Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

PURPOSE: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. METHODS: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. RESULTS: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. CONCLUSION: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.

Resting state connectivity immediately following learning correlates with subsequent sleep-dependent enhancement of motor task performance.

There is ongoing debate concerning the functions of resting-state brain activity. Prior work demonstrates that memory encoding enhances subsequent resting-state functional connectivity within task-relevant networks and that these changes predict better recognition. Here, we used functional connectivity MRI (fcMRI) to examine whether task-induced changes in resting-state connectivity correlate with performance improvement after sleep. In two separate sessions, resting-state scans were acquired before and after participants performed a motor task. In one session participants trained on the motor sequence task (MST), a well-established probe of sleep-dependent memory consolidation, and were tested the next day, after a night of sleep. In the other session they performed a motor control task (MCT) that minimized learning. In an accompanying behavioral control study, participants trained on the MST and were tested after either a night of sleep or an equivalent interval of daytime wake. Both the fcMRI and the sleep control groups showed significant improvement of MST performance, while the wake control group did not. In the fcMRI group, increased connectivity in bilateral motor cortex following MST training correlated with this next-day improvement. This increased connectivity did not appear to reflect initial learning since it did not correlate with learning during training and was not greater after MST training than MCT performance. Instead, we hypothesize that this increased connectivity processed the new memories for sleep-dependent consolidation. Our findings demonstrate that physiological processes immediately after learning correlate with sleep-dependent performance improvement and suggest that the wakeful resting brain prepares memories of recent experiences for later consolidation during sleep.

Dental therapy: evolving in Minnesota's safety net.

OBJECTIVES: We identified Minnesota's initial dental therapy employers and surveyed dental safety net providers' perceptions of dental therapy. METHODS: In July 2011, we surveyed 32 Minnesota dental safety net providers to assess their prospective views on dental therapy employment options. In October 2013, we used an employment scan to reveal characteristics of the early adopters of dental therapy. RESULTS: Before the availability of licensed dental therapists, safety net dental clinic directors overwhelmingly (77%) supported dental therapy. As dental therapists have become licensed over the past 2 years, the early employers of dental therapists are safety net clinics. CONCLUSIONS: Although the concept of dental therapy remains controversial in Minnesota, it now has a firm foundation in the state's safety net clinics. Dental therapists are being used in innovative and diverse ways, so, as dental therapy continues to evolve, further research to identify best practices for incorporating dental therapists into the oral health care team is needed.

Genetic Testing History in Adults with Autism Spectrum Disorder.

Background & Objectives: Many genes have been identified in autism spectrum disorder (ASD). Yet little is known about how many adults with ASD receive recommended genetic testing and their outcomes. We investigated the percentage of adults with ASD who received genetic testing using recommended methods in our ASD specialty clinic and the percentage with positive findings. Methods: Potentially eligible adults were identified through search of our health system data repository and ASD diagnoses confirmed using review of relevant medical records by consensus of psychiatrists specializing in ASD. Patients were included (N=630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020 and demographic data available. Data were collected through manual retrospective review of the electronic health record. Results: Only 41% of the adults with ASD (261/630) had a history of genetic testing documented in the medical record. Genetic testing was declined by patients or families for 11% (72) of records and not recorded in 47% (297). Mean (SD; range) age for the 261 adults with testing documented was 28.5 (5.3; 22-58) years. Sixty-seven (26%) were identified as female, 14 (6%) as Asian, 8 (3%) as Black or African American, 226 (89%) as White, 6 (2%) as other race, and 2 (1%) as Hispanic. 189 (73%) had intellectual disability. Ninety-one percent (236) had the genetic testing method recorded. Only 54% (95% CI: 46%, 61%) of patients had testing using a recommended method (chromosomal array, autism/intellectual disability sequencing panel, or exome sequencing). Few adults had received testing with sequencing technologies. A genetic cause of ASD was found in 28% (95% CI: 19%, 39%) of the 121 adults with results from ASD-related genetic testing recorded. Conclusions: Genetic testing can offer clinical and research insights. Yet it is underutilized in this population of adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage of adults with confirmed ASD who had any recommended genetic testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the latest genetic testing performed.

Characterizing visual processing deficits in cerebral adrenoleukodystrophy.

BACKGROUND AND OBJECTIVES: Cerebral adrenoleukodystrophy (CALD) can cause visual impairment, but early symptoms are often missed or misdiagnosed. The framework of cerebral visual impairment (CVI) distinguishes deficits in sensory detection ("lower order") from those of perception and interpretation ("higher order"). This study describes visual deficits in patients with CALD and higher order visual function assessed with a virtual reality (VR) interface combined with eye tracking. METHODS: A retrospective medical record review assessed the prevalence of visual deficits in patients with CALD, as well as lesion burden on brain MRI using the Loes MRI severity score. A VR-based task measured visual spatial processing performance in participants with CALD and controls. RESULTS: Out of 89 CALD patients, 69 % had at least one sign or symptom of visual impairment. Lower order deficits were seen in 56 % of patients, and higher order deficits were seen in 59 % of patients who underwent neuropsychological testing. Even in early stage disease (Loes MRI severity score ≤ 3), visual impairment was present in more than half of patients (58 %). On prospective VR-based assessment, the CALD group (n = 30) had impaired visual search performance (lower success rate and longer reaction time) compared with controls (n = 38). In both groups, there was a trend of worsening performance with increasing task difficulty. DISCUSSION: Higher order visual deficits, not just impairment of visual acuity, visual fields, or oculomotor function, are common in all stages of CALD. Beyond neuropsychological testing, VR-based functional testing allows for quantitative assessment of higher order visual perceptual deficits that are relevant to everyday tasks and may serve as an important marker of neurological decline.

The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects.

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy.

CONTEXT: Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. OBJECTIVE: To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. DESIGN: We conducted a retrospective medical chart review of pediatric patients with ALD. SETTING: All patients were seen in a leukodystrophy clinic in an academic medical center. PATIENTS: We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). MAIN OUTCOME MEASURES: We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. RESULTS: Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. CONCLUSIONS: Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Neurologic Manifestations of the World Health Organization's List of Pandemic and Epidemic Diseases.

The World Health Organization (WHO) monitors the spread of diseases globally and maintains a list of diseases with epidemic or pandemic potential. Currently listed diseases include Chikungunya, cholera, Crimean-Congo hemorrhagic fever, Ebola virus disease, Hendra virus infection, influenza, Lassa fever, Marburg virus disease, Neisseria meningitis, MERS-CoV, monkeypox, Nipah virus infection, novel coronavirus (COVID-19), plague, Rift Valley fever, SARS, smallpox, tularemia, yellow fever, and Zika virus disease. The associated pathogens are increasingly important on the global stage. The majority of these diseases have neurological manifestations. Those with less frequent neurological manifestations may also have important consequences. This is highlighted now in particular through the ongoing COVID-19 pandemic and reinforces that pathogens with the potential to spread rapidly and widely, in spite of concerted global efforts, may affect the nervous system. We searched the scientific literature, dating from 1934 to August 2020, to compile data on the cause, epidemiology, clinical presentation, neuroimaging features, and treatment of each of the diseases of epidemic or pandemic potential as viewed through a neurologist's lens. We included articles with an abstract or full text in English in this topical and scoping review. Diseases with epidemic and pandemic potential can be spread directly from human to human, animal to human, via mosquitoes or other insects, or via environmental contamination. Manifestations include central neurologic conditions (meningitis, encephalitis, intraparenchymal hemorrhage, seizures), peripheral and cranial nerve syndromes (sensory neuropathy, sensorineural hearing loss, ophthalmoplegia), post-infectious syndromes (acute inflammatory polyneuropathy), and congenital syndromes (fetal microcephaly), among others. Some diseases have not been well-characterized from a neurological standpoint, but all have at least scattered case reports of neurological features. Some of the diseases have curative treatments available while in other cases, supportive care remains the only management option. Regardless of the pathogen, prompt, and aggressive measures to control the spread of these agents are the most important factors in lowering the overall morbidity and mortality they can cause.