Abstract
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by motor and vocal tics with an estimated prevalence of 1% in children and adolescents. GTS has high rates of inheritance with many rare mutations identified. Apart from the role of the neurexin trans-synaptic connexus (NTSC) little has been confirmed regarding the molecular basis of GTS. The NTSC pathway regulates neuronal circuitry development, synaptic connectivity and neurotransmission. In this study we integrate GTS mutations into mitochondrial pathways that also regulate neuronal circuitry development, synaptic connectivity and neurotransmission. Many deleterious mutations in GTS occur in genes with complementary and consecutive roles in mitochondrial dynamics, structure and function (MDSF) pathways. These genes include those involved in mitochondrial transport (NDE1, DISC1, OPA1), mitochondrial fusion (OPA1), fission (ADCY2, DGKB, AMPK/PKA, RCAN1, PKC), mitochondrial metabolic and bio-energetic optimization (IMMP2L, MPV17, MRPL3, MRPL44). This study is the first to develop and describe an integrated mitochondrial pathway in the pathogenesis of GTS. The evidence from this study and our earlier modeling of GTS molecular pathways provides compounding support for a GTS deficit in mitochondrial supply affecting neurotransmission.
Highlights
Gilles de la Tourette Syndrome (GTS) is a neurodevelopmental disorder with an estimated prevalence of 1% in children and adolescents [1]
The mitochondrial pathways involved in Gilles de la Tourette syndrome (GTS) overlap and interact making it possible to trace these pathways to common endpoints in mitochondrial dynamics and supply
While it is unlikely that all of the genes cited in this study are causative in GTS, or that they all act alone in GTS etiology, we present convincing weight of evidence that mitochondria are implicated in GTS
Summary
Gilles de la Tourette Syndrome (GTS) is a neurodevelopmental disorder with an estimated prevalence of 1% in children and adolescents [1]. Neuroanatomical evidence suggests that GTS pathology is related to abnormal brain development and the physiological involvement of the cortico–striato–thalamo– cortical (CSTC) circuitry connecting the cortex, basal ganglia and thalamus [1]. Clinical evidence further suggests the involvement of neurotransmitters such as dopamine, glutamate and γ-aminobutyric acid (GABA) [1]. Epidemiological, phenomenological and genetic evidence demonstrate broad overlap between GTS and autism spectrum disorder (ASD) [2, 3] with both exhibiting high incidence in first-degree relatives, high monozygotic to dizygotic concordance [4], and with both conditions beginning during childhood with a high male preponderance. GTS and ASD share associated clinical features of compulsive behaviors, obsessions, involuntary movements (tics in GTS and stereotypies in ASD), poor speech control and echolalia common in both conditions [5].
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