PEDBASE.org - The Pediatric Database - Detailed information of LESCH-NYHAN SYNDROME

LESCH-NYHAN SYNDROME

DEFINTION:

An inborn error of purine metabolism characterized by an enzyme deficiency resulting in neurological, renal, and rheumatological manifestations.

incidence: 1/100,000
age of onset:
- 3-6 months of age (developmental delay)
risk factors:
- familial - x-linked recessive
  - chrom.#: Xq26
  - gene: hypoxanthine phosphoribosyltransferase (HPRT)
- M >> W; some female heterozygotes

HPRT catalyzes the metabolic salvage of the purine bases hypoxanthine and guanine into nucleotides, inosinic acid, and guanylic acid
HPRT deficiency was first described as the genetic defect in Lesch-Nyhan Syndrome in 1967 by Seegmiller et al
the HPRT gene has been cloned and is divided into 9 exons - there are 4 autosomal pseudogenes present in the genome

genetic defect -> deficiency of HPRT activity -> accumulation of phosphoribosylpyrophosphate -> accelerated purine production de novo -> excessive uric acid production -> renal and musculoskeletal manifestation
disruption of this salvage pathway in the CNS may result in cells in the brain unable to synthesize required nucleotides
complete deficiency of HPRT activity is associated with Lesch-Nyhan Syndrome while a partial deficiency results in nephrolithiasis, gouty arthritis, & some neurological manifestations
genetic heterogeneity exists with points mutations and small deletions making up the majority of mutations within the HPRT gene

1. Compulsive Self-Injurious Behaviour (85%)

mean age of onset 3.5 years (range 1-16 years)
begin by biting lips and/or buccal mucosa
progresses to biting of fingers and hands and head banging
variable course with periods of remission and may be exacerbated by aggrevating environmental events
less pronounced once patient is older than 10-12 years

initially fine athetoid movements of the hands and feet
become choreiform or
initially hypotonia -> hyperkinetic movements (ataxia, chorea, dystonia) -> hypertonia with spasticity, hyper-reflexia, and ankle clonus

acute gouty arthritis
tophi formation
- due to the accumulation of sodium urate crystals in subcutaneous and other tissues
- over the extensor surfaces of the elbows, knees, fingers, and toes

10 mg/kg/day to a max. of 800 mg/day
inhibits xanthine oxidase activity thus decreasing uric acid levels preventing the renal and musculoskeletal manifestations but does not prevent or alleviate the cerebral manifestations

life expectancy
- to 4th decade with good control
- under 5 years of age without allopurinol therapy

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