia, mental retardation, severe motor deficiency, and recurring self-mutilation. Here, we report the case of a family with 4 affected males and several female obligate carriers. In 1989, Fujimori et al. reported on a patient diagnosed with LNS who had an HPRT variant thereafter codenamed HPRTYale. The same patient was studied by Wilson et al. in 1986, who found no detectable HPRT enzymatic activity, even though normal HPRT mRNA and protein levels were observed. Disease severity is closely related to residual enzymatic activity, which fits the phenotype presented for this previously reported case, as well as for the patients we report on herein. As it has been reported in only one patient, this mutation is still considered a variant of unknown significance. The HPRTYale mutation is a G>C transversion that leads to a different amino acid with different biochemical properties at position 71, potentially causing the major lack of function. To evaluate the impact of this variant, we used the PolyPhen-2 software, which classified it as possibly damaging. Furthermore, the frequency of this mutant allele is likely extremely rare, since it has only been reported on twice, and a population frequency is not yet available. In conclusion, we propose that the HPRTYale variant is pathogenic, and should be included on lab reports hereafter.

Genotypic and phenotypic spectrum in attenuated variants of Lesch-Nyhan disease.

Lesch-Nyhan disease and its attenuated variants are caused by deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). All patients exhibit excessive production of uric acid, which increases the risk for nephrolithiasis, renal failure, gouty arthritis and tophi. The mildest phenotype includes only problems related to overproduction of uric acid. The most severe clinical phenotype includes prominent neurological abnormalities and the universal feature is self-injurious behavior. In between the mildest and most severe syndromes is a broad spectrum of phenotypes with varying degrees of neurological, neurocognitive and behavioral abnormalities. The effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management.

Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase.

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients.

Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants.

Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking.

A population study of Lesch-Nyhan disease in the UK.

AIM: The aims of this study were to identify all people with Lesch-Nyhan disease (LND) born in the UK between 1988 and 2008, and to obtain a clinical profile including age at diagnosis, genetic background, family history, neurological signs, and medications. METHOD: Potential participants were contacted through the British Paediatric Neurology Surveillance Unit. Questionnaires were sent to each child's paediatric neurologist or primary consultant. Two purine laboratories provided metabolic information. RESULTS: Twenty-three live males with LND in the 0- to 20-year age band and eight live males over the age of 20 years were identified. Thirty-one live people with LND were identified in the UK in 2008, giving a prevalence of 1 in 2 million people. Over the 20 years of study, there was a mean incidence rate of 0.18 per 100 000 live births, range 0 to 0.5. INTERPRETATION: To our knowledge, this study is the first to provide details of the prevalence and incidence of LND in the UK. The data highlight that clinical profiles, at the time of diagnosis, and management of the disease are variable. There is the need for ongoing monitoring of allopurinol dosage and metabolic screening.