Comorbid situs inversus totalis and schizophrenia in a young male

To the Editor

Situs inversus is an autosomal recessive disorder of lateralization that is present in 1 in 10,000 live births (Kennedy et al., 1999). Previous case descriptions have linked psychosis or schizophrenia with a related condition, Kartagener’s syndrome (prevalence approximately 1 in 30,000 to 60,000 live births) that additionally involves primary ciliary dyskinesia (PCD) (Quast et al., 2005). We describe here for the first time the comorbid presentation of schizophrenia and situs inversus totalis (SIT) in an intellectually normal and otherwise healthy young male without PCD and speculate on the role of abnormal lateralization in schizophrenia.

An 18-year-old male with SIT was referred for psychiatric crisis assessment with a 3-month history of paranoid delusions. There was no prior psychiatric or substance use history and no family history of psychiatric illness, SIT, or Kartagener’s syndrome. He was born full term with no antenatal, obstetric or post-natal complications. At age 18 months, he was diagnosed incidentally with SIT but has not experienced bronchiectasis, chronic sinusitis, or other disorders associated with PCD. He was right-handed with a score of 53.8 on the Edinburgh handedness inventory. He experienced no developmental delays or difficulties in reading and writing and successfully completed school achieving university entrance.

On presentation the patient was grimacing, smiling to self, and appeared perplexed with a restricted affect. He spoke little with loss of spontaneity and appeared distracted with poor concentration. There was a recent history of decreased socialization and decreased motivation. He disclosed an auditory hallucination of a single voice. There were no abnormalities on physical examination particularly neurological examination. A brain magnetic resonance imaging (multiplanar and multisequence) scan showed no abnormality. He was initially treated with risperidone with improvement in communication, socialization, and paranoia. He was referred to an Early Psychosis Team for case management and has partially responded to treatment with different antipsychotics.

We provide here the first description, as far as we are aware, of schizophrenia with SIT without PCD in an intellectually normal and otherwise healthy individual. Although this case may be the incidental co-occurrence of two disorders, it is also plausible that it can provide an insight into the neurodevelopmental origin of schizophrenia. SIT is proposed as a complete physiological and functional reversal associated with genetic abnormalities in a range of signalling pathways (Sutherland and Ware, 2009) and is associated with PCD in 20–25% of cases. Neuroimaging studies have indicated that there is discordance in brain development with reversed cerebral petalia asymmetry but the planum temporale retaining a solitus asymmetry congruent with hemispheric language dominance (Kennedy et al., 1999) and an inconsistent inferior frontal gyri pattern (Ihara et al., 2010). This may explain the observation that many patients with SIT are right-handed, similarly to the patient described here, and that situs inversus might not predispose to left-handedness. There is, however, supportive evidence of lateralization abnormalities in schizophrenia (Crow, 1990) with observations of changed handedness frequency. We were unable to determine language hemispheric lateralization in our case, although data supports left hemispheric dominance. Nevertheless, the case implies that signalling abnormalities in SIT which may also be involved in schizophrenia do not need to involve language and planum temporale dysfunction (Ihara et al., 2010) or cortical lateralization. In SIT, structural malformations may occur more frequently than in those with situs solitus and similarly mental disorders may be more prevalent due to loss of brain asymmetry suggesting biochemical or genetic commonality. Kartagener’s syndrome is seen in only 20% of patients with situs inversus which raises the possibility of non-ciliary mechanisms responsible for asymmetry in those who do not have PCD. The most important early biophysical component of laterality involves the movement of cilia on the nodal cells during embryonic development. The absence of PCD in our patient suggests earlier intracellular asymmetry due to signalling upstream of the node involving a change in planar cell polarity that can affect lateralization. The developmental processes driving early brain asymmetries are not clear at the molecular level but studies done in mouse hippocampus showed asymmetry in the synaptic distribution of N-methyl-d-aspartate receptor GluRϵ2 subunits (Kawakami et al., 2003) and asymmetry in the shape and glutamate receptor expression (Shinohara et al., 2008). There has been no hippocampal asymmetry in mice with situs solitus or situs inversus suggestive of distinct developmental processes for hippocampal and visceral organ asymmetries. The developmental mechanisms underlying asymmetries in the brain including petalia are closely related to visceral organ asymmetries (Ihara et al., 2010) and this case warrants further research on pathways that are seen in a very early stage of asymmetry and those that determine lateralized brain functions like attention, language, and spatial orientation. The involvement of multiple signalling pathways in heterotaxy may provide a plausible set of genetic loci to investigate in the pathology of schizophrenia.