Serum Ferritin Levels Are Lower in Children With Tic Disorders Compared with Children Without Tics: A Cross-Sectional Study

Introduction

Iron plays an important role in brain development and physiology (Beard 2003; Beard and Connor 2003; Youdim 2008). The metal plays an active role in neurotransmitter synthesis and concentrations in the basal ganglia, particularly in the globus pallidus. Iron is also part of dopamine metabolism, dopamine D2 receptor activity (Beard and Connor 2003; Dusek et al. 2012), myelination (Beard 2003), DNA synthesis/repair, and phospholipid metabolism (Crichton et al. 2011). Several brain iron-dependent enzymes (Sachdev 1993) participate in oxygenation and hydroxylation processes.

Alterations in iron stores and iron metabolism have been linked to several movement disorders. For example, iron excess is thought to mediate oxidative injury underpinning the pathogenesis of Parkinson's disease (Youdim 2008). In addition, alterations in iron levels have been associated with dopamine-related movement disorders such as restless leg syndrome and neuroleptic-induced parkinsonism and akathisia (Brown et al. 1987; Pinero and Connor 2000; Dusek et al. 2012).

Iron deficiency has been suggested as a common denominator in the pathophysiology of Tourette's syndrome, attention-deficit/hyperactivity disorder (ADHD), and restless legs syndrome (Cortese et al. 2008). However, information on the role of iron at the early stages of tic disorders is rather scarce and inconsistent. Ferritin is one of the most reliable and widely used markers for body iron store status (Lopez and Cacoub 2016). Serum ferritin levels exhibit less variability than serum iron levels (Dale et al. 2002; Clark 2009), and decline before serum iron when iron stores are depleted (Worwood 1979).

Tics constitute one of the most common neuropsychiatric conditions, frequently associated with ADHD and obsessive-compulsive disorder (Tagwerker Gloor and Walitza 2016). The pathogenesis of tics involves the basal ganglia, especially the dopaminergic system (Hallgren and Sourander 1958; Gorman et al. 2006).

The aim of the current retrospective chart review study was to compare serum ferritin levels of treatment-naive children with a recent-onset tic disorder with age- and sex-matched children, with headaches followed at the same pediatric neurological clinic, in a ratio of 2 (headaches):1 (tic disorder).

Methods

Results

A total of 1230 files of child neurology outpatients evaluated at the clinic were screened, out of which 96 tic disorder diagnosed cases were reviewed. Forty-seven met the inclusion criteria. For the comparison group of children with headaches, 535 met the inclusion criteria. For statistical analysis, headache patients were chosen at a ratio of 2 children with headaches per each child with a tic disorder. Hence, the tic disorder group included 47 children, while the headache group included 100 patients. In the tic disorder group, the mean age for the boys was 8.94 ± 3.2 years and for the girls 8.07 ± 3.30 years. In the headache group, the average age for boys was 9.47 ± 3.18 years and for girls it was 9.24 ± 3.13 years.

Univariate analysis revealed that the tic disorder group (n = 47) did not differ from the headache group (n = 100) in terms of age and sex (Table 1). Serum ferritin levels of the tic disorder group were 32% lower (p = 0.01) compared with their counterparts with headaches. No differences were detected regarding hemoglobin, iron, transferrin levels, and in platelet counts between the two groups (Table 1).

Binary logistic regression model, with tic disorder or headache as dependent variables, was statistically significant [χ ² (3) = 11.631, p = 0.009]. Serum ferritin level made a statistically significant contribution to the model (β = 0.026, p = 0.016) after controlling for age and sex as covariates (odds ratio [OR] = 1.026, confidence interval [95% CI] = 1.005–1.048).

Discussion

Iron is involved in neurotransmitter synthesis affecting content in the brain and the sensitivity of dopamine D2 receptor, neural functions that are relevant to the pathophysiology of movement disorders (Beard and Connor 2003; Dusek et al. 2012). Notably, the motor cortex harbors substantial iron concentrations (Hallgren and Sourander 1958).

Besides the potential role of iron in Parkinson's disease (Youdim 2008), iron probably plays a role in neuroleptic-induced parkinsonism and akathisia (Brown et al. 1987; Pinero and Connor 2000; Dusek et al. 2012). Restless leg syndrome was reported to be associated with low serum and cerebrospinal fluid ferritin levels, particularly in early stages of the disease (Clardy et al. 2006). Progressive extrapyramidal movement disorders, of which pantothenate kinase-associated neurodegeneration (PKAN, Hallevorden-Spatz disease) is the best recognized, are associated with brain iron accumulation (Hogarth 2015). The distribution of nonheme iron in the brain is parallel to that of dopamine, highly concentrating in the structures of the extrapyramidal pathway, especially in the basal ganglia (Hallgren and Sourander 1958). Iron is also specifically required for oligodendrocyte function and myelin formation (Connor and Menzies 1996). Consequently, neural pathways that are involved in motor regulation, such as the corticospinal and corticostriatal tracts, may be vulnerable to effects of iron deficiency. Lower levels of serum ferritin as the primary iron stores indicator may lead to changes in brain iron concentration and function (Dusek et al. 2012) that may play a role in the pathogenesis of tic disorders.

Iron deficiency has been suggested as a pathophysiological factor in ADHD (Cortese et al. 2012), and iron supplementation is associated with elevation in serum ferritin level and a parallel decrease in the severity of the ADHD symptoms as assessed by the parents' Connors Rating Scale scores (Sever et al. 1997) Interestingly, a large epidemiological population study suggested that children suffering from iron deficiency anemia are at increased risk for developing tics (Chen et al. 2013).

Ferritin is the most reliable and widely used marker for assessing body iron store status (Milman 1996). Ferritin levels exhibit less variability than serum iron levels (Dale et al. 2002; Clark 2009) and decline before serum iron when iron stores are depleted (Worwood 1979).

In the present study, we evaluated ferritin serum levels in treatment-naive pediatric patients recently diagnosed with tic disorder or headaches. We found that ferritin levels were 32% lower (p = 0.01) than our comparison group of children with headaches without a movement disorder. While low serum ferritin levels were still within normal range in both study and comparison group (normal reference range: 10–80 ng/mL). Moreover, iron deficiency anemia was not found either in the tic or in the headache group.

Tics originate primarily in the basal ganglia, and a major corticobasal ganglia circuit is involved in their generation (Yael et al. 2015). Very few studies have addressed body iron stores in patients with tics. Two reports demonstrated reduced serum ferritin in pediatric and adult patients with well-established Tourette syndrome (Peterson et al. 1994; Gorman et al. 2006). However, a more recent study reported higher ferritin and hemoglobin levels in children with Tourette syndrome (Landau et al. 2011). Our study pertained to pharmacotherapy-naive children with recent-onset tics rather than with Tourette's syndrome, the latter characterized by tic duration for over 1 year. Hence, our results are innovative with respect to the potential role of lower body- and possibly brain-iron stores in the early stages of tic disorders. Children with a recent-onset tic disorder had significantly lower ferritin levels, although within the normal range. Thus, it seems that iron body stores may be already reduced at the earlier stages of tic disorders.

Our study supports the notion that the status of iron stores may be clinically relevant for tic disorders in children. Low ferritin levels may be a risk factor for the development of tic disorder or a predictor to the severity of tics in the pediatric population. Our study raises the dilemma whether to treat tic disorder in children without overt anemia with iron supplements, in an attempt to reduce the tics at the early stage of the disorder. However, the potential toxic effects of iron on the maturing brain cannot be disregarded (Akar et al. 2015).

Our study has several limitations: the study design is a cross-sectional retrospective study focusing on patients from a single center and a relatively small sample (n = 47). We report on serum levels of ferritin that may not reflect actual brain levels. Furthermore, due to its retrospective nature, our study could not reveal the possible causes of the relative lower ferritin levels (e.g., blood loss, dietary intake). In addition, we did not include a control group of healthy children. Therefore, the possibility of abnormally increased ferritin values in the control (headache) group cannot be entirely excluded based on the analyzed data. The strengths of our study include the fact that all patients were diagnosed and evaluated by senior child neurologists experienced in the field of movement disorders and headaches and that the control group was composed of highly similar patients from the same catchment area, matched age and sex, and diagnosed with a comparable neurological disorder without movement-related symptoms. Our findings suggest an association rather than a causation of the pathophysiological processes underpinning tic disorder, especially at the early stage. Finally, as data on the final diagnosis were not available in many cases, the possibility that the decreased ferritin levels in this heterogenous group may have been driven by a specific subgroup (e.g., Tourette's syndrome) cannot be completely ruled out.

Conclusion

Our findings suggest that serum ferritin levels may be reduced in children with recent onset tic disorder. More research is needed to understand the role of ferritin and iron metabolism in the pathogenesis and development of tic disorder in children. Iron deficiency was reported to be associated with increased risk of neurodevelopmental psychiatric disorders, including tic disorder (Chen et al. 2013) and ADHD (Sever et al. 1997). A prospective study with iron supplement treatment in pediatric patients with tic disorder, with or without iron deficiency anemia, may be warranted.

Clinical Significance

We found that ferritin serum levels, although within the normal range, are significantly lower in treatment-naive children with tic disorders compared with controls. This finding adds to the increasing body of evidence implicating iron metabolism and iron body stores in the pathogenesis of movement disorders.