Objective: To determine whether levodopa treatment starting at a very young age can prevent the development of the full clinical phenotype in Lesch-Nyhan disease.

Background: Lesch-Nyhan disease (LND) is caused by pathogenic variants of the HPRT1 gene, encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). Absence of HGprt is associated with dopamine deficiency that is thought to contribute to the typical LND neurobehavioral phenotype dominated by dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have not been successful. Levodopa worsened motor function in a prospective open label dose-escalation study [1]. Based on the hypothesis that very early levodopa treatment may prevent the development of the full phenotype, we attempted to restore dopamine levels in 3 infants with LND.

Method: We treated 3 infants with LND off-label with levodopa/carbidopa (ratio 4:1), starting at 11—13 months of age, aiming at escalating up to at least 5-6 mg/kg levodopa per day in divided doses. During regular outpatient visits, the severity of the dystonia was estimated and history was taken whether self-injury had occurred. In addition, we reviewed the literature to delineate the age at onset of self-injury for all reported cases to date.

Results: An obvious effect of levodopa on the dystonia could not be determined. However, during follow-up, up to 13 and 14 years of age respectively, two patients never started self-injury, while their HPRT1 pathogenic variants have been invariably associated with self-injury in prior reports (available at www.lesch-nyhan.org). In the literature, self-injury has been reported for 264 LND cases, starting between 6 months and 20 years of age, with a median of 2.0 years. Less than 2% of these cases had self-injury onset later in life than the current age of these patients. A third patient started self-injury at 1.5 years of age, despite the levodopa treatment. Of note, he was on a lower dose of levodopa after a deterioration of motor function, simultaneously with a viral infection.

Conclusion: Our observations suggest that levodopa might be able to prevent self-injury in LND, only if given early enough and sufficiently dosed. It remains unclear whether early levodopa can improve motor function. We propose to consider levodopa in LND patients as early as possible, at least before the self-injury appears.

References: [1] Visser, J. E., D. J. Schretlen, B. R. Bloem and H. A. Jinnah (2011). Levodopa is not a useful treatment for Lesch-Nyhan disease. Mov Disord 26(4): 746-749.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/can-very-early-levodopa-prevent-self-injury-in-lesch-nyhan-disease/