Down syndrome: trisomy 21

Patients with trisomy 21, or Down’s syndrome, which has an incidence of 1 in 800 births [Reference Bull29], are at risk of developing a catatonic syndrome. The risk of having a catatonic episode, which is often chronic, occurs during adolescence and is generally accompanied by behavioral regression [Reference Rosso, Fremion, Santoro, Oreskovic, Chitnis and Skotko30, Reference Smith, Baldwin, Lim and Luccarelli31]. This behavioral regression, known as Down syndrome regression disorder, has been increasingly described in the literature in recent years, and a recent international experts consensus has established diagnostic criteria, including a criterion for catatonia [Reference Santoro, Patel, Kammeyer, Filipink, Gombolay and Cardinale32]. Some studies highlight the effectiveness of immunomodulatory treatments, e.g. intravenous immunoglobulin (IVIg) infusions, which are effective in 85% of cases [Reference Santoro, Spinazzi, Filipink, Hayati-Rezvan, Kammeyer and Patel33, Reference Santoro, Jafarpour, Khoshnood, Boyd, Vogel and Nguyen34]. This robust IVIg response rate is intricately linked to the well-documented autoimmune context inherent to Down syndrome [Reference Malle, Patel, Martin-Fernandez, Stewart, Philippot and Buta35]. Patients with Down syndrome regression disorder exhibit a heightened prevalence of autoimmune conditions compared to those with Down syndrome without regression, as evidenced by elevated inflammatory markers in their bloodstream [Reference Santoro, Partridge, Tanna, Pagarkar, Khoshnood and Rehmani36]. A recent study has detected 365 auto-antibodies in the plasma of individuals with Down syndrome, some targeting the central nervous and immune system [Reference Malle, Patel, Martin-Fernandez, Stewart, Philippot and Buta35]. This increased vulnerability to catatonia in these patients reinforces the hypothesis of brain inflammation as a potential causative factor in catatonia [Reference Rogers, Pollak, Blackman and David24, Reference Beach, Luccarelli, Praschan, Fusunyan and Fricchione25].

Phelan-McDermid syndrome: SHANK3 gene

Phelan-McDermid syndrome is a rare condition characterized by deletion or mutation within the SHANK3 gene in chromosome region 22q13.33. The prevalence of this syndrome is currently unknown. However, it is estimated that approximately 0.5% to 1% of ASD cases with intellectual disability are caused by PMS [Reference Kolevzon, Delaby, Berry-Kravis, Buxbaum and Betancur16]. The prevalence of catatonia within this syndrome reaches 53% [Reference Kohlenberg, Trelles, McLarney, Betancur, Thurm and Kolevzon37]. Fifty-one cases of Phelan-McDermid syndrome with catatonia have been reported in the literature see Table 1. Haploinsufficiency of SHANK3 appears to be a risk factor for catatonic syndrome [Reference Breckpot, Vercruyssen, Weyts, Vandevoort, D’Haenens and Van Buggenhout38]. SHANK3 encodes a scaffolding protein of the postsynaptic density of glutamatergic excitatory synapses. Deficiency of this protein causes hypofunction of NMDA receptors (NMDAR) [Reference Duffney, Wei, Cheng, Liu, Smith and Kittler39]. The Phelan-McDermid syndrome with catatonia model further supports the overarching hypothesis of glutamatergic system hypofunctionality in catatonia, a concept advanced by several authors, especially concerning the intricate balance between GABA and glutamate neurotransmitters [Reference Walther, Stegmayer, Wilson and Heckers23]. Furthermore, it is essential to note that all episodes of catatonia noted within Phelan-McDermid syndrome exhibit a chronic course (>12 weeks) and limited response to conventional therapeutic approaches. In this syndrome, benzodiazepines such as lorazepam can increase impulsivity, psychomotor excitation, confusion, and insomnia, limiting the use of this treatment [Reference Kolevzon, Delaby, Berry-Kravis, Buxbaum and Betancur16]. Several alternative treatments have been tried in Phelan-McDermid syndrome with catatonia, such as lithium [Reference Serret, Thümmler, Dor, Vesperini, Santos and Askenazy40] and transcranial direct current stimulation (tDCS) in 4 patients with good efficacy and safety [Reference Moyal, Plaze, Baruchet, Attali, Cravero and Raffin41]. tDCS is postulated to enhance glutamatergic synaptic function through the induction of sustained long-term potentiation, thereby fostering metaplasticity that can persist for weeks [Reference Cirillo, Di Pino, Capone, Ranieri, Florio and Todisco42].

Di George syndrome: 22q11.2 deletion

Di George syndrome, also known as 22q11.2 deletion syndrome, occurs in approximately 1 in 4,000 births, and is characterized by a deletion of variable size in the 22q11.2 region [Reference Morrow, McDonald-McGinn, Emanuel, Vermeesch and Scambler43]. A total of 21 cases of 22q11.2 deletion syndrome is reported in the literature (Table 1) is most likely underestimated, given the well-known prevalence of psychotic and mood disorders among 22q11 deletion syndrome [Reference Schneider, Debbané, Bassett, Chow, Fung and Van Den Bree44], as well as various motor abnormalities [Reference Boot, Butcher, Van Amelsvoort, Lang, Marras and Pondal45]. A less expected case of catatonia has been described in a 22q11.2 duplication [Reference Breckpot, Vercruyssen, Weyts, Vandevoort, D’Haenens and Van Buggenhout38]. The management of catatonic syndrome in these patients appears to be challenging. In Butcher and colleagues’ case series, few patients were treated with the specific treatment for catatonic syndrome, i.e. lorazepam and ECT, and the efficacy was variable. Two were unsuccessfully treated with IVIg for suspected encephalitis, and four patients had a poor outcome, including malignant catatonia [Reference Butcher, Boot, Lang, Andrade, Vorstman and McDonald-McGinn21]. The other case report shows a good response to ECT but highlights the difficulty of diagnosing catatonia with BFCRS in these patients with 22q11.2 deletion syndrome [Reference Termini, Anand, Hickox, Richter and Smith46]. The 22q11.2 region involves about 90 genes, including 46 protein-coding genes, pseudogenes, non-coding RNAs, and microRNAs [Reference Zinkstok, Boot, Bassett, Hiroi, Butcher and Vingerhoets47], in particular, the PRODH gene, which encodes a mitochondrial enzyme involved in balancing GABA/glutamate transmission [Reference Butcher, Boot, Lang, Andrade, Vorstman and McDonald-McGinn21, Reference Guna, Butcher and Bassett48]. A case of catatonia associated with a missense mutation in the PRODH gene has been reported in the literature [Reference Raffin, Consoli, Giannitelli, Philippe, Keren and Bodeau8] (Table 1). This gene may be essential in developing catatonic symptoms in patients with 22q11.2 deletion syndrome. In addition, immune dysregulation has been highlighted in this syndrome, which appears to be associated with neuropsychiatric manifestations with elevated levels of pro-inflammatory cytokines, complement activity, increased neutrophils, and blood-brain barrier dysfunction [Reference Beach, Luccarelli, Praschan, Fusunyan and Fricchione25]. This underlying neuroinflammation presents an additional avenue of risk for catatonia development, potentially synergizing with the influence of the PRODH gene.

Kleefstra syndrome: EHMT1 gene

Kleefstra syndrome emerges from the haploinsufficiency of EHMT1 due to either a deletion at 9q34.3 or pathogenic variants of EHMT1 [Reference Kleefstra, van Zelst-Stams, Nillesen, Cormier-Daire, Houge and Foulds49]. The prevalence is unknown [Reference Kleefstra, van Zelst-Stams, Nillesen, Cormier-Daire, Houge and Foulds49]. Six cases of catatonia in Kleefstra syndrome have been described in the literature (Table 1) in the context of regression of abilities. Little is known about the therapeutic approach for catatonia in these patients. EHMT1 orchestrates histone methylation and facilitates gene silencing. Alongside EHMT2, it plays a pivotal role in synaptic scaling [Reference Benevento, Iacono, Selten, Ba, Oudakker and Frega50]. A study involving excitatory cortical neurons derived from induced pluripotent stem cells obtained from Kleefstra syndrome patients exhibited EHMT1 deficiency-triggered NMDAR hyperactivity [Reference Frega, Linda, Keller, Gümüş-Akay, Mossink and Van Rhijn51]. Furthermore, insights from a Kleefstra syndrome mouse model illuminated elevated expression of specific inflammatory genes, including IL-1b, alongside an increase in activated microglial cells within the brain, thereby underscoring the presence of cerebral inflammation in these patients [Reference Yamada, Hirasawa, Nishimura, Shimura, Kogo and Fukuda52]. The predisposition to catatonia within Kleefstra syndrome might be linked to the perturbation of the E/I balance within a neuroinflammatory cerebral milieu.

Prader-Willi syndrome: 15q11-q13 region

Catatonia has been reported in Prader-Willi syndrome, associated with lack of expression of paternally inherited imprinted genes in the chromosome 15q11-q13 region generally caused by a paternal deletion or maternal disomy in with both chromosomes 15 being inherited from the mother [Reference Butler, Miller and Forster53]. Prader-Willi syndrome occurs in approximately 1 in 15,000 individuals. Neuropsychiatric features are common in this condition, with anxiety and compulsive behaviors being the most prevalent [Reference Shelkowitz, Gantz, Ridenour, Scheimann, Strong and Bohonowych54]. The use of lorazepam can be challenging in these patients with extreme obesity and obstructive sleep apnea syndrome with a higher risk of dyspnea [Reference Butler, Miller and Forster53]. ECT treatment seems to be somewhat effective [Reference Zwiebel, Rayapati and de Leon55, Reference Poser and Trutia56]. The gene region implicated in Prader-Willi syndrome also includes the brain-specific, non-coding, Small Nucleolar Ribonucleic acid C/D box 115-1(SNORD 115). SNORD 115 dysfunction, reported in 3 case reports [Reference Peter-Ross57], is hypothesized to contribute to catatonia across various neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, and major depressive disorder, as well as genetic and immune-related conditions through the regulation of five downstream genes: CRHR1, PBRM1, TAF1, DPM2, RALGPS1 and the alternative splicing of serotonin 2C receptor [Reference Peter-Ross57]. TAF1 and DPM2 provide potential clues about parkinsonism and increased creatine phosphokinase in neuroleptic malignant syndrome, while abnormalities in RALGPS1 suggest links to both anti-NMDAR antibody encephalitis and the SHANK3 gene, which is known to predispose to catatonia.

Huntington’s disease: HTT gene

Huntington’s disease, caused by an expanded CAG trinucleotide repeat in the HTT gene encoding a non-functional huntingtin protein [Reference Bates, Dorsey, Gusella, Hayden, Kay and Leavitt58], is often associated with psychiatric features in addition to motor dysfunction. It occurs approximately in one in 7,300 individuals [Reference Bates, Dorsey, Gusella, Hayden, Kay and Leavitt58]. Catatonia in Huntington’s disease is described in five cases in the literature in the context of concurrent schizophrenia and mood disorders with good response to ECT. ECT should be widely offered to patients with catatonia in Huntington’s disease. However, the diagnosis is difficult to make in patients whose psychiatric manifestations precede their motor symptoms by several years [Reference Mowafi and Millard59].

X-linked syndrome

Inborn errors of metabolism

Inborn errors of metabolism are linked to genetic mutations, resulting in deficiencies in metabolic enzymes and leading to the accumulation or reduced excretion of protein, carbohydrates, and lipids. These diseases are most often diagnosed in early childhood, although milder forms occurring in adolescence and adulthood may be marked by psychiatric manifestations [Reference Van De Burgt, Van Doesum, Grevink, Van Niele, De Koning and Leibold75]. Inborn errors of metabolism are individually rare, however, more than 1,000 types have been identified, with a combined prevalence of approximately 1 in 800 to 1 in 1,000 individuals [Reference Van De Burgt, Van Doesum, Grevink, Van Niele, De Koning and Leibold75]. Lahutte and colleagues have compiled a list of inborn errors of metabolism likely associated with catatonia [Reference Lahutte, Cornic, Bonnot, Consoli, An-Gourfinkel and Amoura76]. We present inborn errors of metabolism and catatonia cases documented in the literature (Table 1). Two cases of G6PD deficiency were associated with catatonia [Reference Raj, Chism, Minckler and Denysenko77] and, in particular, one with malignant catatonia requiring ECT. G6PD deficiency has been associated with psychiatric disorders, notably psychosis and mood disorders [Reference Gandar, Scott and Warren78]. It is relatively common, with an estimated global prevalence of over 500 million individuals [Reference Luzzatto, Ally and Notaro79]. Among treatable diseases, two cases of cobalamin C deficiency leading to hyperhomocysteinemia presented with catatonia in two girls of 10 and 15 years old [Reference Engel, Rashid, Beshri and Ananth80, Reference Ben-Omran, Wong, Blaser and Feigenbaum81]. In both cases, catatonia regressed with the specific treatment of hydroxocobalamin, betaine and carnitine. Cobalamin C deficiency occurs in approximately 1 in 100,000 live births [Reference Martinelli, Deodato and Dionisi-Vici82]. In addition, 2 cases of MTHFR deficiency also led to hyperhomocysteinemia in two girls, 34 and 18 years old. One was treated with betaine, yielding limited effectiveness, while the other underwent ECT [Reference Lossos, Teltsh, Milman, Meiner, Rozen and Leclerc83, Reference Ezer, Karakasli, Gurel, Ayhan and Ulusahin84]. MTHFR deficiency is the most frequent folate metabolic disorder although the incidence is very rare( <1/400,000) [Reference Froese, Huemer, Suormala, Burda, Coelho and Guéant85]. Regarding Wilson’s disease, with an estimated incidence of ~1 per 7,000 individuals [Reference Czlonkowska, Litwin, Dusek, Ferenci, Lutsenko and Medici86], five cases of catatonia have been reported, including one marked by malignant catatonia [Reference Davis and Borde87–Reference Nayak, Shetageri, Bhogale, Patil, Chate and Chattopadhyay90]. These cases raised diagnostic challenges, and in four cases, identifying the Kayser–Fleischer ring facilitated accurate diagnosis and the proposal of targeted treatments. Indeed, cases were effectively treated with the specific therapy based on penicillamine and zinc in addition to a benzodiazepine, with one case necessitating ECT. In addition, two cases of acute porphyria, with catatonia alongside psychosis exhibited significant improvements with ECT [Reference Santosh and Malhotra91, Reference Vitória-Silva and Mota92]. Acute porphyria has an estimated incidence of 10 per million [Reference Stein, Badminton and Rees93]. A case of cerebrotendinous xanthomatosis, incidence 1 in 50,000 [Reference Nie, Chen, Cao and Zhang94], and catatonia was effectively treated with the specific treatment of chenodeoxycholic acid and HMG-CoA reductase inhibitor coupled with valproate for seizure control [Reference Yadav, Singh, Mishra, Joshi, R N C and Sharda95]. A case of Niemann-Pick type C disease, incidence 0.82/100,000 [Reference Vanier96], is reported in a 23-year-old boy who exhibited recurrent catatonia alongside neurological manifestations like vertical supranuclear gaze palsy [Reference van Verseveld, Koens, de Koning, Derikx and van Waarde97]. Finally, two cases of GM2 gangliosidosis, also known as Tay–Sachs disease, incidence of one in 320,000 births [Reference Lew, Burnett, Proos and Delatycki98], were reported, and catatonia in these cases was alleviated with lorazepam [Reference Rosebush, MacQueen, Clarke, Callahan, Strasberg and Mazurek99, Reference Saleh100].

Interferonopathies

Catatonia has been described in two patients with Aicardi–Goutières syndrome [Reference Ayrolles, Ellul, Renaldo, Boespflug-Tanguy, Delorme and Drunat101, Reference Andrés, Arteche-López, Granado and Llorente102]. Aicardi-Goutières syndrome is an autosomal recessive encephalopathy within the type 1 interferonopathies characterized by increased type 1 interferon (IFN) signaling[Reference Crow and Manel103] with an incidence less than 0.7600/100,000 live births [Reference Liu and Ying104]. Both cases presented with neurodevelopmental delay associated with bilateral basal ganglia calcifications on CT scan. One had typical skin lesions. In one case, the catatonic syndrome was successfully treated with immunoadsorption (22 treatments over 8 weeks) [Reference Ayrolles, Ellul, Renaldo, Boespflug-Tanguy, Delorme and Drunat101]. Another case of catatonia was described in a woman with post-infectious psychosis and a TBK1 variant [Reference Izu, Mooneyham, Ngo, Pleasure, Wilson and Nath105]. TBK1 upregulates type 1 IFN transcription genes. Type 1 IFN is essential as an antiviral cytokine and regulates innate and adaptive immune responses. Dysregulation of IFN signaling could play a key role in triggering the cerebral inflammation that leads to catatonia [Reference Beach, Luccarelli, Praschan, Fusunyan and Fricchione25].

Mitochondrial DNA mutation

Catatonia has been documented in two cases involving mitochondrial DNA mutation, the MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) syndrome, prevalence of 16 to 18/100,000 [Reference El-Hattab, Adesina, Jones and Scaglia106]. A 41-year-old woman presented with catatonia following stroke-like episodes (SLE) [Reference Montano, Simoncini, LoGerfo, Siciliano and Mancuso107], a hallmark symptom of MELAS driven by ictal activity leading to a range of neurological and psychiatric manifestations. The catatonic episode was successfully resolved with benzodiazepines. In another case, a patient with MELAS exhibited acute catatonia in the context of a major depressive disorder, which responded well to antidepressant treatment [Reference Ryu, Lee, Sung, Ko and Yoo108]. Psychiatric symptoms are prevalent in mitochondrial disorders ranging from 6 to 28%, including anxiety, mood, and psychosis disorders [Reference Anglin, Garside, Tarnopolsky, Mazurek and Rosebush109], and are likely to be related to a dysfunction of the brain’s respiratory chain. Antipsychotics must be cautiously considered, both typical and atypical, as they have been shown to inhibit complex I of the respiratory chain, potentially exacerbating the symptoms [Reference Anglin, Garside, Tarnopolsky, Mazurek and Rosebush109].

Clinical and therapeutic overview

Of 353 cases with a complete clinical description, 241 cases (68%) had a chronic or recurrent presentation, and 14 cases (4%) presented with malignant catatonia. Of 311 cases with documented treatment data, 261 cases (84%) showed a poor response to lorazepam, and 135 cases (43%) were treated with ECT, in contrast to the typical 70% good response rate to lorazepam in catatonia [Reference Rogers, Zandi and David1]. Only three were reported to be treated with clozapine.

Enrichment analyses

This systematic literature review identified 50 genetic variants associated with catatonia alongside 23 small-scale duplications and deletions. In our analysis, we have excluded genes encompassed by deletions and duplications, as it is challenging to determine which subset of genes plays a significant role in catatonia. The 50 genetic variants exhibit high interconnectivity, suggesting a potential convergence of shared biological processes, as illustrated in Figure 3. The protein-protein interaction revealed pathway enrichment in postsynaptic membrane organization (p = 6.31×10⁻¹³), positive regulation of excitatory postsynaptic potential (p = 10–12), and receptor clustering (p = 5×10⁻¹²). The variants are enriched in genes involved in behavior (p = 2 × 10⁻¹⁵), social behavior (p = 2 × 10⁻¹²), regulation of transmembrane transporter activity (p = 3.63 × 10⁻¹¹), synapse organization (p = 1.2 × 10⁻¹⁰) and neuromuscular process (p = 1.1 × 10⁻¹⁰) (Figure 4). These genes are mainly expressed in GABAergic (p = 1.5 × 10⁻⁴), serotoninergic (p = 1 × 10⁻⁴), dopaminergic (p = 2 × 10⁻⁴), and excitatory (p = 1.6 × 10⁻³) neurons as well as in microglial cells (p = 5 × 10⁻³) (Figure 4).