Tourette‐Like Syndrome in a Patient with RBFOX1 Deletion

Imbalances in γ‐aminobutyric acid (GABA) and glutamate activity have been implicated in the pathogenesis of Tourette syndrome (TS).1, 2, 3 The RNA binding protein, Fox‐1 homolog 1 gene (RBFOX1) codes for the FOX1 protein, which regulates alternative splicing of many genes (including GABA‐A receptor subunit γ2 [GABRG2] and glutamate ionotropic receptor N‐methyl‐d‐aspartate [NMDA] type subunit 1 [GRIN1]) and hence is involved in the regulation of GABA and glutamate activity.4 The RBFOX1 gene, also known as ataxin‐2 binding protein‐1 (A2BP1), encompasses a large genomic region of 1.7 Mb on chromosome 16p.5 Here, we report a case of Tourette‐like syndrome with an RBFOX1 gene deletion, providing further evidence in favor of GABA and glutamate dysregulation in TS.

Case Report

A 24‐year‐old woman presented with a history of involuntary, stereotypical neck movements of 9 years’ duration. In her teenage years, she used to make simple vocal sounds, like grunting and gagging noises. She had a history of delayed motor and language milestones. Her brother was diagnosed with generalized anxiety disorder (GAD) and had simple vocal tics in primary school. Examination revealed dysmorphic toes and bilateral fifth finger clinodactyly. Her Mini‐Mental State Examination score was 29 of 30. She had involuntary, stereotypical, mild to moderate‐amplitude, sideways‐tilting, and retroflexion movements of neck, which were transiently suppressible. The remainder of the general physical and neurologic examination was normal.

Magnetic resonance imaging of brain revealed mild, generalized cerebral atrophy. Due to the presence of dysmorphic features, microarray comparative genomic hybridization was performed. The results showed heterozygous 16p13.3 microdeletion of 277 540 base pairs, corresponding to the RBFOX1 gene location (Fig. 1). This deletion was maternally inherited, but the mother did not have tics. Her brother was not tested for the deletion due to lack of consent. Our final diagnosis was 16p13.3 microdeletion syndrome with mild dysmorphic features presenting with Tourette‐like syndrome. Multiple trials of oral medications produced either no benefit or significant side effects. Because she was bothered most by her neck movements, injection of the neck muscles with botulinum toxin were performed with remarkable success.

Figure 1.

RNA binding protein, Fox‐1 homolog 1 gene (RBFOX1) location and structure. The red box on chromosome 16 (Chr16) shows the location of the RBFOX1 gene. The short vertical lines are exons of the RBFOX1 gene, and blue band indicates the deletion, which includes Exon 2 and portion of Introns 1 and 2. UCSC, University of California Santa Cruz; CCDS, Consensus Coding Sequence Project; hg19, Human Genome database 19. Source: http://genome.ucsc.edu. 11

Discussion

The RBFOX1 gene codes for the FOX1 protein and regulates alternative splicing of many genes.6 Fox1 protein has been implicated in regulation of the Gabrg2 and Grin1 genes and hence is involved in regulating GABAergic and glutaminergic systems.4 Transcripts encoding Gabrg2 and Grin1 are modified in Rbfox1−/− mouse brain.4 Deletion of the Rbfox1 gene can result in heightened susceptibility to spontaneous and kainic acid‐induced seizures.4 Mutations in the RBFOX1 gene can cause mental retardation, autism, attention‐deficit hyperactivity disorder, and developmental hemiparesis.5, 7, 8 There is also evidence of RBFOX1 gene involvement in the development of GAD. Patients with GAD have abnormal GABAergic activity, resulting from the down‐regulation of GABA‐A.6 However, to date, tourettism has not been reported.

GABA and glutamate dysfunction plays an integral part in the pathogenesis of TS.1, 2, 3, 9 Short‐interval intracortical inhibition, a phenomenon that depends on GABA‐A receptors, is reduced in individuals with TS.9 Decreased binding of GABA‐A receptors has been reported among patients with TS in the ventral striatum, globus pallidus, thalamus, amygdala, and right insula on functional neuroimaging.1 GRIN2B has been implicated in the pathogenesis of TS in the Chinese Han population.2 A transgenic mouse model of comorbid TS and obsessive‐compulsive disorder (TS + OCD) has demonstrated that TS + OCD‐like behavior is mediated by cortical‐limbic glutamate.3

Our patient had 16p13.3 (6 248 324–6 525 864; Human Genome database 19) deletion, which was similar to a deletion in a patient who had autism with developmental hemiparesis.5 It is well known that tourettism can be associated with autism spectrum disorders.10 The patient's mother carried the same deletion but did not manifest the features of tourettism. This may be explained by reduced penetrance of this deletion and by the complex interactions of genetic and environmental factors.10 The patient's younger brother had a history of GAD, and the RBFOX1 gene has been linked with the development of GAD.6

Mutations in the genes IMMP2L (inner mitochondrial membrane peptidase subunit 2), CNTNAP2 (contactin‐associated protein‐like 2), SLITRK1 (SLIT and NTRK‐like family member 1), and HDC (histidine decarboxylase) have been linked to TS,10 whereas the RBFOX1 gene has not been implicated in tourettism. Deletion of 1 copy of the RBFOX1 gene may be sufficient to produce clinical manifestations. Heterozygous RBFOX1 gene mutation has been associated with epilepsy.8 Mice with deletion of 1 copy of the Rbfox1 gene have increased susceptibility to seizures.4 Although heterozygous, RBFOX1 microdeletion in our patient could have resulted in the dysfunction of GABA‐A and NMDA receptors, resulting in the hyperactive movement disorder of Tourette‐like syndrome.

Conclusion

We describe a case of Tourette‐like syndrome with deletion of the RBFOX1 gene, which is linked to GABA and glutamate regulation. This may shed light on the possible physiology of the involvement of GABA‐A and NMDA receptors in the pathogenesis of tourettism.

Author Roles

1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

A.A.M.: 1A, 1B, 1C, 2A, 2B, 3A

N.K.: 1B, 1C, 2C, 3B

M.S.J.: 1A, 2A, 2C, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest: The authors report no source of funding. The authors report no conflicts of interest.

Financial Disclosures for the previous 12 months: Mandar S. Jog reports speaker and consultant honoraria from Merz Pharmaceuticals, Allergan, and AbbVie; research grants from the Canadian Institute of Health Research (CIHR), the Academic Medical Organization of Southwestern Ontario (AMOSO), Allergan, Merz Pharmaceuticals, and the Lawson Health Research Institute; and he is part of the AGE‐WELL Network of Centers of Excellence (NCE) of Canada program and, from time to time, he serves on the advisory boards of Allergan, Boston Scientific, AbbVie, and Merz Pharmaceuticals. Aditya A. Murgai and Niraj Kumar report no sources of funding and no conflicts of interest.