Cognitive abilities of patients with Lesch-Nyhan disease

Anderson, Lowell T.; Ernst, Monique; Davis, Susan V.

doi:10.1007/bf01058150

Cited by 37 publications

(30 citation statements)

References 9 publications

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“…The neurobehavioral phenotype also includes severe motor disability that resembles dystonic cerebral palsy [18,48]. Most patients also have mild or moderate neurocognitive abnormalities with intellectual disability and IQ scores in the 55–75 range, but severe mental retardation is uncommon [1,24,37,41]. …”

Section: Spectrum Of Clinical Phenotypesmentioning

confidence: 99%

Genotypic and phenotypic spectrum in attenuated variants of Lesch–Nyhan disease

Chen

Jinnah

2014

Molecular Genetics and Metabolism

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Lesch-Nyhan disease and its attenuated variants are caused by deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). All patients exhibit excessive production of uric acid, which increases the risk for nephrolithiasis, renal failure, gouty arthritis and tophi. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe clinical phenotype includes prominent neurological abnormalities and the universal feature is self-injurious behavior. In between the mildest and most severe syndromes is a broad spectrum of phenotypes with varying degrees of neurological, neurocognitive and behavioral abnormalities. The effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management.

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Section: Spectrum Of Clinical Phenotypesmentioning

confidence: 99%

Genotypic and phenotypic spectrum in attenuated variants of Lesch–Nyhan disease

Chen

Jinnah

2014

Molecular Genetics and Metabolism

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“…The motor impairments are dominated by dystonia, but are sometimes accompanied by choreoathetosis or spasticity [4]. Neurocognitive disability also occurs, but usually it is not severe [5–7]. …”

Section: Introductionmentioning

confidence: 99%

Clinical severity in Lesch–Nyhan disease: The role of residual enzyme and compensatory pathways

Sutcliffe

Zhao

et al. 2015

Molecular Genetics and Metabolism

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Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), cause Lesch-Nyhan disease (LND) and more mildly affected Lesch-Nyhan variants. Prior studies have suggested a strong correlation between residual hypoxanthine recycling activity and disease severity. However, the relevance of guanine recycling and compensatory changes in the de novo synthesis of purines have received little attention. In the current studies, fibroblast cultures were established for 21 healthy controls and 36 patients with a broad spectrum of disease severity related to HGprt deficiency. We 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 HGprt-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from the cells. The normal intracellular purines in the HGprt-deficient fibroblasts was 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. These results refine our understanding of the potential sources of phenotypic heterogeneity in LND and its variants.

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“…Most also exhibit recurrent self-injurious behaviour, often with other difficult behaviours such as impulsivity, striking or spitting at others, or use of socially unacceptable language (Nyhan, 1976; Anderson and Ernst, 1994; Schretlen et al , 2005). Finally, most have intellectual disability (Anderson et al , 1992; Matthews et al , 1995; Schretlen et al , 2001). …”

Section: Introductionmentioning

confidence: 99%

Attenuated variants of Lesch-Nyhan disease

Jinnah

Ceballos-Picot

Torres

et al. 2010

Brain

146

116

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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.

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Cognitive abilities of patients with Lesch-Nyhan disease

Cited by 37 publications

References 9 publications

Genotypic and phenotypic spectrum in attenuated variants of Lesch–Nyhan disease

Genotypic and phenotypic spectrum in attenuated variants of Lesch–Nyhan disease

Clinical severity in Lesch–Nyhan disease: The role of residual enzyme and compensatory pathways

Attenuated variants of Lesch-Nyhan disease

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