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Treatment of motor and behavioural symptoms in three Lesch-Nyhan patients with intrathecal baclofen


Current therapies for the Lesch-Nyhan Syndrome (OMIM: 300322) are off-label and experimental, often leading to inconsistent outcomes. We here report the effects of an intrathecal baclofen therapy, carried out at the Scientific Institute Eugenio Medea (Lecco, Italy), on three patients who no longer received benefit from previous therapies. This treatment, as expected, ameliorated the motor symptoms and, unexpectedly, it also improved behavioural components. This result may involve a functional interaction between baclofen and dopamine, complemented by an anxiolytic effect. Our observations provide the rationale for the use of intrathecal baclofen administration in the therapy of the Lesch-Nyhan Syndrome.

Letter to the editor


The Lesch-Nyhan Syndrome [1] (LN) (OMIM: 300322) involves dystonia, ballism, and self-injurious and aggressive behaviours. Although LN is severely disabling, no therapeutic standard can yet be indicated and treatment proceeds on the basis of isolated observations. Many therapies for LN, both pharmacological (antispastic drugs, antipsychotics, anti-parkinsonian drugs, dietary supplements) and cellular (enzyme replacement and stem cell therapies), are currently experimented, with inconsistent results [2]. We report on three patients with a genetic diagnosis of classical LN, who were referred to the Scientific Institute Eugenio Medea (Lecco, Italy) for rehabilitation. They were treated with intrathecal baclofen (ITB) and showed an improvement regarding both dystonia and pathological behaviours.

Patients and methods

Patient 1 was 19 years old at referral. During motor development, he never achieved head control, did not crawl or walk; instead, he developed bilateral clubfoot and phasic extensor hypertonia of the upper limbs, with dystonia and ballism. His pathological behaviour involved very severe self-injury and involuntary aggression, by punching and biting. The patient constantly wore whole-body restraints in order to contain these exacerbations. Patient 2 was referred at 39 years of age. He never achieved head control, but crawled and walked until 9, when severe dystonia and ballism of the limbs began. He displayed severe finger biting and required permanent finger protection. Patient 3 was 20 years old at referral. He never achieved head control, crawled scantly and never walked. He developed strong retropulsive reactions, with dystonia involving neck and limbs, and ballism of the arms. By punching, he injured himself and attacked others. Patients were weaned off their previous therapies (Table 1) and subsequently implanted with the intrathecal drug delivery device Synchromed II - 20 ml (Medtronic, Minneapolis, MN, USA). Individual ITB dosages were up titrated to achieve a satisfactory effect on dystonia.

Table 1 Patients’ previous pharmacological therapies


Dystonia was controlled with ITB dosages of 270 to 550 μg per day. ITB improved the quality of sleep for all patients, as expected. This happened in the absence of serious adverse reactions; patient 3 only experienced mild drowsiness. In addition, within three days after reaching the stable ITB dosage, ballism was abolished and aggression and self-injurious behaviours ceased, thus allowing the removal of protective restraints (details in Tables 2 and 3). The beneficial effects of ITB therapy at unchanged dosages persisted throughout the follow up period (5 to 16 months).

Table 2 Patients’ symptoms before and after treatment with intrathecal baclofen
Table 3 Detailed scores from patients’ UDRS scales


Currently, treatment approaches for LN are experimental, as therapeutic targets are not fully elucidated [4],[5]. Dysregulation of dopaminergic pathways may be the cause of self-injurious behaviours in LN patients [6] and anatomical/physiological alterations were recently demonstrated in specific brain regions [7]. Impaired dopamine signalling during cerebral development could lead to the compensatory hypersensitivity of dopamine receptors, especially of the D1 subtype: this prevents the success of either dopaminergic drugs (which increase symptoms [8]) and antipsychotics (which do not target D1 receptors). The dopaminergic and GABAergic systems are connected at multiple levels and GABA has a prominent influence on dopamine release in the mesolimbic and nigrostriatal circuits [9]. Moreover, baclofen may serve as a functional antagonist of dopamine: GABAB receptors are coupled to G proteins that inhibit adenylyl cyclase activity, while D1 dopamine receptors activate it. Baclofen may also have a direct anxiolytic effect [10] that could complement its activity on the dopaminergic balance and be useful for behavioural improvement. The use of baclofen and ITB for LN patients is not uncommon, a population study reported on ten users of oral baclofen and one of ITB, although it did not discuss therapeutic efficacy [2]. Good results of ITB therapy were also previously observed in two patients, although only little information was reported [11]. In order to compare available data, debate should be fostered between clinicians with different experiences on baclofen treatment in LN. Our cases further support the use of ITB in patients with LN within a multi-targeted therapy that may ameliorate both motor and behavioural symptoms. ITB may represent a viable therapy for LN patients, especially in light of the severity of this disease and of the lower comparative risk of severe side effects. Nevertheless, catheters for ITB administration may become infected, leading to removal in spite of partial ITB efficacy [12]. The risks of infection may be avoided by oral administration of baclofen, which is in general safe, apart from rare cases of hepatic toxicity [13]. We conclude that baclofen is potentially useful as a therapy for LN, but that additional studies should be conducted, in order to properly assess its efficacy. Both intrathecal and oral administration routes should be investigated, with systematic measurements and long follow-up periods.



Lesch-Nyhan syndrome


Intrathecal baclofen


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We are thankful to dr. Valeria Padovano for language revision.

Funding sources

This work was supported by Agenzia Italiana del Farmaco (AIFA) and by the Italian Ministry of Health (Ricerca Corrente 2014, to EC). The funding public institutions had no role in any part of the work.

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Correspondence to Emilio Clementi.

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The authors declare that they have no competing interests.

Authors’ contributions

MP: research conception, manuscript preparation. LP: research conception, patient management, manuscript review. MG, FM: patient management, data collection, manuscript review. SR, EC: research conception, manuscript review. All authors read and approved the final version of the manuscript.

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Pozzi, M., Piccinini, L., Gallo, M. et al. Treatment of motor and behavioural symptoms in three Lesch-Nyhan patients with intrathecal baclofen. Orphanet J Rare Dis 9, 208 (2014).

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