Lesch Nyhan Syndrome: Clinical Presentation and Biochemical Diagnosis

A 3-year-old child was brought to the hospital with a complaint of self-mutilation. He had a chronic ulcer on the buccal surface of lips, and self-inflicted trauma with biting his finger. History revealed that severe motor retardation was apparent by 6 months and he has never been able to lift or support his trunk. The growth chart showed that he has growth retardation. Biochemical analysis was performed which are represented below:

Serum Uric acid: 9.0 mg/dL
Blood Urea : 32 mg/dL
Serum Sodium : 139 mmol/l
Potassium: 5.1 mmol/l
Calcium 39 mmol/l
Total Protein: 70 g/L
Albumin: 23 g/L
Urinary Uric acid: 160mg/100 ml
Urinary Glucose: Absent
Urinary Protein: Absent
Microscopic urine examination: triphosphate crystals

Provisional Diagnosis: Based on the behavioral pattern of self-mutilation, growth retardation, dystonia, and increased serum and urinary uric acids are suggestive of Lesch-Nyhan Syndrome.

Biochemical Basis of Lesch-Nyhan Syndrome
Lesch-Nyhan Syndrome (LNS) is an X-linked inborn error of metabolism caused by mutation of the gene HPRT1 encoding enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). HGRT enzyme catalyzes the recycling of purine bases and lack of this enzyme leads to decreased recycling and increase degradation of purines to uric acid. In addition, lower cellular GMP level increases the denovo synthesis of purines (Figure 1). Therefore, increase synthesis and degradation of purines are responsible for the aggravated level of uric acids in these patients and also result in nephrolithiasis, gouty arthritis, and subcutaneous tophi.

Figure 1: Overview of Purine Metabolism and Biochemical Basis of Lesch-Nyhan Syndrome.a) In LNS, the reduced activity of HPRT results in the decreased salvage pathway of purine nucleotide biosynthesis and cellular level of AMP/GMP. b) The reduced cellular AMP/GMP activates the denovo synthesis of purines. c) The overproduction of purines results in increased formation of uric acid that is deposited as crystals in various soft tissues.

These patients also exhibit a distinctive neurobehavioral phenotype, characterized by dystonia, attentional deficits, and behavioral disturbances including self-injury, presumably attributable to dysfunction of the basal ganglia dopamine system. However, it is unclear how a shortage of hypoxanthine phosphoribosyltransferase 1 causes neurological and behavioral problems characteristic of Lesch-Nyhan syndrome.

Genetics and Diagnosis of Lesch-Nyhan Syndrome
Human HPRT is encoded by a single structural gene spanning approximately 45 kb on the long arm of the X chromosome at Xq26 and consists of nine exons with a coding sequence of 654 bp. In LNS, the high heterogeneity of mutations is observed within the HPRT1 gene including deletions, insertions, duplications, and point mutations. To date more than 300 disease-causing mutations in HPRT1 gene have been reported.

For the diagnosis of Lesch-Nyhan syndrome, the serum, and urinary uric acid are evaluated. With elevated serum and urinary uric acid levels, the patients are subjected to genetic testing for the characterization of HPRT1 gene mutation and HPRT enzyme activity. The pathogenic mutation in the HPRT1 gene and lower HPRT enzyme activity confirms the diagnosis of Lesch-Nyhan Syndrome. HPRT1 gene is constitutively expressed in peripheral blood cells and, biochemically diagnosed by a null HPRT activity in erythrocytes. The presence of HPRT mRNA expression and molecular diagnosis is performed using HPRT complementary DNA (including 3′ and 5′ regions) sequencing and genomic DNA sequencing analysis. In some cases, the normal coding region with a reduced expression requires quantification of mRNA using real-time PCR. Prenatal diagnosis for Lesch–Nyhan syndrome may be performed in amniotic cells obtained by amniocentesis at about 15–18 weeks gestation, or chorionic villus cells obtained at about 10–12 week's gestation. Both HPRT enzymatic assay and molecular analysis for the known disease-causing mutation are performed.