Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Abstract

Childhood dystonia that does not respond to treatment with levodopa (dopa-nonresponsive dystonia, DND) has an unclear pathogenesis and is notoriously difficult to treat. To test the hypothesis that there may be abnormalities in serotonin turnover in DND we measured cerebrospinal fluid (CSF) concentrations of homovanillic (HVA) and 5-hydroxyindoleacetic (HIAA) acids, metabolites of dopamine and serotonin, respectively, in 18 children with dystonia not responsive to levodopa. These were combined with a reference population of 85 children with neurologic or metabolic disease known not to affect dopamine or serotonin metabolism. Because of the known natural age-related decrement in HVA and HIAA concentrations, the results were analyzed using multiple regression using age and DND as predictors of CSF HIAA and HVA concentrations. DND was a highly significant predictor of CSF HIAA concentration (p Ͻ 0.001) but not of CSF HVA concentration (p ϭ 0.59). After fitting a regression model, the geometric mean ratio of CSF HIAA in DND compared with the reference range was 0.53 whereas that for CSF HVA was 0.95. We also analyzed CSF HIAA/HVA ratios. After fitting a regression model, we found no dependence on age, and the mean of CSF HIAA/HVA in DND was 0.28 whereas that for the reference range was 0.49 (p Ͻ 0.001). We conclude that a significant number of children with DND have reduced CNS serotonin turnover. Treatment with drugs that increase serotonin concentration in the synaptic cleft should be considered in this group of patients. Childhood dystonias can pragmatically be divided into those that respond to treatment with levodopa and those that do not. Those that do respond to levodopa usually have some parkinsonian features and have been termed parkinsonism-dystonia. Parkinsonism-dystonia syndromes are often caused by deficiency of the neurotransmitter dopamine resulting from inborn errors of the dopamine biosynthesis pathways (1, 2). Dystonia that does not respond to levodopa has a wide variety of causes, and its pathogenesis is poorly understood. Although the study of the acidic metabolites of dopamine and the individual pterin species in human CSF has been fruitful in understanding the mechanisms causing parkinsonism-dystonia in children and young adults (1,(3)(4)(5), it has been disappointing in other movement disorders such as DND. This latter group of patients is also notoriously difficult to treat.Serotonin and dopamine metabolism in the brain are closely linked at both a biochemical and at a physiologic level (6, 7). The basal ganglia of both animals and man have a large serotoninergic projection from the midbrain raphe nuclei (8 -12). However, the function of this in the control of movement is not entirely clear. Impaired CNS serotonin metabolism has been found in adult-onset idiopathic focal dystonias (13). Rats depleted of serotoninergic neurons show no abnormality of baseline movement (14). Yet the genetically dystonic rat has diminished motor responses that involve serotoninergic systems and increased sensitiv...

Cerebrospinal fluid alterations of the serotonin product, 5‐hydroxyindolacetic acid, in neurological disorders

“…Regarding movement disorders, results are also controversial. Reduced 5-HIAA levels were previously reported in idiopathic dystonia and dopa nonresponsive dystonia (Naumann et al 1996;Assmann et al 2002). In our study, patients with extrapyramidal disorder did not seem to be frequently affected by 5-HIAA deficiency.…”

“…Alterations of 5-HIAA have been reported in progressive myoclonic epilepsies, infantile spasms, and burst suppression pattern-associated disorders ). However, these results have been controversial (Langlais et al 1991;Airaksinen et al 1992) and an association between biogenic amines and antiepileptic drugs has not been excluded in previous studies (García-Cazorla et al 2007;Assmann et al 2002).…”

“…By contrast, and although serotoninergic innervation in the brain is more evenly distributed, its implication in different neurological disorders other than psychiatric diseases has scarcely been described. Previous studies showed secondary low 5-HIAA levels in infants with diverse neurological disorders and cortical brain atrophy (García-Cazorla et al 2007), idiopathic adult-onset dystonia (Naumann et al 1996), malignant epilepsies (Langlais et al 1991), and dopa nonresponsive dystonia (Assmann et al 2002). However, to date and to our knowledge, a large study determining the frequency and reviewing the possible causes of serotoninergic alterations in patients with diverse neurological problems has not been reported.…”

Secondary abnormalities of neurotransmitters in infants with neurological disorders

“…Some studies report reduced 5-HIAA levels in idiopathic adult-onset dystonia 19 and in children with dopa-nonresponsive dystonia. 20 However, most of the patients of the last report presented with neurodegenerative disorders that did not manifest during the first year of life.…”

Low CSF 5‐HIAA in Myoclonus Dystonia

“…Isolated cerebral serotonin deficiency is increasingly recognized as a distinct clinical disorder (Fig. ) . A recent study showed ∼20% of childhood‐onset movement disorders to be associated with reduced CSF 5‐HIAA levels, 49% of these demonstrating an isolated CSF 5‐HIAA reduction .…”