Genetics of catatonia: a systematic review of case reports and a gene pathway analysis

Abstract

Background: 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.

Methods: 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.

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

Conclusions: 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.

Keywords: GABAergic interneurons; catatonic syndrome; excitation/inhibition imbalance; genetic; neurodevelopmental; variants.

Figure 1.

Flow chart.

Figure 2.

Location of genetic variants and small deletions and duplications reported in catatonia. The main phenotypes associated with catatonia are shown in color. The name of the gene or the size of the deletion or duplication is indicated next to it. ID = intellectual disability; ASD= autism spectrum disorder. The circle corresponds to mitochondrial DNA.

Figure 3.

Gene network mapping for the 50 variants reported in catatonia.

Figure 4.

Gene ontology biological processes and cell type signatures of the 50 variants reported in catatonia. p-values are corrected for multiple testing and the colors represent the p-value magnitude, with darker shades indicating smaller p-values.