Catatonia is a neuropsychiatric disorder characterized by motor, behavioral and autonomic abnormalities, historically linked to mood and psychotic disorders but increasingly recognized across a wide spectrum of medical and neurological conditions. While well-described, the mechanisms underlying catatonia remain poorly understood. While often considered treatable with benzodiazepines, electroconvulsive therapy (ECT) and N-methyl-D-aspartate (NMDA) antagonists, catatonia remains underdiagnosed leading to life-threatening complications (1).

In pediatric populations, catatonia is rare and may follow a distinct clinical course. Presentations can include acrocyanosis, automatic compulsive movements, schizophasia, regression of previously acquired skills or communicative abilities and urinary incontinence (2). Prolonged and treatment-refractory catatonia has a strong association with schizophrenia, autism spectrum disorder and other neurodevelopmental disorders (3, 4). Importantly, genetic contributions appear especially relevant in youth. In the largest pediatric case series to date, Raffin et al. reported a high prevalence of underlying genetic conditions among children and adolescents with catatonia, underscoring the need to consider genetic testing early in complex or atypical presentations (5). Genetic underpinnings of catatonia are beginning to be explored, with emerging reports linking variants in synaptic signaling (particularly GABAergic transmission), mitochondrial function and neurodevelopmental pathways to catatonic presentations (6).

There is no universally accepted definition of chronic or prolonged catatonia. Most available data are limited to case reports, in which symptom duration have been greater than 30 days (7). Here, we describe an adolescent with profound and prolonged catatonia spanning months and progressive neurological decline, including prolonged mutism, functional regression, and retrograde amnesia, following a brief psychotic episode. The patient’s worsening presentation and diagnostic odyssey spanned five years before she showed significant improvement with a combination of memantine, oxcarbazepine and ECT. After extensive diagnostic workup, a de novo likely pathogenic variant in SIK1 was identified through trio-based clinical exome sequencing. SIK1 (Salt-Inducible Kinase 1) encodes a serine/threonine kinase critical in neuronal development including neurogenesis, dendritic growth and synaptic plasticity. Pathogenic variants in SIK1 are linked to a rare autosomal dominant early infantile epileptic encephalopathy, marked by early-onset refractory seizures, severe developmental delay, hypotonia and intellectual disability, and early death (MIM:616341) (8). Later-onset cases show global impairment, absent speech, poor eye contact, inability to walk, behavioral manifestations, and feeding tube dependence (9). This case illustrates the importance of considering genetic contributions in refractory neuropsychiatric presentations and highlights the role of multidisciplinary, precision-guided approaches in care.

This case describes an adolescent who developed severe, treatment-refractory catatonia with progressive neurological decline over five years following a brief, acute psychotic episode following a prodromal period with disorganized behavior and restricted, stereotyped interests. Her atypical presentation marked by prolonged mutism, function loss, and retrograde amnesia, unresponsive to standard therapies, showed dramatic but incomplete improvement with a combination of memantine, oxcarbazepine, and electroconvulsive therapy (ECT).

Over the years, Taylor received a wide range of diagnoses — many likely inaccurate — including schizophrenia, autism spectrum disorder, traumatic brain injury, selective mutism and catatonia, with only minimal improvement. The chronicity and refractoriness of her catatonic presentation prompted consideration of a broad differential diagnosis encompassing but not limited to primary psychiatric illness, especially since up to 20% of pediatric catatonia cases are secondary to medical conditions (15) and often have specific treatments (16, 17). Medical etiologies for her catatonia including structural abnormalities, epileptic, autoimmune, infectious, metabolic and toxicological causes were extensively worked-up, with no diagnostic evidence other than transient and partial recovery with immunologic therapies and antiepileptic agents. Psychiatrically, her course raised consideration of schizophrenia and autism spectrum disorder, but also less common syndromes such as pervasive refusal syndrome (PRS) and neurodevelopmental disorder with regression and abnormal movements, loss of speech and seizures (NEDAMSS). Pervasive refusal syndrome has been described in youth with severe functional decline, the core features of refusal across multiple domains (eating, mobilizing, communicating) typically emerge in the context of psychological stressors (commonly reported among asylum seekers) and without the neurological signs or fluctuating response to pharmacologic and neuromodulating interventions observed here (18). However, given the overlapping features of mutism, immobility, and withdrawal, some experts argue that PRS is better understood as a misnomer for catatonia rather than a distinct syndrome (18). Similarly, NEDAMSS, a recently described genetic disorder linked to IRF2BPL variants and characterized by developmental regression, movement abnormalities, and profound speech loss with phenotypic overlap with our patient’s course but different genetic variants (19). Taken together, these comparisons underscore the diagnostic complexity and highlight the need for careful longitudinal assessment before attributing catatonia solely to a primary psychiatric disorder, as well as consideration of neurodevelopmental and genetic etiologies, particularly given the high rates of pathogenic variants reported in pediatric catatonia (5).

Based on recent clinical exome sequencing, our current understanding is that her catatonia is secondary to a late-onset autism spectrum disorder, likely associated with a pathogenic variant in SIK1, potentially explaining her incomplete and transient response to multiple treatment regimens. Notably, Taylor’s most sustained improvement followed treatment with oxcarbazepine, raising the possibility that subclinical epileptiform activity underlies aspects of her catatonia. Taylor’s variant (NM 173354.5:c.1760G>A, p.Arg587Gln) has not been previously reported in affected individuals. It is absent in large germline population studies (gnomAD v4.1.0), though sequencing coverage at that position is limited. The substitution occurs at a moderately conserved position, and computational analyses suggest it may impact protein function. With both parents showing normal sequences at this locus, it is considered a de novo candidate variant to contribute to her presentation.

Pathogenic SIK1 variants are most often described in early-onset epileptic encephalopathy, though later-onset cases with broader neurodevelopmental impairment and behavioral features are also briefly mentioned in the literature but remain poorly characterized (8, 9). Using GeneMatcher (20), an online platform that connects clinicians and researchers sharing rare genetic variants, we identified nine global cases with SIK1 pathogenic variants presenting atypically; none matched Taylor’s exact variant or symptoms. Across these reports, phenotypes were heterogeneous but generally included neurodevelopmental delay, seizures or abnormal EEG findings, and motor and speech impairment. One patient had autism and “staring spells” with abnormal but non-epileptic EEG, and another had speech delay, mild intellectual disability, and facial dysmorphisms. To our knowledge, catatonia has not previously been associated with SIK1 variants, suggesting that Taylor’s presentation may expand the recognized phenotypic spectrum. Nonetheless, causality cannot be inferred from a single case.

Beyond being a diagnostic odyssey with hope for a meaningful recovery, Taylor’s case highlights the clinical utility of genomic diagnostics in psychiatric diagnosis and treatment, and underscores the need for sustained, multidisciplinary advocacy in complex neuropsychiatric care.

Genetic findings may contribute important insights in diagnostically complex psychiatric presentations by clarifying underlying etiologies. Though the mechanistic pathways remain unclear, this case highlights the value of integrating early genetic testing into diagnostic workup for atypical first break psychosis, particularly when catatonic features are present. In youth with neurodevelopmental disorders, catatonia is often atypical and refractory to benzodiazepines, with emerging evidence supporting the efficacy of ECT in such cases (3). For Taylor, identification of a candidate variant in SIK1 suggests a previously unrecognized neurodevelopmental etiology, suggesting that earlier trials of antiepileptic, glutamatergic agents, or ECT may have been beneficial. This is especially relevant in pediatric psychiatry, where atypical presentations often defy conventional categories. As exome sequencing becomes more accessible, it may help clarify etiology, inform treatment selection, and challenge the divide between “functional” and “organic” disorders, ushering in a more personalized era of psychiatric care.

Perhaps most critically, this case illustrates the consequences of fragmented care and premature diagnostic closure. Across top institutions, opportunities for coordinated, multidisciplinary oversight were repeatedly missed. Neurology teams repeatedly disengaged after ruling out primary structural or autoimmune disease. Outpatient psychiatrists were uncomfortable managing her case and medications. One provider, assuming her catatonia was secondary to schizophrenia, discontinued medications that had supported her functional recovery. Despite Herculean persistence from her family, it took years to reach a working diagnosis and initiate effective treatment. Taylor’s case is a stark reminder of the need for multidisciplinary persistence – bridging psychiatry, neurology and genetics– in complex cases where siloed care delays diagnosis, worsens symptoms, and leads to preventable decline.

Taylor and her family are encouraged by the meaningful progress she has made in recent months through a combination of pharmacotherapy and ECT. As described in the case, Taylor had been in a state of stupor for over three years, with no recollection of events since her steep cognitive decline began in 2021. When she emerged from this state at the age of 18, Taylor believes she was still 15. Since then, she has expressed renewed self-direction including a desire to finish high school and go to college. She enjoys activities including shopping, listening to music and singing. She has regained her happy disposition. However, it is apparent that her cognitive and motor functions are not at baseline: her processing and responses delayed, her actions slowed, her posture stooped with a hunched back and forward head, and her gait shuffling. These symptoms, along with intermittent stereotypies, become more pronounced in the week leading to her next ECT treatment, and remain present even on her best days.

The family has been very intrigued by the genetic findings discussed in this report, and wonders whether seizures, even undetected in prior video EEGs, may contribute to her condition. Their journey continues with regular maintenance ECT, continued adjustment of psychopharmacotherapies, and multidisciplinary support including physical, occupational and speech therapy.

This case illustrates the complexity of pediatric catatonia, a syndrome increasingly recognized as arising from diverse medical and genetic etiologies rather than solely primary psychiatric disorders. In this context, we identified a de novo likely pathogenic SIK1 variant that may contribute to the patient’s phenotype and represents, to our knowledge, the first reported expansion of the SIK1 spectrum to include catatonia. The case also underscores the importance of sustained multidisciplinary follow-up across psychiatry, neurology, and genetics in complex diagnostic presentations to optimize outcomes and guide management.