Clinical, Post-mortem, Biochemical and Therapeutic Observations on the Lesch-Nyhan Syndrome with Particular Reference to the Neurological Manifestations

SUMMARY This paper reports our 10 years experience in the management of patients with the Lesch-Nyhan syndrome. It is based on the detailed study of eight patients, the longest period of follow-up being about eight years. The usual clinical descriptions have emphasized spasticity with pyramidal tract signs, choreoathetosis, compulsive self-injurious behaviour and mental handicap as the outstanding features of the syndrome. We report the development of a cervical cord lesion in two cases and the modification of the clinical phenotype which this complication produces. We have not encountered evidence of a pyramidal tract lesion except in association with this complication. In our experience, a generalized muscle hypotonia which is present from infancy is the basic motor abnormality on which torsion dystonia with its two components of abnormal posturing and episodic rigidity are superimposed. The apparent degree of mental handicap may be affected by the extreme disorder of expressive motor function, which exceeds the comprehension defect, by lack of basic social and educational opportunities and by lack of intelligence tests suitable for older children who have lacked these opportunities. Detailed histopathological and electron microscopic examination of the brain in one case showed no abnormalities. None of the 13 regions of the brain examined showed residual hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8) activity but phosphoribosylpyrophosphate amidotransferase (PRPP-At; EC 2.4.2.14) activity was consistently present and of similar activity to that observed in a non HPRT-deficient control brain. A wide range of other tissues showed a similar enzymological picture. Computerized cranial tomography was normal in the three patients examined. The electroencephalographic findings were also normal in the three patients studied in this way. Neither haloperidol, pimozide, diazepam, nor a combination of 5-hydroxytryptophan with clomipramine and carbidopa influenced significantly the severity of either the torsion dystonia or the compulsive self injurious behaviour. Levodopa with carbidopa ( Sinemet ) increased the torsion dystonia in the one patient to whom it was given. The bearing of these observations on the practical management of the patients and on our understanding of the pathogenesis of the neurological manifestations of HPRT deficiency are discussed.