Neurodevelopmental conditions are crucial risk factors for catatonia in pediatric and adult populations. Recent case reports and studies have identified an increasing number of genetic abnormalities likely contributing to catatonia. Catatonia associated with genetic abnormalities is challenging in terms of identification, chronicity, and resistance to treatment. In addition, understanding these genetic abnormalities through identifying rare single nucleotide and copy number variants may offer valuable insights into the underlying pathophysiology.

We conducted a systematic review of all genetic abnormalities reported with catatonia and performed a gene-set enrichment analysis. Our systematic literature search for relevant articles published through July 15, 2024, using combinations of “catatonia,” “catatonic syndrome,” “genetic,” and “genes” in PubMed, yielded 317 articles. Of these, 94 were included, covering 374 cases of catatonia and 78 distinct genetic abnormalities.

This review discusses the clinical presentation of catatonia for each genetic disorder, the treatment strategies, and the putative underlying mechanisms.

The review highlights that catatonia underpinned by genetic abnormalities presents specific clinical and treatment-response features. Therefore, we propose genetic testing guidelines for catatonia and advocate for systematically investigating catatonia in several genetic diseases. Regarding the pathophysiology of catatonia, the gene ontology of biological processes reveals significant enrichment of variants in synaptic and post-synaptic regulatory genes, particularly within GABAergic neurons, reinforcing the implication of the excitatory/inhibitory imbalance. Finally, genetic variants are enriched in microglial cells, highlighting the role of brain inflammation in triggering catatonia. This comprehensive insight could pave the way for more effective management strategies for this condition.

Catatonia is a psychomotor syndrome frequently observed in disorders with neurodevelopmental impairments, including psychiatric disorders such as schizophrenia. The orbitofrontal cortex (OFC) has been repeatedly associated with catatonia. It presents with an important interindividual morphological variability, with three distinct H-shaped sulcal patterns, types I, II, and III, based on the continuity of the medial and lateral orbital sulci. Types II and III have been identified as neurodevelopmental risk factors for schizophrenia. The sulcal pattern of the OFC has never been investigated in catatonia despite the role of the OFC in the pathophysiology and the neurodevelopmental component of catatonia.

In this context, we performed a retrospective analysis of the OFC sulcal pattern in carefully selected homogeneous and matched subgroups of schizophrenia patients with catatonia (N = 58) or without catatonia (N = 65), and healthy controls (N = 82).

Logistic regression analyses revealed a group effect on OFC sulcal pattern in the left (χ2 = 18.1; p < .001) and right (χ2 = 28.3; p < .001) hemispheres. Catatonia patients were found to have more type III and less type I in both hemispheres compared to healthy controls and more type III on the left hemisphere compared to schizophrenia patients without catatonia.

Because the sulcal patterns are indirect markers of early brain development, our findings support a neurodevelopmental origin of catatonia and may shed light on the pathophysiology of this syndrome.