Ocular features of NGLY1 deficiency from a prospective longitudinal cohort.

BACKGROUND: NGLY1 deficiency is a rare autosomal recessive disorder with core features of global developmental delay, liver enzyme abnormalities, movement disorder, polyneuropathy, and hypo- or alacrima. We characterized the full spectrum and evolution of the ocular phenotype in a prospective natural history of NGLY1 deficiency. METHODS: We collected ophthalmological data on 29 individuals with NGLY1 deficiency in a natural history study. Medical records were reviewed to confirm caregiver-reported symptoms. Of the 29, 15 participants appeared for at least one ophthalmological examination. RESULTS: Caregivers reported at least one ocular sign or symptom in 90% of participants (26/29), most commonly decreased tears, refractive error, and chronic infection. Daily eye medication, including artificial tears, ophthalmic ointment, and topical antibiotics were used by 62%. Ophthalmological examination confirmed refractive errors in 93% (14/15) and corneal abnormalities in 73% (11/15). CONCLUSIONS: Given nearly universal hypolacrima and additional prominent ocular findings in NGLY1 deficiency, a targeted ocular history and ophthalmologic examination may facilitate prompt diagnosis and early initiation of preventive eye care, preserving vision and overall ocular health.

De novo FRMD5 Missense Variants in Patients with Childhood-Onset Ataxia, Prominent Nystagmus, and Seizures.

BACKGROUND: FRMD5 variants were recently identified in patients with developmental delay, ataxia, and eye movement abnormalities. OBJECTIVES: We describe 2 patients presenting with childhood-onset ataxia, nystagmus, and seizures carrying pathogenic de novo FRMD5 variants. Weighted gene co-expression network analysis (WGCNA) was performed to gain insights into the function of FRMD5 in the brain. METHODS: Trio-based whole-exome sequencing was performed in both patients, and CoExp web tool was used to conduct WGCNA. RESULTS: Both patients presented with developmental delay, childhood-onset ataxia, nystagmus, and seizures. Previously unreported findings were diffuse choreoathetosis and dystonia of the hands (patient 1) and areas of abnormal magnetic resonance imaging signal in the white matter (patient 2). WGCNA showed that FRMD5 belongs to gene networks involved in neurodevelopment and oligodendrocyte function. CONCLUSIONS: We expanded the phenotype of FRMD5-related disease and shed light on its role in brain function and development. We recommend including FRMD5 in the genetic workup of childhood-onset ataxia and nystagmus. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

What Have Organoids and Assembloids Taught Us About the Pathophysiology of Neuropsychiatric Disorders?

Neuropsychiatric research has been impeded by limited access to human brain tissue, especially from early stages of neurodevelopment when the pathophysiology of many childhood-onset disorders is initiated. Neural organoids are 3-dimensional, self-organizing, multicellular structures generated from pluripotent stem cells that recapitulate some of the cell diversity, cytoarchitecture, and functional features of domains of the developing nervous system. Assembloids are 3-dimensional, self-organizing cultures created by the combination of two or more distinctly patterned organoids or an organoid plus additional cell or tissue type(s) that are used to model cell migration and connectivity. Here we review recent advances in neuropsychiatric disorder research using organoid and assembloid models to study the role of disease-relevant genes and mutations, as well as the impact of environmental risk factors on neural development. We also highlight some of the advantages and limitations of these model systems in bringing insights into the pathophysiology of neuropsychiatric disorders.

A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder.

BACKGROUND: CACNA1C encodes the voltage-gated L-type calcium channel CaV1.2. A specific gain-of-function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relates to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development. METHODS: Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher exact test for comparison of categorical variables between participants with and without cardiac arrhythmia. RESULTS: Twenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention-deficit/hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia. CONCLUSIONS: In our CRD cohort, there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.

Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.

Delineating the epilepsy phenotype of NGLY1 deficiency.

We delineated the phenotypic spectrum of epilepsy in individuals with NGLY1 deficiency from an international cohort. We collected detailed clinical and electroencephalographic data from 29 individuals with bi-allelic (likely) pathogenic variants in NGLY1 as part of an ongoing prospective natural history study. Participants were evaluated in-person at a single center and/or remotely. Historical medical records were reviewed. Published cases were included for comprehensive phenotyping. Of 29 individuals (mean 11.4 years, range 3-27 years), 17 (58.6%) participants had a history of epilepsy. Seizure onset was in early childhood (mean 43 months, range 2 months to 19 years). The most common seizure types were myoclonic and atonic. Epilepsy course was variable, but 35.2% (6/17) of participants with epilepsy achieved seizure freedom. The most common medications included levetiracetam, valproate, lamotrigine, and clobazam. Electroencephalogram (EEGs) were abnormal in 80% (12/15) of participants with or without epilepsy, although encephalopathy was uncommon. There was a trend in neurodevelopmental outcomes that participants with epilepsy had more developmental delays. In summary, epilepsy is common in NGLY1 deficiency. Over half of the participants had a history of epilepsy and nearly all had EEG abnormalities indicating an increased risk of epilepsy. This work expands the electroclinical phenotype of NGLY1 deficiency and supports a high clinical suspicion for seizures. Some of the more common seizure types (epileptic spasms, myoclonic, and atonic seizures) can be subtle and require counseling to ensure early recognition and treatment to ensure the best possible outcomes. Despite transient liver enzyme abnormalities in this disorder, hepatically metabolized medications were well tolerated.

Evaluation of Seizure Risk in Infants After Cardiopulmonary Bypass in the Absence of Deep Hypothermic Cardiac Arrest.

BACKGROUND: Guidelines recommend evaluation for electrographic seizures in neonates and children at risk, including after cardiopulmonary bypass (CPB). Although initial research using screening electroencephalograms (EEGs) in infants after CPB found a 21% seizure incidence, more recent work reports seizure incidences ranging 3-12%. Deep hypothermic cardiac arrest was associated with increased seizure risk in prior reports but is uncommon at our institution and less widely used in contemporary practice. This study seeks to establish the incidence of seizures among infants following CPB in the absence of deep hypothermic cardiac arrest and to identify additional risk factors for seizures via a prediction model. METHODS: A retrospective chart review was completed of all consecutive infants ≤ 3 months who received screening EEG following CPB at a single center within a 2-year period during 2017-2019. Clinical and laboratory data were collected from the perioperative period. A prediction model for seizure risk was fit using a random forest algorithm, and receiver operator characteristics were assessed to classify predictions. Fisher's exact test and the logrank test were used to evaluate associations between clinical outcomes and EEG seizures. RESULTS: A total of 112 infants were included. Seizure incidence was 10.7%. Median time to first seizure was 28.1 h (interquartile range 18.9-32.2 h). The most important factors in predicting seizure risk from the random forest analysis included postoperative neuromuscular blockade, prematurity, delayed sternal closure, bypass time, and critical illness preoperatively. When variables captured during the EEG recording were included, abnormal postoperative neuroimaging and peak lactate were also highly predictive. Overall model accuracy was 90.2%; accounting for class imbalance, the model had excellent sensitivity and specificity (1.00 and 0.89, respectively). CONCLUSIONS: Seizure incidence was similar to recent estimates even in the absence of deep hypothermic cardiac arrest. By employing random forest analysis, we were able to identify novel risk factors for postoperative seizure in this population and generate a robust model of seizure risk. Further work to validate our model in an external population is needed.

Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.

We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

A Case of Abulia From Left Middle Cerebral Artery Stroke in an Adolescent Treated Successfully With Short Duration Olanzapine.

INTRODUCTION: Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower. It presents with a challenging array of overlapping symptoms, making effective identification and treatment difficult. CASE PRESENTATION: We describe the first known report of an adolescent with a ventricular assist device who developed abulia following a left middle cerebral artery (MCA) stroke who responded successfully to treatment with olanzapine. DISCUSSION: The neurobiological etiology of abulia is still unclear but is postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. There have been reports of poststroke patients with abulia being treated by modulating this dopamine circuitry and in some cases with short-term low-dose olanzapine. CONCLUSION: Further research is needed to develop a better understanding of the pathophysiology of abulia leading to more effective treatment algorithms including more specific diagnostic tools and effective pharmacological interventions.

A Previously Healthy Adolescent With Acute Psychosis and Severe Hyperhidrosis.

A previously healthy 15-year-old boy presented with 3 months of progressive psychosis, insomnia, back and groin pain, and hyperhidrosis. On examination, the patient was disheveled, agitated, and soaked with sweat, with systolic blood pressure in the 160s and heart rate in the 130s. Aside from occasional auditory and visual hallucinations, his neurologic examination was normal. The patient was admitted for an extensive workup, including MRI of the brain and spine and lumbar puncture, which were normal. Through collaboration with various pediatric specialists, including psychiatry and neurology, a rare diagnosis was ultimately unveiled.

Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures.

Investigating human oligodendrogenesis and the interaction of oligodendrocytes with neurons and astrocytes would accelerate our understanding of the mechanisms underlying white matter disorders. However, this is challenging because of the limited accessibility of functional human brain tissue. Here, we developed a new differentiation method of human induced pluripotent stem cells to generate three-dimensional brain organoids that contain oligodendrocytes as well as neurons and astrocytes, called human oligodendrocyte spheroids. We found that oligodendrocyte lineage cells derived in human oligodendrocyte spheroids transitioned through developmental stages similar to primary human oligodendrocytes and that the migration of oligodendrocyte lineage cells and their susceptibility to lysolecithin exposure could be captured by live imaging. Moreover, their morphology changed as they matured over time in vitro and started myelinating neurons. We anticipate that this method can be used to study oligodendrocyte development, myelination, and interactions with other major cell types in the CNS.

Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency.

OBJECTIVE: Thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial pyrimidine salvage pathway, is essential for mitochondrial DNA (mtDNA) maintenance. Mutations in the nuclear gene, TK2, cause TK2 deficiency, which manifests predominantly in children as myopathy with mtDNA depletion. Molecular bypass therapy with the TK2 products, deoxycytidine monophosphate (dCMP) and deoxythymidine monophosphate (dTMP), prolongs the life span of Tk2-deficient (Tk2-/- ) mice by 2- to 3-fold. Because we observed rapid catabolism of the deoxynucleoside monophosphates to deoxythymidine (dT) and deoxycytidine (dC), we hypothesized that: (1) deoxynucleosides might be the major active agents and (2) inhibition of deoxycytidine deamination might enhance dTMP+dCMP therapy. METHODS: To test these hypotheses, we assessed two therapies in Tk2-/- mice: (1) dT+dC and (2) coadministration of the deaminase inhibitor, tetrahydrouridine (THU), with dTMP+dCMP. RESULTS: We observed that dC+dT delayed disease onset, prolonged life span of Tk2-deficient mice and restored mtDNA copy number as well as respiratory chain enzyme activities and levels. In contrast, dCMP+dTMP+THU therapy decreased life span of Tk2-/- animals compared to dCMP+dTMP. INTERPRETATION: Our studies demonstrate that deoxynucleoside substrate enhancement is a novel therapy, which may ameliorate TK2 deficiency in patients. Ann Neurol 2017;81:641-652.

Long survival in patients with leigh syndrome and the m.10191T>C mutation in MT-ND3 : a case report and review of the literature.

We report an unusual case of Leigh syndrome due to the m.10191T>C mutation in the complex I gene MT-ND3. This mutation has been associated with a spectrum of clinical phenotypes ranging from infant lethality to adult onset. Despite infantile onset and severe symptoms, our patient has survived to early adulthood because of a strict dietary regimen and parental care. This patient is an extreme example of the frequently prolonged course of Leigh syndrome due to this particular mutation.

Copy number variation and psychiatric disease risk.

Psychiatric disorders are multifactorial in nature with complex genetic architecture. A number of recent studies, building upon earlier findings of copy number variants (CNVs) at the 22q11.2 locus, suggest that rare CNVs represent an important component of genetic heterogeneity in the etiology of complex psychiatric diseases, such as schizophrenia. De novo CNVs are found with higher frequency among sporadic cases, whereas inherited CNVs are enriched among familial cases. Despite substantial progress, a number of challenges remain, such as pinpointing causative relationships between specific gene(s) affected by CNVs and disease phenotypes as well as distinguishing abnormal structural mutations from neutral polymorphisms and establishing a clear association between individual pathogenic CNV and disease phenotypes.

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.