Table 3.

Catatonia and genetic anomalies.

Genetic anomaly	Genes implicated	Details	Reference
Recurrent rare copy number variations and chromosomal anomalies
22q11.2 deletion	Multiple	18 reported cases with catatonic features and/or clinically diagnosed catatoniaa	Current study (including 5 previous reports; Table 2)
15q11q13 maternal duplication or maternal UPD Prader-Willi syndrome	Multiple	8 cases: 6 (of 29) cases with 15q11q13 duplication and schizophrenia or other psychotic disorders had catatonia; one adolescent female with psychotic illness, mood disorder, and mild ID with recurrent catatonia responsive to lorazepam and haloperidol (initially) and later to ECT; one adolescent male with psychotic illness responsive to lorazepam and risperidone	[Isles et al., 2016]; [Poser and Trutia 2015]; [Dhossche and Bouman 1997]
Trisomy 21 (Down syndrome)	Multiple	8 cases: 4 adolescents with mood disorders, borderline to severe ID, responsive to benzodiazepines with ECT; 2 adolescent females, one with mood disorder NOS and borderline ID responsive to ECT, one with mood disorder NOS, PDD, severe ID, responsive to lorazepam and fluoxetine; 1 adult female (mosaic type) with depressed mood responsive to ECT; 1 adult male with unspecified psychosis, mood disorder, severe ID responsive to ECT	[Ghaziuddin et al., 2015]; [Jap and Ghaziuddin 2011]; [Jacobs et al., 2016]; [Torr and D’Abrera 2014]; [Breckpot et al., 2016]
22q13.3 deletion	SHANK3	4 cases: 2 adult females with PNOS, severe/profound ID, ASD/PDD, responsive to lorazepam/ECT; 2 brothers with moderate to severe ID clinically diagnosed with Clark-Baraitser syndrome	[Breckpot et al., 2016]; [Tabolacci et al., 2005]
16p11.2 duplication	Multiple	1 case: adult female (typical 600 kb duplication) with schizophrenia, moderate ID, epilepsy, parkinsonism responsive to lorazepam	[Breckpot et al., 2016]
22q11.2 duplication	Multiple	1 case: adult male with schizophrenia, mild ID, epilepsy, and parkinsonism responsive to ECT (typical 3 Mb duplication)	[Breckpot et al., 2016]
Other rare copy number variations
9q34.3 deletions	EHMT1	5 of 5 cases surviving past age 19 years had dramatic behavioral changes in adolescence with psychiatric diagnoses (all with severe ID): “psychosis, bipolar mood disorder and/or autistic catatonia”	[Kleefstra et al., 2009]
14q11.2 duplication	SUPT16H, CHD8	1 case with schizophrenia, moderate ID, and epilepsy, responsive to clozapine	[Breckpot et al., 2016]
Rare single gene variants
Trinucleotide repeat expansion (Huntington’s disease)	HTT	4 cases: Adult female with Westphal variant (juvenile) Huntingon’s disease, psychotic symptoms, responsive to ECT, lorazepam, augmented with amantadine and levodopa; Adult female with psychotic symptoms, mild depression, anxiety, who had become increasingly psychotic and agitated, not eating or bathing, responsive to ECT; Adult male with psychotic symptoms, suicidal ideation, responsive to ECT, lorazepam, antipsychotic, antidepressant treatment; Adolescent male (refused molecular testing; parent with Huntington’s) with schizophrenia	[Merida-Puga et al., 2011] [Magid et al., 2014] [Cusin et al., 2013] [Consoli et al., 2012]
Hexanucleotide repeat expansion	C9orf72	2 cases: Adult male with traumatic brain injury, depression with suicide attempt, responsive to antidepressants, aripiprazole augmentation, lorazepam, and ECT; Adult male with major depression/possible dementia and drug-induced parkinsonism. Notably, this mutation is associated with frontotemporal dementia and ALS.	[Holm 2014]; [Bieniek et al., 2014]
Trinucleotide repeat expansion (Fragile X premutation)	FMR1	1 case: Adult male with bipolar disorder, psychotic symptoms, ADHD, ASD, PDD NOS, OCD, and Tourette syndrome, responsive to benzodiazepines with ECT	[Winarni et al., 2015]
Heterozygous mutations (microdeletion and nonsense)	SHANK3	22q13.3 locus; 2 cases with atypical bipolar disorder, ASD, and severe ID, responsive to lithium carbonate	[Serret et al., 2015]
Missense mutation (homozygosity not assessed)	PRODH	22q11.2 locus; 1 case with schizophrenia and hyperprolinemia, partially responsive to ECT	[Consoli et al., 2012]
Heterozygous missense mutations	KCNT1	9q34.3 locus; Nocturnal frontal lobe epilepsy (ENFL5; OMIM #615005), childhood onset, with reported psychosis and catatonia in some cases	[Heron et al., 2012]
Homozygous missense mutations	HARS	5q31.3 locus; Usher syndrome, type III B (USH3B; OMIM #614504) in Old Order Amish families; several cases with psychosis responsive to antipsychotics, 1 with catatonia	[Puffenberger et al., 2012]
Homozygous nonsense mutation	MMACHC	1p34.1 locus; Methylmalonic aciduria and homocystinuria, cblC type (OMIM #277400; 609831.0003), in 2 unrelated girls from 2 consanguineous South Asian families, one with “catatonic psychotic behavior”, seizures, and mild ID, responsive to cobalamin	[Ben-Omran et al., 2007]
Heterozygous missense mutationa	PRNP	20p13 locus; Fatal familial insomnia (OMIM #600072) prion protein disease in adult (18 y) male with psychotic mood disorder; medications and ECT worsened course	[Dimitri et al., 2006]
Genome-wide linkage to familial periodic catatonia
(No mutations identified)	Uncertain; ?VSP19	15q15 locus; Deemed a schizophrenia susceptibility locus (SCZD10) for chromosome 15q15-related periodic catatonia (OMIM #605419) using linkage evidence from multiplex periodic catatonia families with a further potential locus at 22q13 in these families; VSP19 was proposed as a 15q15 locus candidate gene for schizophrenia and catatonia from de novo variants identified in a trio study	[Stober et al., 2002] [Xu et al., 2012]

Abbreviations: ADHD, attention deficit hyperactivity disorder; ALS, amyotrophic lateral sclerosis; ASD, autism spectrum disorder; ECT, electroconvulsive therapy; ID, intellectual disability; k, kilobase; Mb, megabase; NOS, not otherwise specified; OCD, obsessive compulsive disorder; OMIM, Online Mendelian Inheritance in Man; PDD, pervasive developmental disorder; PNOS, psychotic disorder not otherwise specified; UPD, uniparental disomy

^aPRNP D178N/129 (causative haplotype for fatal familial insomnia involves presence of normal variant M129 in addition to Asp178Asn mutation)