Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2023 Jan 26:13:1044936.
doi: 10.3389/fgene.2022.1044936. eCollection 2022.

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

Albandary AlBakheet  1 , Hanan AlQudairy  1 , Joud Alkhalifah  2 , Sheikhah Almoaily  3 , Namik Kaya  1 , Zuhair Rahbeeni  4
Affiliations
Case Reports

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

Albandary AlBakheet et al. Front Genet. .

Abstract

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.

Keywords: HPRT1; Lesch–Nyhan syndrome; RTPCR; X-inactivation assay; de novo.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
(A) Pedigree of the study family. (B,C) Abdomen US indicating bilateral echogenic foci within the renal collecting system. (D) Sanger sequence chromatogram showing the heterozygous HPRT1 variant (NM_000194.2:c.539del. p. G180Dfs*10) in the patient and wild-type sequence in her parents.
FIGURE 2
FIGURE 2
(A) Schematic drawing of HPRT1 transcript displaying the affected exon with the variant. (B) Analysis of RT-PCR on fibroblast-derived RNA, followed by 2% agarose gel electrophoresis. (C) Sanger sequencing for cDNA showing the presence of the mutant allele.
FIGURE 3
FIGURE 3
(A) Analysis of X-inactivation as signified by the AR locus. DNA was amplified before and after HhaI digestion. (B) Locations of the previously reported mutations are indicated on the schematic diagram of the gene and exons.
See this image and copyright information in PMC

References

    1. Aldhalaan H., AlBakheet A., AlRuways S., AlMutairi N., AlNakiyah M., AlGhofaili R., et al. (2021). A novel GEMIN4 variant in a consanguineous family leads to neurodevelopmental impairment with severe microcephaly, spastic quadriplegia, epilepsy, and cataracts. Genes (Basel) 13, 92. 10.3390/genes13010092 - DOI - PMC - PubMed
    1. Aral B., de Saint Basile G., Al-Garawi S., Kamoun P., Ceballos-Picot I. (1996). Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient. Hum. Mutat. 7, 52–58. 10.1002/(SICI)1098-1004(1996)7:1<52::AID-HUMU7>3.0.CO;2-R - DOI - PubMed
    1. Cho J. H., Choi J. H., Heo S. H., Kim G. H., Yum M. S., Lee B. H., et al. (2019). Phenotypic and molecular spectrum of Korean patients with Lesch-Nyhan syndrome and attenuated clinical variants. Metab. Brain Dis. 34, 1335–1340. 10.1007/s11011-019-00441-0 - DOI - PubMed
    1. Davidson B. L., Tarle S. A., Van Antwerp M., Gibbs D. A., Watts R. W., Kelley W. N., et al. (1991). Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Am. J. Hum. Genet. 48, 951–958. - PMC - PubMed
    1. de Gemmis P., Anesi L., Lorenzetto E., Gioachini I., Fortunati E., Zandona G., et al. (2010). Analysis of the HPRT1 gene in 35 Italian lesch-nyhan families: 45 patients and 77 potential female carriers. Mutat. Res. 692, 1–5. 10.1016/j.mrfmmm.2010.07.003 - DOI - PubMed

Publication types