Genetic Diversity and Expanded Phenotypes in Dystonia: Insights from Large-Scale Exome Sequencing.

Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (∼25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex.

Unleashing the Power of Induced Pluripotent stem Cells in in vitro Modelling of Lesch-Nyhan Disease.

Lesch-Nyhan disease (LND) is a monogenic rare neurodevelopmental disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT), the key enzyme of the purines salvage pathway. Beyond its well-documented metabolic consequences, HPRT deficiency leads to a distinctive neurobehavioral syndrome characterized by motor disabilities, cognitive deficits, and self-injurious behavior. Although various cell and animal models have been developed to investigate LND pathology, none have adequately elucidated the underlying mechanisms of its neurological alterations.

Adenylyl cyclase 2 expression and function in neurological diseases.

Adenylyl cyclases (Adcys) catalyze the formation of cAMP, a secondary messenger essential for cell survival and neurotransmission pathways in the CNS. Adcy2, one of ten Adcy isoforms, is highly expressed in the CNS. Abnormal Adcy2 expression and mutations have been reported in various neurological disorders in both rodents and humans.

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.

Metabolic and neurobehavioral disturbances induced by purine recycling deficiency in .

Adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) are two structurally related enzymes involved in purine recycling in humans. Inherited mutations that suppress HGPRT activity are associated with Lesch-Nyhan disease (LND), a rare X-linked metabolic and neurological disorder in children, characterized by hyperuricemia, dystonia, and compulsive self-injury. To date, no treatment is available for these neurological defects and no animal model recapitulates all symptoms of LND patients.

A rare case of congenital insensitivity to pain with anhidrosis.

A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body.

Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

Background: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa.

Amyloidogenic Propensity of Metabolites in the Uric Acid Pathway and Urea Cycle Critically Impacts the Etiology of Metabolic Disorders.

Novel insights into the etiology of metabolic disorders have recently been uncovered through the study of metabolite amyloids. In particular, inborn errors of metabolism (IEMs), including gout, Lesch-Nyhan syndrome (LNS), xanthinuria, citrullinemia, and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, are attributed to the dysfunction of the urea cycle and uric acid pathway. In this study, we endeavored to understand and mechanistically characterize the aggregative property exhibited by the principal metabolites of the urea cycle and uric acid pathway, specifically hypoxanthine, xanthine, citrulline, and ornithine.

An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

Background: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging.

Objective: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm.

Methods: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing.

A new physiological medium uncovers biochemical and cellular alterations in Lesch-Nyhan disease fibroblasts.

Background: Lesch-Nyhan disease (LND) is a severe neurological disorder caused by the genetic deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme involved in the salvage synthesis of purines. To compensate this deficiency, there is an acceleration of the de novo purine biosynthetic pathway. Most studies have failed to find any consistent abnormalities of purine nucleotides in cultured cells obtained from the patients.

Generation of an iPSC line (SDQLCHi030-A) derived from PBMCs of a patient with Lesch-Nyhan syndrome caused by HPRT1 mutation.

Lesch-Nyhan syndrome (LNS, MIM300322) is a rare inherited disorder caused by mutations in HPRT1 gene. Here we describe the generation of induced pluripotent stem cells (iPSCs) from an infected child carrying the HPRT1 mutation c.508C > T(p.

Naringin corrects renal failure related to Lesch-Nyhan disease in a rat model via NOS-cAMP-PKA and BDNF/TrkB pathways.

This study explored the effect of naringin (NAR) on HGPRT1 deficiency and hyperuricemia through NOS-cAMP-PKA and BDNF/TrkB signaling pathways induced by caffeine (CAF) and KBrO in a rat model. Sixty-three adult male albino rats were randomly assigned into nine (n = 7) groups. Group I: control animals, Group II was treated with 100 mg/kg KBrO , Group III was treated with 250 mg/kg CAF, Group IV was treated with 100 mg/kg KBrO  + 250 mg/kg CAF, Group V was administered with 100 mg/kg KBrO  + 100 mg/kg haloperidol, Group VI was administered with 100 mg/kg KBrO  + 50 mg/kg NAR, Group VII was administered with 500 mg/kg CAF + 50 mg/kg NAR, and Group VIII was administered with 100 mg/kg KBrO  + 250 mg/kg CAF + 50 mg/kg NAR.

Red Blood Cells from Individuals with Lesch-Nyhan Syndrome: Multi-Omics Insights into a Novel S162N Mutation Causing Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency.

Lesch-Nyhan syndrome (LN) is an is an X-linked recessive inborn error of metabolism that arises from a deficiency of purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disease manifests severely, causing intellectual deficits and other neural abnormalities, hypercoagulability, uncontrolled self-injury, and gout. While allopurinol is used to alleviate gout, other symptoms are less understood, impeding treatment.

Lesch-Nyhan syndrome: a case report.

Lesch-Nyhan syndrome (LNS) is a rare X-linked recessive disorder caused by a mutation in the (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.

The Role of Video-EEG Monitoring in Lesch-Nyhan Syndrome.

Lesch-Nyhan syndrome (LNS) is a rare genetic disease secondary to a HPRT1 mutation on chromosome X. It is characterized by dystonia, developmental delay, hyperuricemia and self-harming behaviours. The HPRT enzyme is implicated in the purine salvage pathway.

Clinical and genetic characteristics of 36 children with Joubert syndrome.

Background And Aims: Joubert syndrome (JBTS, OMIM # 213300) is a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosing JBTS. It is a clinically and genetically heterogeneous disorder involving mutations in more than 40 ciliopathy-related genes.

Renal function, sex and age influence purines and pyrimidines in urine and could lead to diagnostic misinterpretation.

Glomerular filtration rate (GFR) is commonly used in clinical practice for the diagnosis and follow-up of chronic kidney disease. Screening for inborn errors of metabolism (IEM) is based on analysis of biomarkers in urine, reported by their ratio to urinary creatinine (crn). Impaired renal function may complicate the interpretation of several biomarkers used for screening of IEM.

Discovering functionally important sites in proteins.

Proteins play important roles in biology, biotechnology and pharmacology, and missense variants are a common cause of disease. Discovering functionally important sites in proteins is a central but difficult problem because of the lack of large, systematic data sets. Sequence conservation can highlight residues that are functionally important but is often convoluted with a signal for preserving structural stability.