18q Deletion Syndrome-Associated Schizophrenia: A Case Report.

INTRODUCTION: 18q deletion syndrome is a rare genetic disorder characterized by various neurodevelopmental anomalies and medical issues. Although the occurrence of psychosis has been reported in a small number of cases, details regarding the nature of such symptoms and their response to treatment have not been described. CASE PRESENTATION: We describe a 31-year-old male with a history of speech delays, autistic features, a tethered spinal cord, bilateral vertical talus, subaortic stenosis and aortic regurgitation, recurrent otitis media, mild hearing loss, and hypospadias, who experienced a first episode of psychosis in his late 20s. His psychotic symptoms included auditory hallucinations, various delusions, and disorganization of thought. Although his presentation is atypical in certain ways (e.g., exhibiting highly fluctuant symptoms), he nonetheless meets criteria for schizophrenia. Given his overall clinical picture, chromosomal microarray analysis was completed, which revealed a 19.78 Mb deletion at 18q21.32 from nucleotide 58,226,713 to 78,015,180 (GRCh37). Despite exhibiting a somewhat idiosyncratic response to numerous antipsychotic medications, he eventually achieved partial remission of symptoms with improved insight on relatively low dose oral aripiprazole therapy. CONCLUSION: This is the first in-depth description of 18q deletion syndrome-associated schizophrenia. While our patient's atypical presentation and idiosyncratic response to treatment may be mediated by his comorbid diagnosis of autism, his unusual psychiatric phenotype may alternatively be directly related to his underlying genetic disorder. The description of additional cases in the future will hopefully help clarify matters further.

Presenilin Gene Mutation-associated Psychosis: Phenotypic Characteristics and Clinical Implications.

Although psychotic symptoms have been described in association with rare presenilin ( PSEN ) gene mutations underlying early-onset Alzheimer disease (AD), no contemporary reviews on this topic exist. The purpose of this review is to characterize the psychiatric phenotype (specifically with respect to psychosis) of PSEN1 and PSEN2 variant-associated AD. A PubMed search was completed in July 2023. Only articles that described individuals harboring a PSEN1 or PSEN2 mutation who experienced symptoms of psychosis were included in the review. Thirty-three articles describing 52 individuals were included in the review, as well as one other study that provided limited information pertaining to an additional 21 cases. While visual hallucinations were the most common psychotic symptom, followed by persecutory delusions, auditory hallucinations occurred in ~17% of individuals. In ~33% of the reviewed cases psychotic symptoms were present at or near disease onset, and 9 of these individuals experienced auditory hallucinations and/or delusions in the absence of visual hallucinations (~17% of all cases). In many cases, symptoms developed at a relatively young age. As presenilin gene variant-associated psychosis may resemble a primary psychotic disorder, clinicians should be vigilant with respect to screening for signs/symptoms suggestive of neurodegeneration in first-episode psychosis.

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases.

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

Psychosis and autism without functional regression in a patient with Kleefstra syndrome.

Kleefstra syndrome is a rare genetic disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 (EHMT1) gene. It is characterized by a variety of dysmorphic features, comorbid medical issues, and developmental delays/intellectual disability. Neuropsychiatric symptoms may also occur, including autistic features and psychosis, and are often accompanied by functional regression. However, the phenomenology of psychotic symptoms in this syndrome has not been well described in the literature. As such, in this brief report, we review the literature with respect to the occurrence of psychosis in Kleefstra syndrome and describe the symptom profile of a 35-year-old affected male with an intellectual disability, autism spectrum disorder, and schizophrenia (in association with manic features). This is the first report of psychotic symptoms fully remitting in response to zuclopenthixol therapy in an individual with Kleefstra syndrome. This case is also unique as it demonstrates that functional regression does not necessarily coincide with the development of schizophrenia-like presentations in affected individuals.

A 1p31.3 deletion encompassing the nuclear factor 1A gene presenting as possible temporal lobe epilepsy in association with schizoaffective disorder.

Chromosome 1p32-p31 deletion syndrome, which is characterized by a variety of neurodevelopmental abnormalities, is thought to occur as a result of nuclear factor 1A (NFIA) haploinsufficiency. We present a case of a right-handed 40-year-old female with a 1p31.3 deletion, who exhibited numerous common features of this syndrome, in addition to treatment resistant schizoaffective disorder and possible temporal lobe epilepsy, making her presentation unique. While neither psychosis nor temporal lobe epilepsy has been described in this syndrome previously, these conditions likely occurred in our patient as a result of NFIA haploinsufficiency.

The characterization of psychotic symptoms in succinic semialdehyde dehydrogenase deficiency: a review.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an ultra-rare inborn error of metabolism that results in disrupted gamma-amino butyric acid (GABA) catabolism. In addition to developmental delay, intellectual disability, hypotonia, ataxia, and seizures, a variety of neuropsychiatric symptoms may occur, including psychosis. By highlighting all available and relevant case reports/series, this qualitative review seeks to characterize the prevalence, clinical manifestation, pathophysiology, and treatment of psychotic symptoms in this population. Psychosis occurs in a minority of SSADH-deficient individuals, and most commonly presents as auditory or visual hallucinations with an onset in adolescence or young adulthood. Although the pathophysiology underlying the development of psychosis in this context is not fully understood, it likely in part relates to increased GABA and/or gamma hydroxybutyric acid activity. Although antipsychotic medications should be used cautiously in SSADH deficiency, they may be effective at treating emergent psychotic symptoms.

Psychosis in Later Life: A Review and Update.

Psychosis is relatively common in later life and can present in a wide variety of contexts, including early-onset and late-onset schizophrenia, delusional disorder, mood disorders, and various dementias. It can also occur as the result of numerous medical and neurological diseases and from the use of certain medications. Although identifying the cause of psychosis in older patients can be challenging, the unique clinical features associated with the different disorders can help in making the diagnosis. Accurate diagnosis of psychosis in older populations is essential, as its treatment varies depending on the context in which it appears. Despite the safety concerns regarding the use of antipsychotics in older patients, certain pharmacological treatments appear to be both efficacious and reasonably safe in treating psychosis in older populations. Additionally, although research is limited, numerous psychosocial therapies appear promising. This review summarizes the literature on the epidemiology, clinical characteristics, neuroimaging, and treatment of psychosis in later life, and serves as an update to past reviews on this topic.

Amyloid and Tau Biomarkers in Subjective Cognitive Impairment.

Subjective cognitive impairment (SCI) refers to concerns regarding one's cognitive functioning in the absence of objective evidence of impairment, and may represent an early stage of Alzheimer's disease. However, as not all individuals with SCI cognitively decline, there is growing interest in the early identification of those individuals with SCI who are most at risk of developing Alzheimer's disease. One promising method of early identification involves the use of biomarkers that are known to be associated with the pathophysiology of the disease; in particular, markers of amyloid and tau accumulation. While there has been substantial research on amyloid and tau biomarkers in the context of mild cognitive impairment (MCI), only recently has attention shifted to SCI, which may represent an even earlier stage in the disease course. The purpose of this paper is to qualitatively review the literature on amyloid and tau biomarkers in SCI. A brief discussion of non-amyloid/tau biomarkers is also included. Not surprisingly, we found that amyloid and tau biomarker profiles become increasingly abnormal from SCI, to MCI, to Alzheimer's disease. Additionally, although amyloid and tau biomarkers appear to be unable to differentiate between SCI and healthy controls, there is some evidence to suggest that they may be able to differentiate between those individuals with SCI who cognitively decline over time and those who do not. While this finding has potential clinical implications, achieving optimal predictive value will likely require further research into the use of numerous biomarkers in combination.

Pathways to care for those at clinical high risk of developing psychosis.

AIM: Understanding the pathways to care is a prerequisite for early detection in first-episode patients with psychosis. Less in known about the pathways to care for individuals at clinical high risk for psychosis. METHODS: A sample of 35 clinical high risks for psychosis individuals were administered a semistructured questionnaire inquiring about pathways to care. RESULTS: The majority of contacts were made to general practitioners (32.8%). Various symptoms of concern were reported among the sample, the most common being depression (15.9%) followed by anxiety (11.0%). Delusions/paranoia were the most frequent symptoms associated with successful referral to contacts (14.3%). CONCLUSION: Education on the pathway to successful access to care and treatment in a putatively prodromal for psychosis group of individuals is valuable information that can potentially aid in a faster discovery of these individuals and their access to treatment and care.

The course of cognitive functioning over six months in individuals at clinical high risk for psychosis.

Cognitive impairment is common in psychosis and has recently been observed in individuals at clinical high risk (CHR) of developing psychosis. The purpose of this study was to characterize longitudinal change in cognition among CHR individuals, and compare cognition of CHR individuals who later convert to psychosis to that of CHR who do not convert. Participants were tested at baseline and followed-up after six months using a comprehensive cognitive test battery. Individuals who did not convert to psychosis either remained stable or significantly improved in their cognitive performance. At baseline participants who converted to psychosis compared to non-converters exhibited poorer performance in several cognitive tests, suggesting that some cognitive impairment is already present before conversion. Future longitudinal research should address if further decline takes place during the prodrome or after conversion to psychosis.

Investigating the role of substance P in photic responses of the circadian system: individual and combined actions with gastrin-releasing peptide.

The suprachiasmatic nucleus (SCN) contains the master mammalian circadian pacemaker. It is comprised of several phenotypically distinct cell groups, some of which are situated in the weakly rhythmic retinoresponsive ventrolateral region while others are found in the rhythmic, non-retinoresponsive dorsomedial region. The mechanism by which retinorecipient cells convey photic information to the dorsomedial clock cells is unclear. The ventrolateral SCN core contains a variety of cell phenotypes. Two neuropeptides, namely substance P (SP) and gastrin-releasing peptide (GRP) extensively colocalize with calbindin D28K, a marker for SCN cells that are strongly light-responsive. Previous studies have implicated these neuropeptides in photic phase shifting of the circadian system. The present study examines how these peptides interact to regulate photic responses of the circadian system. It was observed that 55.5 +/- 9.1% of SP cells colocalized GRP. SP did not enhance GRP-induced phase shifts in the early-subjective night, while it significantly attenuated GRP-induced phase shifts during the late-subjective night. SP induced significant phase shifts that did not resemble light in the early-subjective night, but was not necessary for light-induced phase shifts and Fos expression at this time. SP induced significant Fos expression only in the late subjective night. SP may not be a necessary component in the pathway(s) involved in photic phase shifting during the early-subjective night, but may modulate phase shifts during the late-subjective night. Distinct biochemical mechanisms that underlie behavioral phase shifts may account for the differences observed in the early- vs. late-subjective night.