Lesch-Nyhan Syndrome, HPRT-Related Hyperuricemia and Gout via the HPRT1 Gene

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency results in a spectrum of clinical phenotypes which include Lesch-Nyhan syndrome, HPRT1-related hyperuricemia and gout (Fasullo and Endres 2015).

Lesch-Nyhan syndrome is characterized by motor dysfunction, cognitive impairment, behavioral disturbance and hyperuricemia with onset in infancy and childhood. Symptoms of Lesch-Nyhan syndrome include choreoathetosis, variable intellectual disability, cerebral palsy, developmental delay, nephrolithiasis, and persistent self-mutilation which is a hallmark of this disease (Fasullo and Endres 2015). A variable spectrum of neurological involvement occurs predominantly in males. In rare occasions, females may exhibit Lesch-Nyhan syndrome due to skewed inactivation of X chromosomes (Jinnah et al. 2000).

HPRT-related hyperuricemia, in contrast to Lesch-Nyhan syndrome, is due to partial HPRT deficiency with disease onset usually in childhood. Hyperuricemia increases the risk for crystalluria, nephrolithiasis and gout. Resulting renal complications can lead to nephropathy, even renal failure (Srivastava et al 2002; Jinnah et al 2010; Fu et al 2014). Female carriers may develop hyperuricemia later in life.

HPRT-related gout is another consequence of hyperuricemia due to partial HPRT1 deficiency. This type of gout accounts for less than 2% of all adult male patients with gout (Jinnah et al. 2010; Fu and Jinnah 2012).

Lesch-Nyhan syndrome and other HPRT1-related disorders are inherited in an X-linked recessive manner and caused by pathogenic variants in the HPRT1 gene encoding hypoxanthine guanine phosphoribosyltransferase. This transferase catalyzes the conversion of hypoxanthine to inosine monophosphate and guanine to guanine monophosphate. This transferase plays a central role in the generation of purine nucleotides through the purine salvage pathway. HPRT1 is the only gene known to be responsible for Lesch-Nyhan syndrome. Pathogenic variants in HPRT1 include missense, nonsense, small deletion and insertion, and splice mutations, as well as large deletions in the HPRT1 locus (Jinnah et al. 2000; Fuh and Jinnah 2012; Fu et al. 2014). De novo pathogenic variants have also been reported (Nyhan et al. 2014).

In the case of HPRT1-related hyperuricemia and gout, genotype-phenotype studies imply that pathogenic variants resulting in little or no residual enzyme function are responsible for classic Lesch-Nyhan syndrome, while pathogenic variants retaining residual enzyme activity manifest HPRT1-related hyperuricemia and gout (Jinnah et al 2010).

DNA sequence analysis detects HPRT1 pathogenic variants in ~90 -95% of affected Lesch-Nyhan syndrome males and 80% of female carriers due to germline mosaicism (Nyhan et al. 2014). Sensitivity is not available for HPRT1-related gout.

This test provides full coverage of all coding exons of the HPRT1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.