Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

Abstract

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15-18 weeks' gestation, or chorionic villus cells obtained at about 10-12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments.

Figure 1

Purine metabolism. The metabolic scheme shows the first and rate-limiting step of de novo purine synthesis mediated by the enzyme 5'-phosphoribosyl-1-pyrophosphate (PRPP) amidotransferase, and the salvage pathway mediated by hypoxanthine phosphorybosyltransferase (HPRT) and adenine phosphorybosyltransferase (APRT). The de novo synthesis occurs through a multi-step process and requires the contribution of four aminoacids, one PRPP, two folates and three ATP to synthesize an inosine monophosphate (IMP) molecule. HPRT catalyzes the salvage synthesis of inosine monophosphate (IMP) and guanosine monophosphate (GMP) from the purine bases hypoxanthine and guanine respectively, utilizing PRPP as a co-substrate. The HPRT defect results in the accumulation of its substrates, hypoxanthine and guanine, which are converted into uric acid by means of xanthine oxidase. Elevated APRT activity may also contribute to purine overproduction.

Figure 2

Management of self-injurious behaviour. The cornerstone of day-to-day management of Lesch-Nyhan syndrome is still adapted physical restraint to protect patients from themselves. For instance, elbow restraints allow hand use without the possibility of finger mutilation, and dental guards prevent cheek biting. Patients themselves request restrictions and became anxious if they are unrestrained.