Whole-genome sequencing analysis of clozapine-induced myocarditis.

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

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.

Subjective cognitive functioning, depressive symptoms, and objective cognitive functioning in people with treatment-resistant psychosis.

Introduction: Relationships between subjective cognitive functioning (SCF), objective cognitive functioning (OCF), and depressive symptoms are poorly understood in treatment-resistant psychosis (TRP). This study (a) compares SCF in TRP using positively and negatively worded scales, (b) assess these scales' accuracy, and (c) explores the association between these scales and depressive symptoms. We hypothesised that both SCF scales would be highly correlated, minimally associated with OCF, and similarly associated with depressive symptoms. Methods: Archival clinical data from 52 TRP inpatients was utilised. OCF composite scores were derived from a broad neuropsychological battery. SCF was assessed using the norm-referenced PROMIS 2.0 Cognitive Abilities (positively worded) and Concerns (negatively worded) subscales. A depressive symptom score was derived from the Positive and Negative Syndrome Scale. Results: SCF ratings were higher in patients than OCF. There was a small but significant correlation between PROMIS subscales (r = .30). Neither PROMIS subscale was associated with OCF (r = -.11, r = .01). Depressive symptoms were correlated with the positively (r = -.29) but not negatively worded scale (r = -.13). Conclusion: Individuals with TRP inaccurately rate their cognitive functioning and tend to overestimate their ability. Positively and negatively worded SCF scales associate variably with depressive symptoms, indicating they may not be used interchangeably in TRP.

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

Clinical and biochemical footprints of inherited metabolic diseases. III. Psychiatric presentations.

Psychiatric symptoms are common manifestations in many inborn errors of metabolism (IEMs), ranging from attention deficit, anxiety and mood and behavioral disorders to psychosis. Furthermore, IEMs represent a significant percentage of all autism cases. We reviewed and updated the list of metabolic disorders known to be associated with various psychiatric manifestations and found more than 100 relevant IEMs. This represents the third of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Pediatric polysomnography-A review of indications, technical aspects, and interpretation.

Polysomnography is an elaborate diagnostic test composed of numerous data-collecting sensors working concomitantly to aid in the evaluation of varied sleep disorders in all age groups. Polysomnography is the study of choice for the assessment of pediatric sleep-disordered breathing, including obstructive sleep apnea syndrome, central apnea, and hypoventilation disorders, and is used to help determine treatment efficacy. Beyond the purview of snoring and breathing pauses, polysomnography can elucidate the etiology of hypersomnolence, when associated with a multiple sleep latency test, and abnormal movements or events, whether nocturnal seizure or complex parasomnia, when a thorough patient history cannot provide clear answers. This review will highlight the multitudinous indications for pediatric polysomnography and detail its technical aspects by describing the multiple neurophysiologic and respiratory parametric sources. Knowledge of these technical aspects will provide the practitioner with a thoughtful means to understand the limitations and interpretation of polysomnography.

A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8.

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.

LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency.

Lipoic acid is an essential cofactor for the mitochondrial 2-ketoacid dehydrogenase complexes and the glycine cleavage system. Lipoyltransferase 1 catalyzes the covalent attachment of lipoate to these enzyme systems. Pathogenic variants in LIPT1 gene have recently been described in four patients from three families, commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes. We report a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease. Exome sequencing implicated compound heterozygous LIPT1 pathogenic variants. We describe the fifth case of LIPT1 deficiency, whose phenotype progressed to that of an early infantile epileptic encephalopathy, which is novel compared to previously described patients whom we will review. Due to the significant biochemical and phenotypic overlap that LIPT1 deficiency and mitochondrial energy cofactor disorders have with pyruvate dehydrogenase deficiency and/or nonketotic hyperglycinemia, they are and have been presumptively under-diagnosed without exome sequencing.

Virtual twins for model-informed precision dosing of clozapine in patients with treatment-resistant schizophrenia.

Model-informed precision dosing using virtual twins (MIPD-VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD-VT approach (Simcyp version 21), we predicted the steady-state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment-resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD-VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2 ) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady-state clozapine concentrations were overpredicted two to four-fold. This work supports the application of a high virtualization MIPD-VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug-drug interactions, particularly with fluvoxamine augmentation.

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.

Deep Brain Stimulator (DBS) Artifact in the EEG of a Pediatric Patient.

We report the first case of deep brain stimulator (DBS) artifact in the EEG of a pediatric patient. Our case is a 7-year-old male with bilateral globus pallidus interna (GPi) DBS for whom the EEG recorded a rhythmic 7.5 Hz theta activity on EEG related to DBS artifact. This artifact was also appreciated as a monochromatic invariable frequency band over 7.5 Hz on density spectral array (DSA). This rhythmic artifact may mimic an ictal pattern and should be recognized as artifact in order to avoid unnecessary treatment with anti-seizure medications (ASM).

Patient Pain and Satisfaction With 10, 30, and 70 mL Transcervical Foley Balloons for Cervical Ripening During Induction of Labor.

Objective To assess patient pain and satisfaction and time to delivery following transcervical Foley catheter balloon inflation to 10, 30, or 70 mL with simultaneous administration of oxytocin. Methods We performed a randomized prospective study with 30 or 70 mL transcervical Foley balloon catheters in combination with oxytocin during labor induction at term. A 10 mL group was included as a sham control group. Time to delivery was measured, and a patient questionnaire was administered at the time the catheter was expelled to determine patient pain and satisfaction. Results In 120 enrolled patients, there was a non-significant trend toward reduced time to delivery in the large Foley balloon group (10 mL: 30:45 ± 38:53, 30 mL: 26:41 ± 20:53, and 70 mL 22:40 ± 15:35, hh:mm, P = 0.412). The pain score at the time the balloon was expelled was significantly higher in the 70 ml group compared to the 10 ml and 30 ml groups (P = 0.004 and P = 0.034, respectively). We found no other differences in patient satisfaction or pain scores at the time of placement of the Foley catheter for the three groups. Conclusion Small gains in time to delivery should be balanced against patient experiences, and expectations of pain during the ripening process should be addressed at the time of Foley insertion.

Polysomnographic predictors of abnormal brainstem imaging in children.

STUDY OBJECTIVES: Evaluation of elevated central apnea-hypopnea index (CAHI) or prolonged central apneas in pediatric patients typically includes neuroimaging with a focus on brainstem pathology. There is little evidence guiding thresholds of polysomnographic variables that accurately predict abnormal neuroimaging. We sought to evaluate whether additional polysomnographic variables may help predict brainstem pathology. METHODS: A 10-year retrospective review of patients ages 1-18 years who received a brain magnetic resonance imaging (MRI) for an indication of central sleep apnea diagnosed via polysomnography was performed. Demographics, medical history, polysomnogram variables, and MRI results were compared. RESULTS: This study included 65 patients (69.2% male). The median age was 5.8 years (interquartile range, 3.0-8.3). Most patients had negative (normal or nonsignificant) MRIs (n = 45, 69.2%); 20 (30.8%) had abnormal MRIs. Of the patients with abnormal MRIs, 13 (20.0%) had abnormalities unrelated to the brainstem. Seven patients (10.8%) were found to have brainstem pathology and had a median CAHI of 10.8 events/h (interquartile range, 6.5-21.9), and three of seven (42.9%) had hypoventilation and were more likely to have developmental delay, abnormal neurological examinations, and reflux. Other patients (n = 58) had a median CAHI of 5.6 events/h (interquartile range, 3.1-9.1), and seven (12.1%) had hypoventilation. Area under the curve and receiver operating characteristic curves showed a CAHI ≥ 9.5 events/h and ≥ 6.4% of total sleep time with end-tidal CO2 ≥ 50 mm Hg predicted abnormal brainstem imaging. Prolonged central apneas did not predict abnormal brainstem imaging. CONCLUSIONS: Most patients with central sleep apnea do not have MRIs implicating structurally abnormal brainstems. Utilizing a cutoff of CAHI of ≥ 9.5 events/h, ≥ 6.4% total sleep time with end-tidal CO2 ≥ 50 mm Hg and/or frank hypoventilation, and additional clinical history may optimize MRI utilization in patients with central sleep apnea.

A novel description of converting a gastric plication to sleeve gastrectomy for weight loss: A case report.

INTRODUCTION: Bariatric surgery is a rapidly growing field with trends and standards of care changing more rapidly than most. Gastric plication was once an exciting novel procedure which showed promise, however it has fallen out of favor for other procedures such as the sleeve gastrectomy. Existing literature on the surgical conversion of a gastric plication to a sleeve gastrectomy does not provide specific details on the operative technique of this rarely encountered operation. CASE REPORT: In this case report we describe a morbidly obese female who presented weight gain after laparoscopic gastric plication and gastric banding. We provide the operative technique involved in conversion to a laparoscopic sleeve gastrectomy. CONCLUSION: This case provides specific operative technique with detailed media for the conversion of gastric plication to LSG.

Sleep Abnormalities in the Synaptopathies-SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome.

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children's Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies-Phelan-McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1-46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1-64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1-17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders.

Postnatal expression of GAD67.

N-methyl-D-aspartate receptor blockade promotes apoptosis at postnatal day 7 (P7) and is linked to loss of glutamic acid decarboxylase 67 (GAD67) expression in older animals. To more fully appreciate this relationship we must first understand how GAD67 is regulated postnatally. Thus, the brains of P7, P14 and P21 rats were examined for expression of GAD67 protein and we found that levels of this GABAergic marker increased steadily with age, such that by P21 there was as much as a 6-fold increase compared to P7 animals and a 1.5- to 2-fold increase compared to P14 animals, depending on the region sampled. At P7, GAD67 was almost exclusively detected in puncta, with very few cell bodies displaying this marker. In contrast, at P14 and especially P21, both puncta and cell bodies were robustly labeled. Our data indicate that adult-like expression of GAD67 emerges quite late in the postnatal period.

Postnatal exposure to MK801 induces selective changes in GAD67 or parvalbumin.

Brain injury during the last trimester to the first 1-4 years in humans is now thought to trigger an array of intellectual and emotional problems later in life, including disorders such as schizophrenia. In adult schizophrenic brains, there is a specific loss of neurons that co-express glutamic acid decarboxylase-parvalbumin (GAD67-PV). Loss of this phenotype is thought to occur in mature animals previously exposed to N-methyl-D: -aspartate receptor (NMDAR) antagonists during late gestation or at postnatal day 7 (P7). However, in similarly treated animals, we have previously shown that GAD67 and PV are unaltered in the first 24 h. To more precisely define when changes in these markers first occur, we exposed rat pups (P7 or P6-P10) to the NMDAR antagonist MK801 and at P11 co-stained brain sections for GAD67 or PV. In the cingulate cortex, we found evidence for a reduction in PV (GAD67 levels were very low to undetectable). In contrast, in the somatosensory cortex, we found that expression of GAD67 was reduced, but PV remained stable. Further, repeated but not single doses of MK801 were necessary to see such changes. Thus, depending on the region, NMDAR antagonism appears to influence expression of PV or GAD67, but not both. These observations could not have been predicted by previous studies and raise important questions as to how the GAD67-PV phenotype is lost once animals reach maturity. More importantly, such differential effects may be of great clinical importance, given that cognitive deficits are seen in children exposed to anesthetics that act by blocking the NMDAR.

A case of persistent visual hallucinations of faces following LSD abuse: a functional Magnetic Resonance Imaging study.

In this study, we report the case of a patient experiencing hallucinations of faces that could be reliably precipitated by looking at trees. Using functional Magnetic Resonance Imaging (fMRI), we found that face hallucinations were associated with increased and decreased neural activity in a number of cortical regions. Within the same fusiform face area, however, we found significant decreased and increased neural activity according to whether the patient was experiencing hallucinations or veridical perception of faces, respectively. These findings may indicate key differences in how hallucinatory and veridical perceptions lead to the same phenomenological experience of seeing faces.

First Whole Transcriptome RNAseq on CHD8 Haploinsufficient Patient and Meta-Analyses Across Cellular Models Uncovers Likely Key Pathophysiological Target Genes.

In 2019, we confirmed that the haploinsufficiency of CHD8 does indeed cause the novel syndromic neurodevelopmental disease we first discovered a dozen years before. Here, we report the first whole transcriptome RNAseq gene expression profiling for a patient with this new syndrome, as a preliminary exploration of potential pathophysiological mechanisms. We compared our patient transcriptome profile with that of all publicly available RNAseq datasets from human cellular models including neuronal progenitor cells, neurons and organoids. We compared differential gene expression profiles overall and conducted phenotype-informed data filtration based on the characteristic syndrome presentation. We found that concordance among differential gene expression profiles was poor across all datasets. Nevertheless, remarkably, we show that the patient blood differential gene expression profile most resembled that of the neuronal cell model, a finding that encourages further transcriptome profiling using patient blood samples. In addition, our custom phenotype-informed analyses yielded important, differentially expressed syndrome pathophysiology target genes. Finally, we note that genes dysregulated due to CHD8 heterozygous deletion are linked to known neurological as well as oncological pathways.