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

Mylène Moyal, Anton Iftimovici, Wafa Ghoul, Marion Plaze, Boris Chaumette

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Mylène Moyal, Anton Iftimovici, Wafa Ghoul, Marion Plaze, Boris Chaumette. Genetics of Catatonia: a systematic review of case reports and a gene pathway analysis. European Psychiatry, 2025, 68 (1), pp.e72. 10.1192/j.eurpsy.2025.2458. inserm-05086525

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1 **Genetics of Catatonia: a systematic review of case reports and a gene pathway analysis**

2 *Mylène Moyal*¹,², *Anton Iftimovici*¹,², *Wafa Ghoul*², *Marion Plaze*¹,², *Boris Chaumette*¹,²,³,⁴

3

4 ¹GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014 Paris, France.

5 ²Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM

6 U1266, 75014 Paris, France.

7 ³Human Genetics and Cognitive Functions, Institut Pasteur, CNRS UMR3571, Université Paris

8 Cité, Paris, France

9 ⁴Department of Psychiatry, McGill University, Montreal, Canada

10

11

12 Corresponding author: Boris Chaumette,

13 GHU Paris Psychiatrie et Neurosciences, bâtiment G, Pôle PEPIT, 1 rue Cabanis, 75014 Paris,

14 France

15 Tel: +33(0)1 45 65 81 79

16 Email address: boris.chaumette@inserm.fr

17

18 Running title: Genetics of Catatonia

19

This peer-reviewed article has been accepted for publication but not yet copyedited or typeset, and so may be subject to change during the production process. The article is considered published and may be cited using its DOI.

This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
20 **Abstract**

21 BACKGROUND

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

28 METHODS

29 We conducted a systematic review of all genetic abnormalities reported with catatonia and
30 performed a gene-set enrichment analysis. Our systematic literature search for relevant articles
31 published through July 15, 2024, using combinations of “catatonia,” “catatonic syndrome,”
32 “genetic,” and “genes” in PubMed, yielded 317 articles. Of these, 94 were included, covering
33 374 cases of catatonia and 78 distinct genetic abnormalities.

34 RESULTS

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

37 CONCLUSIONS

38 The review highlights that catatonia underpinned by genetic abnormalities presents specific
39 clinical and treatment-response features. Therefore, we propose genetic testing guidelines for
40 catatonia and advocate for systematically investigating catatonia in several genetic diseases.

41 Regarding the pathophysiology of catatonia, the gene ontology of biological processes reveals
42 significant enrichment of variants in synaptic and post-synaptic regulatory genes, particularly
43 within GABAergic neurons, reinforcing the implication of the excitatory/inhibitory imbalance.

44 Finally, genetic variants are enriched in microglial cells, highlighting the role of brain
45 inflammation in triggering catatonia. This comprehensive insight could pave the way for more
effective management strategies for this condition.

47

48 Keywords: catatonic syndrome, genetic, variants, neurodevelopmental, excitation/inhibition
49 imbalance, GABAergic interneurons

50

51
52

## 53 Introduction

Catatonia is a life-threatening psychomotor syndrome observed in psychiatric disorders, such as psychotic or mood disorders, alongside other medical conditions[1]. It is common in adult psychiatric wards, with a prevalence ranging from 9 to 30%[1]. In children and young adults, prevalence varies from 0,6 to 17%[2]. Moreover, its prevalence among neurodevelopmental disorders is increasingly recognized[3,4], and imaging studies point to anomalies in brain development (i.e. deviation of sulcation and gyrification indexes)[5,6] as a critical risk factor for its emergence in pediatric and adult populations[2]. By proxy, genetic anomalies reported in neurodevelopmental conditions have also been identified in catatonia with neurodevelopmental features[7] and in pediatric populations[8]. In addition, these neurodevelopmentally-associated-catatonia tend to exhibit heightened complexity in identification, chronicity, and resistance to treatment[2,9,10]. Indeed, besides the DSM-5 criteria for catatonia (i.e. catalepsy, stupor, waxy flexibility, agitation, mutism, negativism, posturing, mannerisms, stereotypies, grimacing and echophenomena[11]), the onset of incontinence, regression in acquisitions or worsening of pre-existing symptoms such as stereotypies and self-injurious behaviours are frequent features of neurodevelopmentally-associated-catatonia[2]. Notably, the established diagnostic tool for catatonia, the Bush-Francis Catatonia Rating Scale (BFCRS)[12], lacks consideration of specific clinical signs often observed in these cases, such as functional regression[2]. Within this neurodevelopmental context, the catatonic episodes tend to be chronic, lasting more than 12 weeks[13] and show suboptimal response to first-line treatments, lorazepam and electroconvulsive therapy (ECT)[9,14], due to poor drug tolerance but also because the physical condition limits access to ECT[15,16]. Identifying and treating catatonic episodes linked to genetic anomalies is, therefore, a significant healthcare problem that needs to be addressed.
In addition, genetic abnormalities offer valuable insights into the underlying pathophysiology[3,17]. Genome-wide association studies (GWAS) conducted on schizophrenia, bipolar disorder, and autism spectrum disorder have pinpointed various genetic polymorphisms linked to these conditions[18]. Some of these genes significantly influence neurotransmitter signalling, brain development, and synaptic function. An initial GWAS study involving 119 catatonia patients failed to unveil any specific single nucleotide polymorphism (SNPs) tied to catatonia[19], mainly due to the limited sample size. Much can be gained by investigating the rare variants that have been extensively reported in neurodevelopmental condition[20]. A 2018 literature review[21] and a recent genetic study[7] highlighted a wide range of genetic abnormalities associated with catatonia with several variants implicated in the GABA/glutamate pathway. Excitation/inhibition (E/I) imbalance is a strong hypothesis in the pathophysiology of catatonia that is supported by the efficacy of GABA<sub>A</sub> agonists (such as lorazepam) and neuroimaging studies[22,23]. Moreover, emerging evidence suggests an autoimmune facet to catatonia[24,25], wherein genetic elements associated with immune system dysregulation and dysimmunity could contribute.

Hence, characterising genetic abnormalities may provide valuable insights into catatonia's underlying mechanisms and pave the way for more effective management strategies for these challenging, treatment-resistant catatonic episodes. In this systematic review, we aim to update the subject with a systematic review of all the genetic abnormalities reported as leading to catatonia in light of the increasing number of case reports over the last years and to perform a gene enrichment analysis to refine our understanding of the pathophysiology.

98

## Methods

A systematic literature search was conducted for articles, including case reports, describing subjects with catatonia and genetic abnormalities. We applied the Preferred Reporting Items
for Systematic Reviews and Meta-Analysis (PRISMA) guideline[26] and declared the review
in Prospero (ID: CRD42024526691). We used PubMed and followed up on the references cited
in the papers that were thus identified. The following keywords were used: (catatonia or
catatonic syndrome) and (genes or genetic or variants or mutations). All relevant articles
published up to July 15, 2024, were included (Figure 1). The database search was done on 15
July 2024. Papers were included in the systematic review if (a) they were published in an
English-language peer-reviewed journal; (b) the study enrolled patients with catatonia; (c) the
study described one or more cases of patients with catatonia and genetic anomalies. We
excluded reviews and case series that did not provide data on individual patients. Articles in
line with Wernicke-Kleist-Leonhard catatonia (N=29) were also excluded from the analysis as
the definition does not fit the DSM-5 catatonia criteria[11]. Following PRISMA guidelines, two
different reviewers (MM and WG) searched, selected and included articles. In case of
disagreement, the other authors had to make the decision.

For each report, we collected the following information: age, underlying pathology, episode
characteristics, treatment used, and the catatonia diagnostic scale (Table 1). All data were
extracted on 20 July 2024.

We used the PhenoGram software[27] (http://visualization.ritchielab.org/phenograms/plot) to
represent graphically the genetic abnormalities linked to catatonia (Figure 2). We used the
String software (http://string-db.org) for a map of interaction (Figure 3) and the Metascape
software[28] (https://metascape.org) to identify the biological processes and the cell type
enrichment (Figure 4).

123
124 **Results**

125

126 Ninety-four articles met the criteria for our systematic review (Figure 1). This corresponds to

127 374 cases of catatonic syndrome and 78 different genetic abnormalities, as described in Table

128 1 and Figure 2. Below, we extensively describe the conditions where multiple cases of catatonia

129 have been reported

130

131 1. *Down syndrome: trisomy 21*

132 Patients with trisomy 21, or Down's syndrome, which has an incidence of 1 in 800 births[29],

133 are at risk of developing a catatonic syndrome. The risk of having a catatonic episode, which is

134 often chronic, occurs during adolescence and is generally accompanied by behavioural

135 regression[30,31]. This behavioural regression, known as Down syndrome regression disorder,

136 has been increasingly described in the literature in recent years, and a recent international

137 experts consensus has established diagnostic criteria, including a criterion for catatonia[32].

138 Some studies highlight the effectiveness of immunomodulatory treatments, e.g. intravenous

139 immunoglobulin (IVIg) infusions, which are effective in 85% of cases[33,34]. This robust IVIg

140 response rate is intricately linked to the well-documented autoimmune context inherent to

141 Down syndrome[35]. Patients with Down syndrome regression disorder exhibit a heightened

142 prevalence of autoimmune conditions compared to those with Down syndrome without

143 regression, as evidenced by elevated inflammatory markers in their bloodstream[36]. A recent

144 study has detected 365 auto-antibodies in the plasma of individuals with Down syndrome, some

145 targeting the central nervous and immune system[35]. This increased vulnerability to catatonia

146 in these patients reinforces the hypothesis of brain inflammation as a potential causative factor

147 in catatonia[24,25].

148
2. *Phelan-McDermid syndrome: SHANK3 gene*

Phelan-McDermid syndrome is a rare condition characterised 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[16]. The prevalence of catatonia within this syndrome reaches 53%[37]. 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[38]. *SHANK3* encodes a scaffolding protein of the postsynaptic density of glutamatergic excitatory synapses. Deficiency of this protein causes hypofunction of NMDA receptors (NMDAR)[39]. 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[23]. 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[16]. Several alternative treatments have been tried in Phelan-McDermid syndrome with catatonia, such as lithium[40] and transcranial direct current stimulation (tDCS) in 4 patients with good efficacy and safety[41]. tDCS is postulated to enhance glutamatergic synaptic function through the induction of sustained long-term potentiation, thereby fostering metaplasticity that can persist for weeks[42].

171

3. *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 characterised by a deletion of variable size in the 22q11.2 region[43]. 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[44], as well as various motor abnormalities[45]. A less expected case of catatonia has been described in a 22q11.2 duplication[38]. 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 [21]. 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[46]. The 22q11.2 region involves about 90 genes, including 46 protein-coding genes, pseudogenes, non-coding RNAs and microRNAs[47], in particular, the *PRODH* gene, which encodes a mitochondrial enzyme involved in balancing GABA/glutamate transmission[21,48]. A case of catatonia associated with a missense mutation in the *PRODH* gene has been reported in the literature[8] (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[25]. This underlying neuroinflammation presents an additional avenue of risk for catatonia development, potentially synergising with the influence of the *PRODH* gene.

196

4. 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* [49]. The prevalence is unknown [49]. 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 [50]. A study involving excitatory cortical neurons derived from induced pluripotent stem cells obtained from Kleefstra syndrome patients exhibited *EHMT1* deficiency-triggered NMDAR hyperactivity [51]. 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 [52]. The predisposition to catatonia within Kleefstra syndrome might be linked to the perturbation of the E/I balance within a neuroinflammatory cerebral milieu.

211

## 5. 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 [53]. 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 [54]. The use of lorazepam can be challenging in these patients with extreme obesity and obstructive sleep apnea syndrome with a higher risk of dyspnea [53]. ECT treatment seems to be somewhat effective [55,56]. 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 [57], 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[57]. 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.

231

## 6. 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[58], is often associated with psychiatric features in addition to motor dysfunction. It occurs approximately in one in 7,300 individuals[58]. Catatonia in Huntington's disease is described in 5 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[59].

241

## 7. X-linked syndrome

### 7.1 *X* fragile syndrome: *FMR1* gene

Fragile X syndrome is related to several CGG trinucleotide repeats > 200 in the FMR1 gene's promoter region. The prevalence of the full Fragile X syndrome mutation in the general population is estimated to be approximately 1 in 5,000 males and between 1 in 4,000 and 1 in 8,000 females[60]. Expansions between 55 and 200 repeats are defined as a premutation, and
its relationship with neuropsychiatric symptoms is discussed[61,62]. A case series described eight patients with Fragile X syndrome with "catatonia-like behaviour" scored by the attenuated behaviour questionnaire (ABQ)[63]. Unfortunately, treatment was not described in this study.
In addition, the ABQ scale used, which was developed to describe patients with ASD and catatonic symptoms, seems to overestimate the prevalence of catatonia and, to be less specific, with correlations with depression and repetitive/restrictive behaviours. Moreover, a case of Fragile X syndrome and a neuro-lupus with catatonia is reported with a good response to ECT[64]. A male with a premutation has been described alongside ASD and ADHD associated with catatonia and a good response to ECT[65]. ECT appears to be well tolerated and effective in Fragile X syndrome or premutation careers—the FMR1 expansion results in reduced levels of Fragile X mental retardation protein (FMRP). The absence of FMRP leads to the downregulation of GABA-A and B receptors and the upregulation of glutamate receptors. This disruption in the balance of GABA/glutamate levels could likely predispose these patients to catatonia[65].

## 7.2 Rett syndrome: MECP2 gene

Rett syndrome results from a methyl CpG binding protein 2 (MECP2) gene mutation. This disorder predominantly impacts girls, accounting for 95 to 97% of cases and has a prevalence of fewer than 1 in 200,000 individuals[66]. Its hallmark features encompass developmental regression coupled with movement disorders, notably hand stereotypies[67]. Within Rett syndrome, an array of additional movement disorders has been documented, including a rigid akinetic syndrome prevalent in older patients. One case of catatonia in a primary school-aged girl with Rett syndrome was associated with new-onset incontinence in addition to posturing, waxy flexibility, rigidity, staring and grimacing and was resolved with 8mg of lorazepam[2].
Catatonia has been described in two 17-year-old males with MECP2 deficiency[68,69]. In males carrying MECP2 variants, intellectual deficiency is associated with parkinsonism
features[68]. One presented with a catatonic episode resolved with lorazepam, alongside a
vertical supranuclear gaze palsy[68]; the other had recurrent lorazepam-resistant catatonia and
was successfully treated with tDCS[69]. A noteworthy conjecture arises that several individuals
with Rett syndrome and presenting parkinsonism features might be misdiagnosed and
potentially could be suffering from catatonia. Using the ABQ scale, 32 patients diagnosed with
Rett syndrome were evaluated[70]. Of this group, 20 exhibited catatonia-like behaviors. Rett
syndrome is primarily a synaptic disorder, and MECP2 deficiency impacts excitatory and
inhibitory synapses, leading to an elevated E/I ratio in animal model[71].

281 *7.3 Klinefelter syndrome: extra X chromosome*

282 Klinefelter’s syndrome arises from the presence of one or more additional X chromosomes (i.e.
283 47XXY). Its incidence is approximately 1 in 750 births[72]. A case of catatonia is described in
284 a 42-year-old patient with Klinefelter's syndrome and bipolar disorder[73]. The presentation
285 was rather severe, with malignant catatonia coupled with respiratory failure and effectively
286 treated with ECT. Association between the extra X chromosome and psychiatric disorders has
287 long been known with, in particular, an increased risk of psychotic disorders[74]. However,
288 very few cases of Klinefelter syndrome with catatonia have been reported, probably due to the
289 underdiagnosis of both Klinefelter syndrome and catatonia.
290

290

291 *8. Inborn errors of metabolism*

292 Inborn errors of metabolism are linked to genetic mutations, resulting in deficiencies in
293 metabolic enzymes and leading to the accumulation or reduced excretion of protein,
294 carbohydrates, and lipids. These diseases are most often diagnosed in early childhood, although
295 milder forms occurring in adolescence and adulthood may be marked by psychiatric
296 manifestations[75]. Inborn errors of metabolism are individually rare, however more than
297 1,000 types have been identified, with a combined prevalence of approximately 1 in 800 to 1
in 1,000 individuals [75]. Lahutte and colleagues have compiled a list of inborn errors of
metabolism likely associated with catatonia [76]. We present inborn errors of metabolism and
catatonia cases documented in the literature (Table 1). Two cases of G6PD deficiency were
associated with catatonia [77] and, in particular, one with malignant catatonia requiring ECT.
G6PD deficiency has been associated with psychiatric disorders, notably psychosis and mood
disorders [78]. It is relatively common, with an estimated global prevalence of over 500 million
individuals [79]. Among treatable diseases, two cases of cobalamin C deficiency leading to
hyperhomocysteinemia presented with catatonia in two girls of 10 and 15 years old [80,81]. 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 [82]. 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 [83,84]. MTHFR deficiency is the most frequent folate metabolic disorder
although the incidence is very rare ( < 1/400,000) [85]. Regarding Wilson's disease, with
estimated incidence of ~1 per 7,000 individuals [86], 5 cases of catatonia have been reported,
including one marked by malignant catatonia [87-90]. 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 [91,92]. Acute porphyria has an estimated incidence of 10
per million [93]. A case of cerebrotendinous xanthomatosis, incidence 1 in 50,000 [94] and
catatonia was effectively treated with the specific treatment of chenodeoxycholic acid and
HMG-CoA reductase inhibitor coupled with valproate for seizure control [95]. A case of
Niemann-Pick type C disease, incidence 0.82/100,000 [96], is reported in a 23-year-old boy who
323 exhibited recurrent catatonia alongside neurological manifestations like vertical supranuclear
gaze palsy[97]. Finally, two cases of GM2 gangliosidosis, also known as Tay-Sachs disease,
324 incidence of one in 320,000 births[98], were reported, and catatonia in these cases was
325 alleviated with lorazepam[99,100].
326

327

328 9. Interferonopathies

329 Catatonia has been described in two patients with Aicardi-Goutières syndrome[101,102].
330 Aicardi-Goutières syndrome is an autosomal recessive encephalopathy within the type 1
331 interferonopathies characterised by increased type 1 interferon (IFN) signaling[103] with an
332 incidence less than 0.7600/100000 live births[104]. Both cases presented with
333 neurodevelopmental delay associated with bilateral basal ganglia calcifications on CT scan.
334 One had typical skin lesions. In one case, the catatonic syndrome was successfully treated with
335 immunoadsorption (22 treatments over 8 weeks)[101]. Another case of catatonia was described
336 in a woman with post-infectious psychosis and a TBK1 variant[105]. TBK1 upregulates type 1
337 IFN transcription genes. Type 1 IFN is essential as an antiviral cytokine and regulates innate
338 and adaptive immune responses. Dysregulation of IFN signalling could play a key role in
339 triggering the cerebral inflammation that leads to catatonia[25].

340

341 10. Mitochondrial DNA mutation

342 Catatonia has been documented in two cases involving mitochondrial DNA mutation, the
343 MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)
344 syndrome, prevalence of 16 to 18/100,000[106]. A 41-year-old woman presented with catatonia
345 following stroke-like episodes (SLE)[107], a hallmark symptom of MELAS driven by ictal
346 activity leading to a range of neurological and psychiatric manifestations. The catatonic episode
347 was successfully resolved with benzodiazepines. In another case, a patient with MELAS
348 exhibited acute catatonia in the context of a major depressive disorder, which responded well
349 to antidepressant treatment[108]. Psychiatric symptoms are prevalent in mitochondrial
350 disorders ranging from 6 to 28%, including anxiety, mood and psychosis disorders[109], and
351 are likely to be related to a dysfunction of the brain's respiratory chain. Antipsychotics must be
352 cautiously considered, both typical and atypical, as they have been shown to inhibit complex I
353 of the respiratory chain, potentially exacerbating the symptoms[109].

354

355 **11. Clinical and therapeutic overview**
356

356

357 Of 353 cases with a complete clinical description, 241 cases (68%) had a chronic or recurrent
358 presentation, and 14 cases (4%) presented with malignant catatonia. Of 311 cases with
359 documented treatment data, 261 cases (84%) showed a poor response to lorazepam and 135
360 cases (43%) were treated with ECT, in contrast to the standard 70% good response to lorazepam
361 in catatonia[1]. Only three were reported to be treated with clozapine.

362

363 **12. Enrichment analyses**
364

364 This systematic literature review identified 50 genetic variants associated with catatonia
365 alongside 23 small-scale duplications and deletions. In our analysis, we have excluded genes
366 encompassed by deletions and duplications, as it is challenging to determine which subset of
367 genes plays a significant role in catatonia. The 50 genetic variants exhibit high
368 interconnectivity, suggesting a potential convergence of shared biological processes, as
369 illustrated in **Figure 3**. The protein-protein interaction revealed pathway enrichment in
370 postsynaptic membrane organisation (p=6,31×10⁻¹³), positive regulation of excitatory
371 postsynaptic potential (p=10⁻¹²) and receptor clustering (p=5×10⁻¹²). The variants are
372 enriched in genes involved in behaviour (p=2×10⁻¹⁵), social behaviour (p=2×10⁻¹²),
373 regulation of transmembrane transporter activity (p=3.63×10⁻¹¹), synapse organisation
374 (p=1.2×10⁻¹⁰) and neuromuscular process (p=1.1×10⁻¹⁰) (Figure 4). These genes are mainly
375 expressed in GABAergic (p=1,5×10⁻⁴), serotoninergic (p=1×10⁻⁴), dopaminergic (p=2×10⁻⁴),
376 and excitatory (p=1,6×10⁻³) neurons as well as in microglial cells (p=5×10⁻³) (Figure 4).

377

378 **Discussion**

379

380 In this review, we reported all the genetic anomalies associated with a catatonic syndrome
381 described in the literature to date. This analysis included 94 articles with 374 cases of catatonia
382 and 78 distinct genetic anomalies.

383 Firstly, regarding clinical presentation, this review highlights that catatonic episodes associated
384 with genetic abnormalities exhibit a chronic course in 241 cases (68%). Additionally, typical
385 clinical signs of catatonia may be absent, with behavioral regression often being a predominant
386 feature. A recent review article proposes assessing a personalised score at baseline based on the
387 BFCRS and the pediatric catatonia rating scale (PCRS)[164] to facilitate diagnosis and
388 assessment of response to treatment[2]. In addition, some cases of catatonia with genetic
389 abnormalities have been described in neurodegenerative disorders such as *C9orf72*, associated
390 with frontotemporal dementia, and in Huntington's disease, reinforcing the importance of
391 looking for genetic abnormalities also in neurodegenerative disorders in line with the known
392 associated vulnerability between neurodevelopmental and neurodegenerative disorders[165].

393 Concerning the therapeutic aspect, in the majority of cases (261 cases; 84%), lorazepam proved
394 inadequate in alleviating catatonia, exhibiting reduced efficacy or poor tolerance.
395 Electroconvulsive therapy was frequently used (135 cases; 43%) and was mostly effective but
396 limited by its restrictive access[15,166]. Thus, although ECT should be widely offered[167],
397 alter/tive treatments must be discussed. Although only three cases of catatonia were treated with
clozapine with significant improvement, clozapine appears to be well tolerated and effective in patients with neurodevelopmental disorders[168] and should therefore be part of the personalized care strategies considered. The efficacy of clozapine may be closely linked to the imbalance in the E/I ratio and, in particular, to the involvement of gabaergic interneurons[169,170]. Indeed, clozapine may facilitate the binding of GABA to the GABA<sub>B</sub> receptor[171]. tDCS, an easy-to-apply noninvasive brain stimulation technique, was effective and safe in 16 cases of catatonic patients, including four patients with Phelan-McDermid syndrome[41,172] and two patients with Down Syndrome Regression Disorder[173]. In addition, in catatonia cases related to neuroinflammation, anti-inflammatory interventions appear promising[34,174]. Anti-inflammatory treatment needs to be offered more widely, even in the absence of autoantibodies identified by lumbar puncture or blood test, in syndromes with known inflammation such as Down Syndrome Regression Disorder[33]. Along the same lines, specific treatment in case of treatable inborn errors of metabolism, such as Cobalamin C disorder or Wilson disease, can treat catatonia. Knowledge of genetic abnormalities can help organise timely personalised care[41,140]. Likewise, it is legitimate to systematically assess catatonic symptoms in genetic diseases, notably in Down syndrome and Phelan-McDermid syndrome, where its prevalence is extremely high[32,37].

In light of this literature review, genetic testing for catatonia should be considered more broadly in patients with the following criteria: the presence of a neurodevelopmental background[7], a chronic episode lasting more than 12 weeks, recurrent episodes, early onset of catatonia, resistance or paradoxical reaction to first-line treatment of catatonia, association with neurological signs including seizures, and the existence of malignant catatonia. Whole-exome or whole-genome sequencing should be considered the first-tier diagnostic framework, considering the high proportion of SNVs.
Although the risk of developing catatonia is high in certain genetic conditions, the onset of a catatonic episode may depend on environmental factors, such as exposure to antipsychotics[17] or the sudden discontinuation of clozapine treatment[175]. Well-conducted studies are needed to identify environmental risk factors in these genetically predisposed patients to develop effective prevention strategies.

Finally, a deeper understanding of the genetic factors involved in catatonia can shed light on its pathophysiology. The protein-protein interaction, enrichment in biological processes and the cell type signatures in the 50 genetic variants associated with catatonia reinforce the hypothesis of a dysfunction at the synaptic level, particularly in GABAergic neurons. It supports the likely central role of GABAergic interneurons in catatonia[175,176] in the hypothesis of E/I imbalance[23]. Glutamate modulates the activity of the GABAergic interneurons through their NMDA receptors that regulate the synchronisation of superficial pyramidal cells, thus ensuring a variety of cognitive processes[177]. A disruption of GABAergic interneurons has been highlighted in several psychiatric disorders, including ASD and schizophrenia[177,178], both of which are associated with catatonia. This disruption may underlie the dysconnectivity between the medial prefrontal, orbitofrontal, and motor areas observed in fMRI studies of catatonia[179] and could represent a shared pathophysiological mechanism linking these disorders to catatonia. Furthermore, as interneuron-dependent prefrontal cortical maturation occurs during adolescence[180], their disruption may also explain the specific timing of catatonia onset in syndromes such as DSRD. Adolescence thus emerges as a vulnerable timeframe for catatonia. Quantitative EEG analyses could be used to provide further support for the hypothesis of disruption of GABAergic interneurons in catatonia[181]. Such anomalies in GABAergic function could be due to various pathological processes, contributing to the diverse clinical presentations observed in catatonia. One potential mechanism is neuro-inflammation, a phenomenon observed in several genetic diseases, notably Down's syndrome
and 22q11DS, and also reported in catatonia[24,25]. Autoantibodies targeting GABAergic interneurons could lead to catatonia, as it has also been observed for autoantibodies targeting NMDA receptors[182]. The microglial cell signature of genetic variants associated with catatonia further underscores the involvement of neuroinflammation. Based on our cell-enrichment analysis, serotonergic and dopaminergic neurons also appear to be involved. Serotonin receptors have previously been associated with catatonia, notably via SNORD 115 mRNA, which regulates alternative splicing of the serotonin 2C receptor[57]. Furthermore, catatonia is frequently associated with both serotonin syndrome and neuroleptic malignant syndrome, each respectively associated with an excess of serotonin and dopamine blockage[183].

Several methodological issues call for caution when interpreting this work. First, catatonia is not always described using the same scale, and sometimes no scale has been used. It is rather difficult to ascertain the diagnosis and severity of the syndrome. Second, we probably missed genetic abnormalities as the vast majority of genetic cases with catatonia have not been published, and there is still limited access to genetic testing in psychiatric disorders. Another form of bias stems from the limited conclusiveness of cases due to our current understanding of genetics. This understanding is influenced by variants found in other psychiatric conditions, resulting in the expectation that biological processes and cell signatures will be concentrated in usual brain pathways. In addition, given the absence of a control group, we cannot ascertain whether these genetic variations are truly enriched in catatonia specifically or if their presence merely reflects broader neurodevelopmental processes associated with catatonia. Nevertheless, these findings provide a valuable foundation for generating research hypotheses. To overcome this limitation, future studies should incorporate larger, well-controlled, and unbiased genetic analyses involving patients with catatonia.

471
472 **Conclusion**

473 This review highlighted the neurodevelopmental burden of catatonia and the clinical relevance
474 of genetic explorations in this syndrome while also discussing the underlying pathophysiology
475 and its implications for treatment. Our systematic description of rare disorders associated with
476 catatonia, providing clear links between genotype and phenotype, strengthens the importance
477 of GABAergic interneuron dysfunction. This work further points out the importance of large-
478 scale whole-exome or whole-genome sequencing studies to identify new genetic variants and
479 pathways associated with catatonia. Improving our knowledge of catatonia's genetic
480 background may allow for the development of more targeted diagnostic approaches and
481 personalized treatment strategies.

482

483
484 Acknowledgements

485 We would like to thank Alexandre Gestin for his assistance with the PhenoGram software.

486

487 Funding

488 Mylène Moyal received funding from the John Bost Foundation.

489 This work is supported by a Young Researcher grant (ANR JCJC ANR-22-CE16-0029), by a

490 grant from Inserm and the French Ministry of Health (Inserm-AAP Messidore2022-N°9), and

491 by a French government grant managed by the Agence Nationale de la Recherche under the

492 France 2030 program (reference ANR-22-EXPR0013).

493

494 Conflict of interest

495 The Authors have declared that there are no conflicts of interest concerning the subject of this

496 study.

497

498 Data availability

499 All the data are available.

500

501
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<table><thead><tr><td>Genetic anomaly</td><td>Genes implicated</td><td>Catatonia case</td><td>Age</td><td>Scale</td><td>Treatment</td><td>Reference</td></tr></thead><tbody><tr><td>21 Trisomy (Down syndrome)</td><td>Multiple</td><td>142 cases</td><td>adolescence</td><td>/</td><td>Lorazepam and ECT in some cases. tDCS in 2 cases. IVIg effective</td><td>[7,8,31,33,3 8,110–122]</td></tr><tr><td>22q11.2 deletion (DiGeorge syndrome) and 1 duplication</td><td>Multiple</td><td>21 cases</td><td>/</td><td>/</td><td>Lorazepam and ECT in some cases. 2 were unsuccessfully treated with IVIg</td><td>[21,38,46,1 14,123]</td></tr><tr><td>22q13.3 deletion or mutation (Phelan McDermid syndrome)</td><td>SHANK 3</td><td>51 cases</td><td>adolescence</td><td>/</td><td>Lorazepam not tolerated Lithium in some cases ECT in some cases tDCS in 4 cases</td><td>[7,8,37,38,4 0,41,124–133]</td></tr><tr><td>15q11-q13 (Prader-Willi syndrome)</td><td>Multiple</td><td>9 cases</td><td>/</td><td>BFCRS</td><td>Lorazepam + ECT</td><td>[55,56,134, 135]</td></tr><tr><td>Huntington disease CAG repeat</td><td>HTT</td><td>6 cases mood disorder or psychosis</td><td>57; 20; 26; 62; 38; 16</td><td>BFCRS; PCRS</td><td>ECT effective</td><td>[8,59,136–138]</td></tr><tr><td>Kleefstra syndrome</td><td>EHMT1</td><td>6 cases</td><td>18, /</td><td>PCRS; /</td><td>/</td><td>[8,49]</td></tr><tr><td>Heterozygous pathogenic variant</td><td>GABRB2</td><td>1 case ASD ID and chronic catatonia</td><td>17</td><td>DSM5 + BFCRS</td><td>Lorazepam + ECT</td><td>[139]</td></tr><tr><td>Pathogenic frameshift variant</td><td>HIVEP2</td><td>2 cases including 1 MC</td><td>22</td><td>/</td><td>1 case: Lorazepam no effect amantadine badly tolerated Celecoxib + quetiapine effective Other case: MC treated with ECT</td><td>[140,141]</td></tr><tr><td>Heterozygous full deletion</td><td>VAMP2</td><td>1 MC</td><td>33</td><td>/</td><td>Lorazepam not tolerated Treated with ECT</td><td>[142]</td></tr><tr><td>Baraitser Winter syndrome</td><td>ACTB and ACTG1</td><td>2 cases</td><td>18</td><td>/</td><td>/</td><td>[143]</td></tr><tr><td>Heterozygote pathogenic variant</td><td>CACNA1A; CACNA1D</td><td>1 case of dementia 1 case with adverse effect on ECT</td><td>9; 14</td><td>/</td><td>Lorazepam not sufficient. Treated with ECT</td><td>[144,145]</td></tr><tr><td>15q duplication</td><td>Multiple</td><td>1 case with ASD</td><td>/</td><td>DSM5</td><td>ECT</td><td>[114]</td></tr><tr><td>3q13.13 intragenic deletion</td><td>/</td><td>1 case with ASD</td><td>/</td><td>DSM5</td><td>ECT</td><td>[114]</td></tr><tr><td>9p24.2 deletion</td><td>/</td><td>1 case with ASD</td><td>/</td><td>DSM5</td><td>ECT</td><td>[114]</td></tr><tr><td>X28q duplication</td><td>/</td><td>1 case with ASD</td><td>/</td><td>DSM5</td><td>ECT</td><td>[114]</td></tr><tr><td>Pathogenic variant</td><td>SYNJI</td><td>1 case co-occurring with PMS with ID and recurrent catatonia</td><td>19</td><td>/</td><td>Alprazolam, Lithium, and Levodopa</td><td>[126]</td></tr><tr><td>Stop-gain mutation</td><td>RCL1</td><td>1 case with very early onset psychosis</td><td>14</td><td>DSM5</td><td>Clonazepam</td><td>[146]</td></tr></tbody></table>
<table><tr><td>Heterozygous variant</td><td>mTOR</td><td>1 case ID and ASD</td><td>19</td><td>BFCRS</td><td>Lorazepam not tolerated Treated with ECT</td><td>[147]</td></tr><tr><td>Pitt-Hopkins Syndrome</td><td>TCF4</td><td>1 case ID and ASD</td><td>23</td><td>/</td><td>ECT</td><td>[148]</td></tr><tr><td>De novo missense variant</td><td>NLGN2</td><td>1 case with ASD and chronic catatonia</td><td>21</td><td>/</td><td>Clonazepam + aripiprazole</td><td>[149]</td></tr><tr><td>Aicardi-Goutières syndrome homozygous</td><td>RNASEH2B SAMHD1</td><td>1 case with leucoencephalitis. 1 case with ID, psychosis and Degos like skin lesions</td><td>15; 19</td><td>DSM5 + BFCRS</td><td>treated with methylprednisolone then prednisone combined with mycophenolate mofetil and hydroxychloroquine then immunoadsorption (22 courses)</td><td>[101,102]</td></tr><tr><td>Missense variant</td><td>TBK1</td><td>1 case of catatonia with post infection psychosis</td><td>/</td><td>/</td><td>/</td><td>[105]</td></tr><tr><td>Rett syndrome</td><td>MECP2</td><td>1 case with ID early-onset parkinsonism, and VSGP + 1 case male with epilepsy + 1 catatonia and regression + 20 catatonia like behavior</td><td>17; 17</td><td>/ DSM-5 and BFCRS; ABQ; PCRS</td><td>Lorazepam effective; tDCS; lorazepam effective</td><td>[2,68–70]</td></tr><tr><td>S93L mutation</td><td>MLC1</td><td>1 case with bipolar disorder and catatonia</td><td>17</td><td>/</td><td>Olanzapine + Sertraline</td><td>[150]</td></tr><tr><td>Fragile X syndrome trinucleotide repeat expansion CGG >200 and 1 premutation career</td><td>FMRI</td><td>1 case with ADHD and ASD 1 case with neuro-lupus 1 premutation career with ADHD, ASD, BP, OCD, Tourette syndrome and recurrent chronic catatonia + 8 cases of catatonia like behavior</td><td>18; 21; 25; /</td><td>DSM-5 BFCRS ABQ</td><td>1 case: Lorazepam partial improvement 3 cases treated with ECT 8 cases: /</td><td>[62–65,151]</td></tr><tr><td>Cornelia de Langes syndrome</td><td>Multiple</td><td>10 cases of catatonia like behavior</td><td>/</td><td>ABQ</td><td>/</td><td>[151]</td></tr><tr><td>15q11 with SNORD 115 mRNA</td><td>CRHR1, PBRMI, TAF1, DPM2, RALGPS1</td><td>3 cases</td><td>9; /; /</td><td>/</td><td>Lorazepam effective for one case</td><td>[57]</td></tr><tr><td>Fatal familial insomnia (FFI)</td><td>PRNP</td><td>1 case with mood disorder, and insomnia</td><td>18</td><td>/</td><td>Worse with BZD and ECT</td><td>[8,152]</td></tr><tr><td>4 missense mutations (P406L, R431H, Q19P, R185W)</td><td>PRODH</td><td>1 case with ASD, ID, schizophrenia and seizures</td><td>14</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>Mucopolysaccharidosis type</td><td>Multiple</td><td>1 case with ID, ASD and dementia</td><td>18</td><td>PCRS</td><td>/</td><td>[8]</td></tr></table>
<table><thead><tr><th colspan="8">III (Sanfilippo syndrome)</th></tr></thead><tbody><tr><td>16p13.1 duplication</td><td>PDXDC1, NTAN1, RRN3, PKD1P6-NPIPP1, NPIPA5, MPV17L, BMERB1, MARF1, NDE1, MYH11, ABCC1, ABCC6</td><td>1 case with ASD, schizophrenia and catatonia</td><td>16</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>8p23.3 deletion</td><td>DLGAP2, CNL8</td><td>1 case with ASD</td><td>17</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>2q22.1 deletion</td><td>THSD7B</td><td>1 case with ID, ASD and seizures</td><td>19</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>13q33.1-34 deletion</td><td>DAOA, EFNB2, ARGLU1, FAM155A, LIG4, ABHD13, TNFSF13B, MYO16, IRS2</td><td>1 case with hemostatic disorder, ID, and seizures</td><td>14</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>2q36 deletion</td><td>DOCK10, NYAP2</td><td>1 case with ID and ASD, seizures</td><td>15</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>6q25.2-27 deletion</td><td>PRKN</td><td>1 case with anti-NMDA receptor encephalitis</td><td>17</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>Xp22.33 duplication</td><td>CRLF2, ASMTL, PERY8</td><td>1 case with ID, ASD, and seizures</td><td>19</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>21q21.1 duplication<br>6q14 duplication<br>Xq25 deletion</td><td>No coding gene<br>No coding gene<br>No coding gene</td><td>1 case with ID, BP</td><td>14</td><td>PCRS</td><td>/</td><td>[8]</td></tr><tr><td>Ala202Val; Gln1557*</td><td>SCN2A</td><td>1 case with seizure<br>1 case with ID and recurrent catatonia</td><td>4; 20</td><td>PCRS</td><td>Corticoids not very effective. Treated with lorazepam. IVIg not effective, lorazepam + ECT</td><td>[153,154]</td></tr><tr><td>Hexanucleotide repeat expansion</td><td>C9orf72</td><td>2 cases with MDD.</td><td>65; 67</td><td>BFCRS</td><td>Antidepressant, Aripiprazole, Lorazepam, and ECT</td><td>[155-157]</td></tr><tr><td>14q11.2 duplication</td><td>SUPTH16, CDH8</td><td>1 case with schizophrenia and seizure</td><td>50</td><td>DSM-5</td><td>Clozapine</td><td>[38]</td></tr><tr><td>2q36.1 duplication</td><td>SGPP2, FARSB, MOGAT1</td><td>Concomitant with DS</td><td>/</td><td>DSM-5</td><td>ECT</td><td>[38]</td></tr><tr><td>16p11.2 duplication</td><td>SLC7A5P1, SPN, QPRT, C16orf54, ZG16, KIF22, MAZ, PRRT2, MVP, CDIPT, SEZ6L2, ASPDH1, KCTD13, TMEM219, TAOK2, HIRIP3, INO80E, DOC2A, C16orf92, TLCD3B, CTD2515O10.6, PPP4C, TBX6, YPEL3, GDPD3, MAPK3</td><td>1 case with neurosyphilis, seizure and SSD</td><td>/</td><td>DSM-5</td><td>Lorazepam</td><td>[38]</td></tr><tr><td>14q11.2 duplication</td><td>ZNF219, TMEM253, OR5AU1,</td><td>1 case with seizure and SSD</td><td>/</td><td>DSM-5</td><td>Clozapine</td><td>[38]</td></tr></tbody></table>
<table><tr><td></td><td>HNRNPC, RPGRIPI, SUPT16H, CHD8</td><td></td><td></td><td></td><td></td></tr><tr><td>Pathogenic variant c.2565del</td><td>CHD8</td><td>1 case of catatonia and regression following viral infection in ASD</td><td>13</td><td>/</td><td>Resistant to Lorazepam, ECT and immunomodulatory medications</td><td>[158]</td></tr><tr><td>16p13.13 duplication</td><td>SNX29, CPPED1</td><td>1 case with psychosis</td><td>/</td><td>DSM-5</td><td>Lorazepam</td><td>[38]</td></tr><tr><td>16p13.11p12.3 duplication</td><td>NPIPA1, PDXDC1, NTAN1, RRN3, NPIPA5, MPV17L, BMERB1, MARF1, NDE1, MYH11, CEP20, ABCC1, ABCC6, NOMO3</td><td>Chronic catatonia with skill regression, ASD and DI</td><td>21</td><td>/</td><td>/</td><td>[7]</td></tr><tr><td>17p13.3 duplication</td><td>SLC43A2, SCARF1, PRPF8, RILP</td><td>1 case with psychosis</td><td>/</td><td>DSM-5</td><td>ECT</td><td>[38]</td></tr><tr><td>Klinefelter extra X chromosome</td><td>Multiple</td><td>1 case with BP and MC</td><td>42</td><td>/</td><td>ECT</td><td>[73]</td></tr><tr><td>Missense mutation</td><td>KCNT1</td><td>5 cases</td><td>/</td><td>/</td><td>/</td><td>[159]</td></tr><tr><td>Nonsense mutation</td><td>HARS</td><td>1 case with psychosis</td><td>/</td><td>/</td><td>/</td><td>[160]</td></tr><tr><td>Missense mutation</td><td>MMACHC</td><td>2 cases, 1 with psychosis</td><td>15; 14</td><td>/</td><td>Betaine, hydroxycobalamine</td><td>[80,81]</td></tr><tr><td>G6PD deficiency</td><td>G6PD</td><td>2 cases, 1 with mood disorder and recurrent catatonia, 1 with MC</td><td>35; 19</td><td>BFCRS</td><td>Lithium; ECT</td><td>[77]</td></tr><tr><td>Wilson disease</td><td>ATB7B</td><td>5 cases with MC</td><td>22; 12; 19; 19; 18</td><td>MRS; BFCRS</td><td>Penicillamine Zinc BZD Lorazepam failed, treated with ECT</td><td>[87–90]</td></tr><tr><td>MTHFR deficiency</td><td>MTHFR</td><td>1 case with psychosis 1 case with MDD</td><td>34; 18</td><td>BFCRS</td><td>1 case treated with betaine 1 case with ECT and AD</td><td>[83,84]</td></tr><tr><td>Acute porphyria</td><td>HMBS</td><td>2 cases with psychosis</td><td>46; 14</td><td>/</td><td>Treated with ECT</td><td>[91,92]</td></tr><tr><td>Cerebrotendinous Xanthomatosis</td><td>CYP27A1</td><td>1 case with seizure</td><td>20</td><td>/</td><td>Chenodeoxycholic acid + HMG-CoA reductase inhibitor + valproate</td><td>[95]</td></tr><tr><td>Niemann-Pick Disease Type C heterozygous mutations</td><td>NPC1</td><td>1 case with recurrent catatonia and VSGP</td><td>23</td><td>BFCRS</td><td>Lorazepam paradoxal response Treated with ECT</td><td>[97]</td></tr><tr><td>GM2 gangliosidosis</td><td>HEXA</td><td>2 cases: 1 with SSD, 1 with ID</td><td>17; 14</td><td>/</td><td>Lorazepam</td><td>[99,100]</td></tr></table>
<table><caption>Table 1: GENETIC ABNORMALITIES REPORTED IN CATATONIA. With '/' = not available or not relevant; BFCRS= Bush Francis catatonia rating scale; PCRS=pediatric catatonia rating scale; MRS= modified Rogers scale; ABQ= attenuated behavior</caption><thead><tr><th colspan="7">(Tay-Sachs disease)</th></tr></thead><tbody><tr><td>Nonsense variant (SHINE syndrome)</td><td>DLG4</td><td>1 case early onset SSD</td><td>13</td><td>/</td><td>Clonazepam and clozapine</td><td>[161]</td></tr><tr><td>Variant of unknown significance</td><td>KIDINS220</td><td>1 case chronic catatonia in ASD and DI</td><td>18</td><td>/</td><td>Clonazepam</td><td>[7]</td></tr><tr><td>Variant of unknown significance</td><td>SORCS1</td><td>1 chronic catatonia with ASD DI and seizure</td><td>13</td><td>/</td><td>BZD and ECT</td><td>[7]</td></tr><tr><td>Variant of unknown significance</td><td>STAG1<br/>IQGAP3<br/>STARD9<br/>CSMD1<br/>NAA15</td><td>/</td><td>/</td><td>/</td><td>/</td><td>[7]</td></tr><tr><td>2p16.3 deletion</td><td>NRXN1</td><td>Chronic catatonia with ASD DI</td><td>16</td><td>/</td><td>BZD</td><td>[7]</td></tr><tr><td>Kallmann syndrome</td><td>PROK2</td><td>Chronic catatonia in ASD DI seizure and regression</td><td>12</td><td>/</td><td>Lorazepam ECT</td><td>[7]</td></tr><tr><td>18p11.32p11.21</td><td>Multiple + pathogenic variant in TNFRSF13B</td><td>Chronic catatonia and ASD and DT1, hashimoto thyroidisme</td><td>17</td><td>BFCRS</td><td>Lorazepam ECT<br/>Then IVIg, mycocophenolic acid and hydroxychloroquine</td><td>[7]</td></tr><tr><td>Xp22.31 deletion</td><td>PUPD, STS, VCX, PNPLA4</td><td>Chronic catatonia regression and ASD</td><td>17</td><td>/</td><td>Lorazepam and ECT</td><td>[7]</td></tr><tr><td>Cohen Gibson syndrome</td><td>EED</td><td>Catatonia with overgrowth, ID, seizure</td><td>49</td><td>/</td><td>/</td><td>[162]</td></tr><tr><td>Pathogenic variant</td><td>KCNQ1</td><td>Catatonia and psychosis</td><td>15</td><td>/</td><td>Lorazepam</td><td>[163]</td></tr><tr><td>Duplication</td><td>ADCY8</td><td>Catatonia and ASD and psychosis</td><td>16</td><td>/</td><td>Lorazepam and ECT</td><td>[163]</td></tr><tr><td>3p26.3-p26.2 intragenic deletion and 2q21.1 duplication</td><td>CNTN4; GPR39, LYPD1</td><td>Catatonia and mood disorder</td><td>15</td><td>/</td><td>Lorazepam and ECT</td><td>[163]</td></tr><tr><td>mtDNA MELAS</td><td>MT-TL1</td><td>Acute catatonia post "stroke like episode"; acute catatonia and MDD</td><td>41; 17</td><td>DSM-IV</td><td>Lorazepam and haloperidol; escitalopram and methylphenidate</td><td>[107,108]</td></tr></tbody></table>
questionnaire; MC=malignant catatonia; ID = intellectual disability; BP= bipolar disorder; SSD=schizophrenia spectrum
disorder; ASD= autism spectrum disorder; ADHD= attention deficit hyperactive disorder; OCD=obsessional compulsive
disorder; MDD= major depressive disorder; DS= Down syndrome; VSGP=vertical supranuclear gaze palsy;
ECT=electroconvulsive therapy; BZD=benzodiazepines; tDCS=transcranial direct current stimulation, IVIg=intravenous
immunoglobulins
<figure><img src="image_2.png" /><figcaption>Figure 1: Flow Chart</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>**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.</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>Figure 3: GENE NETWORK MAPPING for the 50 variants reported in catatonia</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**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.</figcaption></figure>