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

Cho, Ja Hyang; Choi, Jin‐Ho; Heo, Sun Hee; Kim, Gu Hwan; Yum, Mi‐Sun; Lee, Beom Hee; Yoo, Han‐Wook

doi:10.1007/s11011-019-00441-0

Cited by 7 publications

(7 citation statements)

References 25 publications

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“…The HPRT1 gene participates in the metabolism of purine, and defects in its protein products can lead to the accumulation of uric acid, the nal product of purine metabolism. The crystallization of uric acid in different tissues and organs can lead to growth retardation, gout, musculoskeletal changes, and uric acid nephropathy [11] [12]. Although it is speculated that this mutation may affect brain development, its effect on the nervous system has not been speci cally veri ed.Schretlen and others have shown that the areas exhibiting reduced white matter volume in LNS and its variants are consistent with areas that affect neurobehavior.…”

Section: Discussionmentioning

confidence: 99%

The Study on the Clinical Phenotype and Function of HPRT1 Gene

Guo

Chen

Lin

et al. 2021

Preprint

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Background: Lesch-Nyhan disease (LND) is a rare x-linked purine metabolic neurogenetic disease caused by enzyme hypoxanthine-guanine phosphoriribosyltransferase(HGprt) deficiency, also known as self-destructive appearance syndrome. A series of manifestations are caused by abnormal purine metabolism. The typical clinical manifestations are hyperuricemia, growth retardation, mental retardation, short stature, dance-like athetosis, aggressive behavior, and compulsive self-harm.. Results: we identified a point mutation c.151C > T (p. Arg51*) in a pedigree. We analyzed the clinical characteristics of children in a family, and obtained the blood of their parents and siblings for second-generation sequencing. At the same time, we also analyzed and compared the expression of HPRT1 gene and predicted the three-dimensional structure of the protein. And we analyzed the clinical manifestations caused by the defect of the HPRT1 genethe mutation led to the termination of transcription at the 51st arginine, resulting in the production of truncated protein, and the relative expression of HPRT1 gene in patients was significantly lower than other family members and 10 normal individuals. Conclusion: this mutation leads to the early termination of protein translation and the formation of a truncated HPRT protein, which affects the function of the protein and generates corresponding clinical manifestations.

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Section: Discussionmentioning

confidence: 99%

The Study on the Clinical Phenotype and Function of HPRT1 Gene

Guo

Chen

Lin

et al. 2021

Preprint

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“…Lesch–Nyhan syndrome (LNS; OMIM: 300322) is a rare neurogenetic disorder of purine metabolism caused by complete or severe deficiency of the enzyme HPRT1 ( Seegmiller et al, 1967 ). The disease is transmitted in the X-linked recessive mode of inheritance and encountered in different populations including Arabs ( Shaltiel et al, 1981 ; Torres and Puig, 2007 ; de Gemmis et al, 2010 ; Yamada et al, 2014 ; Nguyen et al, 2017 ; Cho et al, 2019 ; Li et al, 2022 ). Hyperuricemia, dystonia, cognitive deficits, and self-injurious behavior are among the reported characteristics of LNS ( Lesch and Nyhan, 1964 ).…”

Section: Introductionmentioning

confidence: 99%

Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: Case report of a female patient from Saudi Arabia with Lesch–Nyhan syndrome

Al-Bakheet

AlQudairy²,

Alkhalifah³

et al. 2023

Front. Genet.

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Background: Hypoxanthine-guanine phosphoribosyltransferase (HPRT1) deficiency is an inborn error of purine metabolism responsible for Lesch–Nyhan syndrome (LNS). The disease is inherited in an X-linked recessive manner and predominantly affects male individuals. Female individuals can carry a mutation as heterozygotes, but typically, they are asymptomatic because of the random inactivation of the affected allele. Nevertheless, although rare, heterozygote female individuals may manifest LNS with full characteristics. Herein, we describe a female patient from Saudi Arabia with LNS.Results: The patient (a 4-year-old girl) presented with typical characteristics of the disease, which include global developmental delay, self-mutilation, hyperuricemia, hypotonia, speech delay, spasticity, and seizures. Her general biochemical laboratory results were normal except for high levels of uric acid. The abdominal MRI\MRS, mostly unremarkable, showed bilateral echogenic foci within the renal collecting system. Genetic testing (whole-exome sequencing, iterative variant filtering, segregation analysis, and Sanger sequencing) pointed a novel de novo frameshift variant in HPRT1. X-inactivation assay using HpaII showed the presence of a 100% skewed X chromosome carrying the affected allele. RT-PCR of the cDNA indicated complete loss of the expression of the normal allele.Conclusion: Our study presents a female patient who has a severe case of LNSand found to be the 15th female patient with the disease in the world. The study emphasizethe need for a streamlined protocol that will help an early and accurate diagnosis of female LNS patients to avoid unnecessary interventions that lead to costly patient care.

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“…Until now, there has been no effective drug that can control SIBs, as the pathophysiology between SIBs and HGPRT deficiency is not clear ( Seifert, 2016 ). Although reports about LND are not uncommon around the world ( Puig et al, 2001 ; Schretlen et al, 2013 ; Cho et al, 2019 ), there are only a few single-case reports about LND in Chinese patients ( Huang et al, 2018 ; Jian* et al, 2013 ; Lee et al, 1995 ). The present study aims to describe Chinese patients with LND with the purpose of improving knowledge of the natural history of the disease and outlining the background for future management recommendations.…”

Section: Introductionmentioning

confidence: 99%

Description of the Molecular and Phenotypic Spectrum of Lesch-Nyhan Disease in Eight Chinese Patients

Qiao²,

Liu

et al. 2022

Front. Genet.

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Background: Lesch-Nyhan disease (LND) is a rare disorder involving pathogenic variants in the HPRT1 gene encoding the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) that result in hyperuricemia, intellectual disability, dystonic movement disorder, and compulsive self-mutilation. The purpose of the present study was to characterize the genetic basis of LND and describe its phenotypic heterogeneity by identifying the variation in the HPRT1 gene in a cohort of Chinese LND patients.Results: The median age at diagnosis was 31 mo (interquartile range (IQR): 7–76 mo), and the initial manifestations were mainly head control weakness and motor development delay. The median age of self-mutilation behavior onset was 19 mo (IQR: 17–24 mo), and all patients were required to travel in a wheelchair and fall into the predicament of compulsive self-harm behavior. There were two patients whose blood uric acid levels were normal for their high urinary acid excretion fraction without taking uric acid-lowering drugs. Seven different pathogenic variants of the HPRT1 gene were identified among eight independent pedigrees, including four novel mutations [c.299 (exon 3) T > A; loss (exon: 6) 84 bp; c.277_281delATTGC; c.468_470delGAT]. The pathogenic variant sites were mainly concentrated in exon 3, and truncating mutations (including frameshift mutations and nonsense mutations) were the most common genetic variant types (5/7, 71.4%).Conclusion: The present study described the phenotypic and molecular spectrum of LND in eight Chinese families, including four novel mutations, which expands our understanding of LND.

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

Cited by 7 publications

References 25 publications

The Study on the Clinical Phenotype and Function of HPRT1 Gene

The Study on the Clinical Phenotype and Function of HPRT1 Gene

Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: Case report of a female patient from Saudi Arabia with Lesch–Nyhan syndrome

Description of the Molecular and Phenotypic Spectrum of Lesch-Nyhan Disease in Eight Chinese Patients

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