SHANK3 AS RISK FACTOR FOR EARLY-ONSET CATATONIA

Abstract Background The SHANK3 gene is located at the end of the long arm of chromosome 22. Ring chromosomes 22 and 22q13.3 deletions, as well as SHANK3 pathogenic sequence variants, lead to disruption of the SHANK3 protein, which is essential for organizing the post-synaptic density of glutamatergic excitatory synapses, expressed in the central nervous system as well as in the neuromuscular junction and the dendrites of sympathetic postganglionic neurons and myenteric neurons (1). In 2001, Phelan et al. (2) reported neonatal hypotonia, global developmental delay, and strongly impaired speech and expressive language, as well as autistic traits, in the absence of major dysmorphisms in patients carrying 22q13.3 deletions. This clinical picture has since been known as Phelan-McDermid syndrome (PMS). There have been recent reports of an association between catatonia and PMS (3,4). Aims & Objectives The aim of this study was to explore the relationship between catatonic symptoms and PMS, and to investigate the presence of catatonic-psychomotor signs in previously reported PMS cases and in three new young adult cases. Method Literature review of the association between catatonia and PMS, and an exploratory case-study in three young adults carrying a mutation or intragenic deletion of the SHANK3 gene, using semi- structured interviews, direct interaction with the participants, and the study of documents reporting observations at school or by other healthcare professionals. Results Catatonic symptoms partially overlap with autistic symptoms in PMS, but are distinguishable and unique. Catatonic manifestations from childhood evolved into a chronic form, with possible phases of sub-acute exacerbations starting from adolescence. Discussion & Conclusion The presence of childhood catatonic symptoms in PMS, that are distinguisable from autistic symptoms, supports that this is a singular entity fundamentally linked to SHANK3 mutations which can be considered as a form of early-onset catatonia. Additional cases are needed to confirm these observations. Therapeutic implications are discussed. References 1.Luciani JJ, de Mas P, Depetris D, Mignon-Ravix C, Bottani A, Prieur M et al. (2003). Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations. J Med Genet. 40(9):690-6. doi: 10.1136/jmg.40.9.690 2.Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H et al. (2001). 22q13 deletion syndrome. Am J Med Genet.101(2):91-9. doi: 10.1002/1096-8628(20010615)101:2<91:aid-ajmg1340>3.0.co;2-c 3.Dhossche D, de Billy C, Laurent-Levinson C, Le Normand M, Recasens C, Robel L, Philippe A.(2023). Early-onset catatonia associated with SHANK3 mutations: looking at the autism spectrum through the prism of psychomotor phenomena. Front Psychiatry. 2023 Sep 22:14:1186555. doi: 10.3389/fpsyt.2023.1186555. eCollection 2023. DOI: 10.3389/fpsyt.2023.1186555 4.Boley G, Pierri J, Finegold D, Pan L. (2024). Evaluation of catatonia in autism and severe depression revealing Phelan-McDermid syndrome and tetrahydrobiopterin deficiency. BMJ Case Rep. 2024 Jan 4;17(1):e256155. doi: 10.1136/bcr-2023-256155.