Attenuated variants of Lesch-Nyhan disease

Abstract

Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.

Figure 1

Schematic representation of the spectrum of clinical features in LND and its variants. Patients are divided into subgroups with the most severe being LND, the intermediate form being HPRT-related neurological dysfunction (HND), and the least severely affected being HPRT-related hyperuricaemia (HRH). The frequency or severity of each problem is depicted by the thickness of the tapering bar, with description of the spectrum of the problem across the groups.

Figure 2

Histogram showing age at onset of self-injury in previously reported cases of classic LND. Among 349 classic LND cases described in 133 previous reports, the age at onset of self-injury was available for 212 cases. Cases were binned in yearly increments, with a mean age of 3.1 ± 2.5 and a median age of 2 years.

Figure 3

Correlations between dystonia and cognition. Dystonia was rated with the BFM dystonia rating scale, with mild motor deficits scored as mild expressions of dystonia. Scores for patients with LND come from our previous study (Jinnah et al., 2006) while those for variants come from Tables 1 and 2. Cognition was assessed with IQ, which was taken from the results of clinical diagnostic testing or previous publications. Patient subgroups are LND (circles), HPRT-related neurological dysfunction (squares), and HPRT-related hyperuricaemia (triangles). Patients with LND and HPRT-related neurological dysfunction were distinguished by the presence of self-injurious behaviour. The HPRT-related hyperuricaemia group was defined as clinically insignificant motor dysfunction with a BFM score of 5 or less. There was a significant negative correlation between BFM and IQ scores (Spearman rho = −0.64, P < 0.001). This correlation remained after controlling for age (Spearman rho = −0.63, P < 0.001). There was no significant correlation between BFM and age (Spearman rho = 0.20, P = 0.21).

Figure 4

Severity of dystonia according to patient subgroup. Dystonia was rated with the BFM dystonia rating scale, with mild motor deficits scored as mild expressions of dystonia. Patient subgroups are LND, HPRT-related neurological dysfunction (HND), and HPRT-related hyperuricaemia (HRH). Patients with LND and HPRT-related neurological dysfunction were distinguished by the presence of self-injurious behaviour. The HPRT-related hyperuricaemia group was defined as clinically insignificant motor dysfunction with a BFM score of 5 or less. Scores for patients with LND come from our previous study (Jinnah et al., 2006) while those for variants come from Tables 1 and 2. Individual scores are overlaid with a box-whisker plot, where the middle horizontal line in each box shows the median. The upper and lower limits of the box define the upper and lower quartiles. Whiskers span the entire data range excepting outliers, defined as values that fell outside the upper or lower quartile plus 1.5 times the inter-quartile distance. The groups were compared statistically using the Kruskal–Wallis H-statistic, which revealed overall significance at P < 0.0001. Post hoc Wilcoxin signed ranked tests revealed significant differences (P < 0.001) between each of the groups.

Figure 5

IQ scores according to patient subgroup. The IQ was not methodically assessed with a standardized instrument due to differences in age and language, but instead was taken from the results of clinical diagnostic testing or previous publications. Patient subgroups include LND, HPRT-related neurological dysfunction (HND), and HPRT-related hyperuricaemia (HRH). Patients with LND and HPRT-related neurological dysfunction were distinguished by the presence of self-injurious behaviour. The HPRT-related hyperuricaemia group was defined as clinically insignificant motor dysfunction with a BFM score of 5 or less. Scores for patients with LND come from our previous study (Jinnah et al., 2006) while those for variants come from Tables 1 and 2. Individual scores are overlaid with a box-whisker plot, where the middle horizontal line in each box shows the median. The upper and lower limits of the box define the upper and lower quartiles. Whiskers span the entire data range excepting outliers, defined as values that fell outside the upper or lower quartile plus 1.5 times the inter-quartile distance. The groups were compared statistically using the Kruskal–Wallis H-statistic, which revealed overall significance at P < 0.0001. Post hoc Wilcoxin signed ranked tests revealed significant differences (P < 0.001) between the LND and each of the other two groups. The difference between HPRT-related neurological dysfunction and HPRT-related hyperuricaemia groups was not significant (P = 0.56).

Figure 6

Motor features in classic versus variant LND. The percent of patients in the current series of LND variants (LNV; n = 46, black bars) is compared with the percent of patients with classic LND (n = 44, grey bars) from our prior studies (Jinnah et al., 2006). Panel A depicts extrapyramidal features while Panel B depicts pyramidal features.