Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 10406007, 124275001; ICD10CM: E79.1; ORPHA: 510; DO: 1919;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq26.2-q26.3 | Lesch-Nyhan syndrome | 300322 | X-linked recessive | 3 | HPRT1 | 308000 |
A number sign (#) is used with this entry because Lesch-Nyhan syndrome (LNS) is caused by mutation in the HPRT gene (308000), which encodes hypoxanthine guanine phosphoribosyltransferase, on chromosome Xq26.
The features of Lesch-Nyhan syndrome (LNS) are intellectual disability, spastic cerebral palsy, choreoathetosis, uric acid urinary stones, and self-destructive biting of fingers and lips. Megaloblastic anemia has been found in some patients (summary by van der Zee et al., 1968, Madeo et al., 2019).
Virtually complete deficiency of HPRT residual activity (less than 1.5%) is associated with the Lesch-Nyhan syndrome, whereas partial deficiency (at least 8%) is associated with HPRT-related hyperuricemia (HRH; 300323), also known as Kelley-Seegmiller syndrome. LNS is characterized by abnormal metabolic and neurologic manifestations. In contrast, Kelley-Seegmiller syndrome is usually associated only with the clinical manifestations of excessive purine production. Renal stones, uric acid nephropathy, and renal obstruction are often the presenting symptoms of Kelley-Seegmiller syndrome, but rarely of LNS. After puberty, the hyperuricemia in Kelley-Seegmiller syndrome may cause gout. A third group of patients, with 1.5 to 8% of HPRT activity, is associated with a neurologic variant of LNS, with uric acid overproduction and neurologic disability that varies from minor clumsiness to debilitating extrapyramidal and pyramidal motor dysfunction (Jinnah and Friedmann, 2001).
Bakay et al. (1979) restudied a patient with HPRT deficiency, choreoathetosis, spasticity, dysarthria, and hyperuricemia, but normal intelligence and no self-mutilation. (A maternal uncle had been identically affected.) Although HPRT deficiency seemed to be complete, cultured fibroblasts had some capacity for metabolism of hypoxanthine and guanine. Page et al. (1987) described 2 brothers and 2 of their maternal uncles who had HPRT deficiency as the cause of mild mental retardation, spastic gait, and pyramidal tract sign. They were, furthermore, short of stature with proximally placed thumbs and fifth finger clinodactyly. Activity of the enzyme was virtually zero in lysates of red cells or hair roots, but in intact fibroblasts the level of activity was 7.5% of normal. Kinetic studies also demonstrated differences. A sister of the brothers was, by enzyme assay, heterozygous. One of the affected uncles had advanced tophaceous gout by age 32 years.
Clinical Variability
Hladnik et al. (2008) reported a family in which 5 individuals carrying the same splice site mutation in the HPRT gene showed marked phenotypic variability resulting from HPRT deficiency. One patient had classic Lesch-Nyhan syndrome with delayed development, spasticity, dystonia, and self-injurious behavior. Two patients had an intermediate phenotype with mild cognitive and learning difficulties, dystonia, and increased uric acid, but no self-injurious behavior, and 2 had mild spasticity, gout, and normal IQ. Hladnik et al. (2008) postulated that each individual had various expression of the mutant and wildtype transcript, and emphasized that individuals with the same genotype may not necessarily have the identical phenotype.
Sarafoglou et al. (2010) reported a 3-generation family in which 3 individuals carrying the same missense mutation in the HPRT1 gene showed phenotypic variability. The proband presented at age 14.5 months with increased uric acid levels and later showed mildly delayed development. His cousin was diagnosed at age 26 months, and had mild generalized hypotonia, delayed motor development, focal dystonia of the lower limbs, and mild developmental impairment with speech delay. The boys' 65-year-old grandfather was more severely affected, with borderline cognitive function, severe dyslexia, spasticity, and flexion contractures leading to motor impairment. He had a long history of gout, nephrolithiasis, and progressive renal dysfunction. Medical history revealed that his symptoms had been attributed to cerebral palsy due to perinatal asphyxia. Enzymatic studies of cultured fibroblasts showed decreased activity in the proband, more severely decreased activity in the cousin, and the most severely decreased activity in the grandfather, consistent with their phenotypes. Cells from the grandfather grew more slowly than those from the grandchildren and appeared less robust.
Madeo et al. (2019) described clinical features in 101 French and Italian patients with HPRT mutations, including 66 with LNS, 22 with the LNS neurologic variant (which the authors called HPRT-related neurologic dysfunction; HND), and 13 with HRH. The clinical manifestations at disease onset were nonspecific, but orange discoloration in the diaper was reported in 22% of patients. Neurologic involvement was overall more severe in LNS than in HND. The median age of presentation of involuntary movements and self-injurious behavior in LNS was 1.0 and 3 years, respectively. At least one epileptic episode was reported in approximately 13% of patients with LNS and HND. Of the approximately 40% of LNS patients and 30% of HND patients who had an MRI, a quarter of the LNS patients had variable abnormalities, the most frequent being mild to moderate brain atrophy, and all HND patients had normal findings. Language delay was common in LNS and HND, but the majority of HND patients could speak in complex sentences whereas the majority of LNS patients could speak in simple sentences or speak single words. Language comprehension was generally preserved. Approximately 60% of patients with HND had cognitive impairment. Renal disease, seen in approximately 66% of patients, occurred with a median onset age of 1.1 years. Six patients (2 with LNS, 2 with HND and 2 with HRH) developed chronic renal failure. In 3 cases, renal failure was a consequence of chronic lithiasis, and in 2 patients renal failure was secondary to focal segmental glomerulosclerosis and nephrotic syndrome. Two patients underwent kidney transplantation. Gout, seen in approximately 26% of patients, occurred with a median age of onset of 18 years and was more frequent in HND and HRH than in LNS.
A 200-fold increase in the conversion of C(14)-labeled glycine to uric acid was observed by Nyhan et al. (1965). Seegmiller et al. (1967) demonstrated deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). That the enzyme deficiency resulted in excessive purine synthesis suggested that the enzyme (or the product of its function) normally plays a controlling role in purine metabolism. Resistance to 8-azaguanine in cultured diploid human fibroblasts was induced by x-ray in pioneer experiments (Albertini and DeMars, 1973). Mutation in the HPRT gene is the basis for this resistance. Lesch-Nyhan cells are resistant to 8-azaguanine. Upchurch et al. (1975) found a normal amount of cross-reacting material in 1 of 12 patients with HPRT deficiency. The others had less than 3% of the normal amount. Ghangas and Milman (1975) confirmed this by another method. Wilson et al. (1986) analyzed cell lines of 24 patients with HPRT deficiency at the levels of residual protein, mRNA, and DNA. At least 16 patients had unique mutations of the HPRT gene. Most cell lines had normal quantities of mRNA but undetectable quantities of enzyme. Eight of the patients retained significant quantities of structurally altered but functionally abnormal HPRT enzyme variants. A minority of patients lacked both enzyme and mRNA.
Fu et al. (2015) created fibroblast cultures for 21 healthy controls and 36 patients with a broad spectrum of disease severity, including Lesch-Nyhan syndrome, related to HPRT deficiency. The authors assessed hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis. There was a strong correlation between disease severity and either hypoxanthine or guanine recycling. Intracellular purines were normal in the HPRT-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from cells. The normal intracellular purines in the HPRT-deficient fibroblasts were likely due in part to a compensatory increase in purine synthesis, as demonstrated by a significant increase in purinosomes. However, the increase in purine synthesis did not appear to correlate with disease severity.
There is variable disease severity in patients with Lesch-Nyhan syndrome, with an inverse relationship between HPRT1 enzyme activity measured in intact cells and clinical severity. Patients with classic Lesch-Nyhan disease, the most severe and frequent form, have the lowest HPRT enzyme activity (less than 1.5% of normal) in intact cultured fibroblasts. Patients with partial HPRT deficiency, designated as Lesch-Nyhan variants, have HPRT1 enzyme activity ranging from 1.5 to 8.0%. Individuals with an intermediate variant form known as the 'neurologic variant' are neurologically indistinguishable from patients with Lesch-Nyhan disease, but they do not have self-injurious behaviors and intelligence is normal or near-normal. The least-affected patients with the variant form have residual HPRT1 enzyme activity exceeding 8%; their only manifestations are attributed to hyperuricemia, and include gout, hematuria, and nephrolithiasis (summary by Sarafoglou et al., 2010).
Madeo et al. (2019) reported the results of treatment in 67 French and Italian patients with LNS (51 patients) or the LNS neurologic variant (16 patients). Although none of the drugs used for neurologic involvement and behavioral abnormalities were fully effective, some therapies were associated with limited clinical improvement. Botulinum toxin and baclofen were partially beneficial for the control of dystonia. Gabapentin was partially efficacious for dystonia and self-injurious behavior in the 13 patients who received it. Among the 12 patients with LNS who were treated with levodopa, one half reported a partial benefit for dystonia and behavior. The average age of patients who improved with levodopa was 3.2 years, whereas the average age of the patients who did not improve was 9.0 years, suggesting improved efficacy with earlier administration. Tetrabenazine was associated with improvement of dystonia in most of the 6 patients to whom it was administered. Madeo et al. (2019) also described results of treatment for renal and joint symptoms in these patients as well as in 9 patients with HRH. Fifty-four patients had improvement with allopurinol treatment, but allopurinol was interrupted in 9.3% of cases due to lack of efficacy or appearance of xanthine stones. Febuxostat was the most frequent alternative therapy. Half of patients received urinary alkalinizing agents. Three patients with persistent uric acid lithiasis and 1 patient with severe gout who were not responsive to standard treatment responded to treatment with recombinant urate oxidase.
X-linkage was first suggested by Hoefnagel et al. (1965) and was supported by a rapidly accumulated series of families with deficiency of HPRT. Rosenbloom et al. (1967) and Migeon et al. (1968) demonstrated 2 populations of fibroblasts, as regards the relevant enzyme activity, in heterozygous females, thus providing support both for X-linkage and for the Lyon hypothesis. Studies using human-mouse somatic cell hybrids indicate, by reasoning similar to that used for locating the thymidine kinase locus to chromosome 17 (188300), that the HPRT locus is on the X chromosome (Nabholz et al., 1969). Mosaicism can be demonstrated by study of hair roots in women heterozygous for the Lesch-Nyhan syndrome (Silvers et al., 1972). Francke et al. (1976) studied the frequency of new mutations among affected males. The Lesch-Nyhan syndrome is particularly favorable for this purpose because no affected males reproduce, the diagnosis is unequivocal and cases come readily to attention, and particularly because heterozygosity can be demonstrated in females by the existence of 2 populations of cultured fibroblasts. There were few new mutations, contrary to the expected one-third. On the other hand, about one-half of heterozygous females were new mutations, as is predicted by theory. The finding may indicate a higher frequency of mutation in males than in females. Another possibility is the role of somatic and half-chromatid mutations (Gartler and Francke, 1975). New mutation cases of heterozygous females had elevated parental age. Vogel (1977) reviewed the evidence concerning hemophilia and the Lesch-Nyhan syndrome leading to the conclusion that the mutation rate is higher in males than in females. Evidence that the mutation rate for the Lesch-Nyhan disease may be higher in males than in females was reviewed by Francke et al. (1976) and criticized by Morton and Lalouel (1977). Francke et al. (1977) answered the criticism. Strauss et al. (1980) showed that females heterozygous for the Lesch-Nyhan mutation have 2 populations of peripheral blood lymphocytes with regard to sensitivity to 6-thioguanine inhibition of tritiated thymidine incorporation following phytohemagglutinin stimulation. Henderson et al. (1969) concluded that the locus for HPRT is closely linked to the Xg (314700) locus; Greene et al. (1970) concluded, however, that the HPRT and Xg loci 'are sufficient distance from each other on the human X chromosome that linkage cannot be detected.' Nyhan et al. (1970) observed a sibship in which both HPRT deficiency and G6PD deficiency (300908) were segregating and found 2 of 4 recombinants. Nyhan et al. (1970) also found that heterozygotes had normal levels of HPRT in red cells. They interpreted this as indicating a selective advantage of G6PD-normal over G6PD-deficient cells. (In adrenoleukodystrophy (300100), it is the mutant cell that enjoys the selective advantage.)
Yukawa et al. (1992) described a seemingly typical case of Lesch-Nyhan syndrome in a female with a normal karyotype. The parents were nonconsanguineous. In addition to unusual lyonization, uniparental disomy is a possible explanation.
Pathogenesis of Mental Retardation and Self-injurious Behavior
Wong et al. (1996) discussed 3 lines of evidence that had suggested that HPRT deficiency is associated with abnormal dopamine (DA) function in LNS: (1) an autopsy study of 3 LNS subjects demonstrated a marked reduction in the DA content and in the activity of DNA-synthesizing enzymes in the caudate and putamen (Lloyd et al., 1981); (2) when neonatal rats are depleted of DA with the neurotoxin 6-hydroxydopamine, self-injurious behavior, similar to that seen in LNS, occurred when the rats were challenged with 3,4-dihydroxyphenylalanine (L-DOPA) as adults (Breese et al., 1990); and (3) in an HPRT-deficient mutant mouse strain, there is a reduction of striatal tyrosine hydroxylase and in the number of striatal dopamine transporters (Jinnah et al., 1994). To establish that DA deficiency is present in LNS, Wong et al. (1996) used a ligand that binds to DA transporters to estimate the density of DA-containing neurons in the caudate and putamen of 6 subjects with classic LNS. They made comparisons with 10 control subjects and 3 patients with Rett syndrome (312750). Depending on the method of analysis, a 50 to 63% reduction of the binding to DA transporters in the caudate and a 64 to 75% reduction in the putamen of LNS patients was observed compared to the normal control group; similar reductions were found between Rett syndrome and LNS patients. Volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LNS patients. To ensure that a reduction in the caudate volume would not confound the results, Wong et al. (1996) performed a rigorous partial volume correction of the caudate time activity curve. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LNS patients when contrasted to controls.
Ernst et al. (1996) concluded that patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggested that they contribute to the characteristic neuropsychiatric manifestations of the disease. These studies were done with positron-emission tomography (PET) with the tracer fluorodopa-F18. This tracer, an analog of dopa, is a large, neutral amino acid that is transported into presynaptic neurons, where it is converted by the enzyme dopa decarboxylase (107930) into fluorodopamine F18, which subsequently enters catecholamine-storage vesicles. Hence, data obtained with the use of fluorodopa-F18 and PET reflect dopa decarboxylase activity and dopamine-storage processes. In an accompanying editorial, Nyhan and Wong (1996) commented on the new findings and reviewed the normal function of HPRT with a diagram.
Ceballos-Picot et al. (2009) demonstrated that HPRT deficiency influences early developmental processes controlling the dopaminergic phenotype. Microarray methods and quantitative PCR were applied to 10 different HPRT-deficient sublines derived from the hybrid MN9D cell line, derived from somatic fusion of embryonic mouse primary midbrain dopaminergic neurons with a mouse neuroblastoma line. There were consistent increases in mRNAs for engrailed-1 (EN1; 131290) and -2 (EN2; 131310), transcription factors known to play a role in the specification and survival of dopamine neurons. The increases in mRNAs were accompanied by increases in engrailed proteins, and restoration of HPRT reverted engrailed expression towards normal levels. The functional relevance of the abnormal developmental molecular signature of the HPRT-deficient MN9D cells was evident in impoverished neurite outgrowth when the cells were forced to differentiate chemically. These abnormalities were also seen in HPRT-deficient sublines from the SK-N-BE(2)-M17 human neuroblastoma line, and overexpression of engrailed was documented in primary fibroblasts from patients with Lesch-Nyhan disease. Ceballos-Picot et al. (2009) concluded that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms.
Cristini et al. (2010) examined the effect of HPRT deficiency on the differentiation of neurons in human neural stem cells (NSCs) isolated from human Lesch-Nyhan disease fetal brain. LNS NSCs demonstrated aberrant expression of several transcription factors and DA markers, and HPRT-deficient dopaminergic neurons demonstrated a striking deficit in neurite outgrowth. Exposure of the LNS NSCs to retinoic acid medium elicited the generation of dopaminergic neurons. The authors concluded that neurogenesis is aberrant in LNS NSCs and suggested a role for HPRT in neurodevelopment.
Prenatal Diagnosis
Fujimoto et al. (1968) presented evidence that the disease can be recognized in the fetus well before 20 weeks, i.e., within the limit for elective abortion. The method used was an autoradiographic test for HPRT activity, applied to cells obtained by amniocentesis. Boyle et al. (1970) made the prenatal diagnosis and performed therapeutic abortion. Gibbs et al. (1984) showed that by ultramicroassay of HPRT it is possible to diagnose the Lesch-Nyhan syndrome on the basis of chorionic villi sampled at 8-9 weeks of gestation.
Graham et al. (1996) investigated 15 pregnancies at risk for Lesch-Nyhan syndrome between 8 and 17 weeks' gestation by measurement of HPRT and APRT (102600) enzyme activities in chorionic villus samples (cultured and uncultured) or in cultured amniotic fluid cells. Ten pregnancies had normal enzyme levels and a normal outcome, while a further 2 predicted to be normal miscarried later in the pregnancy. Three pregnancies had low levels of residual HPRT activity in chorionic villi. Comparable levels of residual activity in the index case in 2 pregnancies and in cells from the abortus in the third case confirmed that the pregnancies were indeed affected.
For a discussion of the molecular defects involved in Lesch-Nyhan syndrome, see the HPRT1 gene (308000).
Madeo et al. (2019) described the association between HPRT mutations and clinical findings in 76 French and Italian patients, including 52 with LNS from 47 families, 19 with the LNS neurologic variant from 12 families, and 12 with HPRT-related hyperuricemia (HRH) from 6 families. They found that overall, patients with missense mutations had significantly later onset of disease and less frequent neurologic manifestations or self-injurious behavior compared to patients with other mutation types including nonsense, deletion, splicing, or complex gene rearrangements. Mutation type was not associated with the development of gout or nephropathy. Intrafamilial phenotypic variability was seen in a few families.
Lesch and Nyhan (1964) described the disorder that bears their names on the basis of 2 brothers. Nyhan (1997) gave an account of the recognition of the syndrome as an inborn error of purine metabolism.
Preston (2007) provided a popular description of the discovery of the disorder and what the study of a rare disorder such as this can tell us about human behavior.
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