Practical Approach to Longitudinal Neurologic Care of Adults With X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy.

Although X-linked adrenoleukodystrophy (ALD) has historically been considered a childhood disease managed by pediatric neurologists, it is one of the most common leukodystrophies diagnosed in adulthood. An increase in both male and female adults reaching diagnosis due to familial cases identified by state newborn screening panels and more widespread use of genetic testing results in a large cohort of presymptomatic or early symptomatic adults. This population is in urgent need of standardized assessments and follow-up care. Adults with ALD/adrenomyeloneuropathy (AMN) may be diagnosed in a variety of ways, including after another family member is identified via genetic testing or newborn screening, presenting for symptomatic evaluation, or following diagnosis with primary adrenal insufficiency. Significant provider, patient, and systems-based barriers prevent adult patients with ALD/AMN from receiving appropriate care, including lack of awareness of the importance of longitudinal neurologic management. Confirmation of and education about the diagnosis should be coordinated in conjunction with a genetic counselor. Routine surveillance for adrenal insufficiency and onset of cerebral ALD (CALD) in men should be performed systematically to avoid preventable morbidity and mortality. While women with ALD do not usually develop cerebral demyelination or adrenal insufficiency, they remain at risk for myeloneuropathy and are no longer considered "carriers." After diagnosis, patients should be connected to the robust support networks, foundations, and research organizations available for ALD/AMN. Core principles of neurologic symptom management parallel those for patients with other etiologies of progressive spastic paraplegia. Appropriate patient candidates for hematopoietic stem cell transplant (HSCT) and other investigational disease-modifying strategies require early identification to achieve optimal outcomes. All patients with ALD/AMN, regardless of sex, age, or symptom severity, benefit from a multidisciplinary approach to longitudinal care spearheaded by the neurologist. This review proposes key strategies for diagnostic confirmation, laboratory and imaging surveillance, approach to symptom management, and guidance for identification of appropriate candidates for HSCT and investigational treatments.

Determination of Health Concepts in ß-Propeller Protein-Associated Neurodegeneration.

ß-Propeller protein-associated neurodegeneration (BPAN) is a rare, X-linked condition caused by pathogenic variants in the WDR45 gene that result in a defect of autophagy. Classified as a disorder of neurodegeneration with brain iron accumulation, ß-propeller protein-associated neurodegeneration is associated with severe neurologic impairments. With the anticipation of future therapeutic trials, this project characterizes the family's perspective of the impact of disease and defines Health Concepts (HC).Children with a molecularly confirmed diagnosis of ß-propeller protein-associated neurodegeneration were enrolled in a prospective natural history study. We administered the Vineland Adaptive Behavior Scales-Third Edition and provided health-related quality of life questionnaires to 42 caregivers. Questionnaires included Pediatric Quality of Life Inventory-Generic Core and Pediatric Quality of Life Inventory-Family Impact modules, Caregiver Priorities and Child Health Index of Life with Disabilities, and Caregiver TBI-CareQoL.The Vineland Adaptive Behavior Scales-Third Edition (n = 42) captured the family's perspective that communication was more affected compared with socialization, activities of daily living (ADL), and motor skills (P < .0001, P < .0001, P = .0053, respectively). Similarly, on the Caregiver Priorities and Child Health Index of Life with Disabilities (n = 26), Pediatric Quality of Life Inventory-Generic Core (n = 27), CareQol (n = 26), and Pediatric Quality of Life Inventory-Family Impact (n = 27), communication abilities, as well as social functioning and activities of daily living, were noted to be most impacted.Through the use of standardized surveys and outcome assessments, we establish the effects of ß-propeller protein-associated neurodegeneration on caregiver quality of life. Key health concepts identified by families included overall health, comfort, and communication. The identified HC will inform the future identification of concept of interest and selection of appropriate clinical outcome assessments through the administration of patient-reported outcomes.

Systemic complications of Aicardi Goutières syndrome using real-world data.

OBJECTIVE: Aicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden. METHODS: All subjects (n = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007-2022; n = 129) with individual-level data was also collected. Neurologic severity at the last available encounter was determined by retrospectively assigning the AGS Severity Scale [severe (0-3), moderate (4-8), and mild (9-11)]. RESULTS: The genotype frequency in the natural history cohort was TREX1 (n = 26, 15.6 %), RNASEH2B (n = 50, 29.9 %), RNASEH2C (n = 3, 1.8 %), RNASEH2A (n = 7, 4.2 %), SAMHD1 (n = 25, 15.0 %), ADAR (n = 34, 20.4 %), IFIH1 (n = 19, 11.4 %), and RNU7-1 (n = 3, 1.8 %). The median age of systemic onset was 0.15 years [IQR = 0.67 years; median range by genotype: 0 (TREX1) - 0.62 (ADAR) years], while the median neurological onset was 0.33 years [IQR = 0.82 years; median range by genotype: 0.08 (TREX1) - 0.90 (ADAR) year]. The most common early systemic complications were gastrointestinal, including dysphagia or feeding intolerance (n = 124) and liver abnormalities (n = 67). Among postnatal complications, thrombocytopenia appeared earliest (n = 29, median 0.06 years). Tone abnormalities (axial hypotonia: n = 145, 86.8 %; dystonia: n = 123, 73.7 %), irritability (n = 115, 68.9 %), and gross motor delay (n = 112, 7.1 %) emerged as the most prevalent neurological symptoms. Previously published case reports demonstrated similar patterns. The median AGS score for the entire cohort was 4 (IQR = 7). The most severe neurologic phenotype occurred in TREX1-related AGS (n = 19, median AGS severity score 2, IQR = 2). Time to feeding tube placement, chilblains, early gross motor delay, early cognitive delay, and motor regression were significantly associated with genotype (Fleming-Harrington log-rank: p = 0.0002, p < 0.0001, p = 0.0038, p < 0.0001, p = 0.0001, respectively). Microcephaly, feeding tube placement, and seizures were associated with lower AGS scores (All: Wilcoxon rank sum test, p < 0.0001). Among the qualifying case reports (n = 129), tone abnormalities were the most prevalent disease feature, with spastic quadriplegia reported in 37 of 96 cases (38.5 %) and dystonia in 30 of 96 cases (31.2 %). CONCLUSIONS: AGS is a heterogeneous disease with multi-organ system dysfunction that compounds throughout the clinical course, resulting in profound neurological and extra-neurological disease impact. Systemic symptoms precede neurologic disease features in most cases. Disease onset before the age of one year, microcephaly, feeding tube placement, and seizures were associated with worse neurological outcomes. This work will inform evidence-based clinical monitoring guidelines and clinical trial design.

Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD) is a severe, lysosomal storage disorder caused by pathogenic variants in the gene SUMF1, encoding the sulfatase modifying factor formylglycine-generating enzyme. Patients with MSD exhibit functional deficiencies in all cellular sulfatases. The inability of sulfatases to break down their substrates leads to progressive and multi-systemic complications in patients, similar to those seen in single-sulfatase disorders such as metachromatic leukodystrophy and mucopolysaccharidoses IIIA. Here, we aimed to determine if hematopoietic stem cell transplantation with ex vivo SUMF1 lentiviral gene therapy could improve outcomes in a clinically relevant mouse model of MSD. We first tested our approach in MSD patient-derived cells and found that our SUMF1 lentiviral vector improved protein expression, sulfatase activities, and glycosaminoglycan accumulation. In vivo, we found that our gene therapy approach rescued biochemical deficits, including sulfatase activity and glycosaminoglycan accumulation, in affected organs of MSD mice treated post-symptom onset. In addition, treated mice demonstrated improved neuroinflammation and neurocognitive function. Together, these findings suggest that SUMF1 HSCT-GT can improve both biochemical and functional disease markers in the MSD mouse.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

IFN-signaling gene expression as a diagnostic biomarker for monogenic interferonopathies.

IFN-signaling gene (ISG) expression scores are potential markers of inflammation with significance from cancer to genetic syndromes. In Aicardi Goutières Syndrome (AGS), a disorder of abnormal DNA and RNA metabolism, this score has potential as a diagnostic biomarker, although the approach to ISG calculation has not been standardized or validated. To optimize ISG calculation and validate ISG as a diagnostic biomarker, mRNA levels of 36 type I IFN response genes were quantified from 997 samples (including 334 AGS), and samples were randomized into training and test data sets. An independent validation cohort (n = 122) was also collected. ISGs were calculated using all potential combinations up to 6 genes. A 4-gene approach (IFI44L, IFI27, USP18, IFI6) was the best-performing model (AUC of 0.8872 [training data set], 0.9245 [test data set]). The majority of top-performing gene combinations included IFI44L. Performance of IFI44L alone was 0.8762 (training data set) and 0.9580 (test data set) by AUC. The top approaches were able to discriminate individuals with genetic interferonopathy from control samples. This study validates the context of use for the ISG score as a diagnostic biomarker and underscores the importance of IFI44L in diagnosis of genetic interferonopathies.

Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. METHODS: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. RESULTS: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. DISCUSSION: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.

Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.

Nucleotide metabolism, leukodystrophies, and CNS pathology.

The balance between a protective and a destructive immune response can be precarious, as exemplified by inborn errors in nucleotide metabolism. This class of inherited disorders, which mimics infection, can result in systemic injury and severe neurologic outcomes. The most common of these disorders is Aicardi Goutières syndrome (AGS). AGS results in a phenotype similar to "TORCH" infections (Toxoplasma gondii, Other [Zika virus (ZIKV), human immunodeficiency virus (HIV)], Rubella virus, human Cytomegalovirus [HCMV], and Herpesviruses), but with sustained inflammation and ongoing potential for complications. AGS was first described in the early 1980s as familial clusters of "TORCH" infections, with severe neurology impairment, microcephaly, and basal ganglia calcifications (Aicardi & Goutières, Ann Neurol, 1984;15:49-54) and was associated with chronic cerebrospinal fluid (CSF) lymphocytosis and elevated type I interferon levels (Goutières et al., Ann Neurol, 1998;44:900-907). Since its first description, the clinical spectrum of AGS has dramatically expanded from the initial cohorts of children with severe impairment to including individuals with average intelligence and mild spastic paraparesis. This broad spectrum of potential clinical manifestations can result in a delayed diagnosis, which families cite as a major stressor. Additionally, a timely diagnosis is increasingly critical with emerging therapies targeting the interferon signaling pathway. Despite the many gains in understanding about AGS, there are still many gaps in our understanding of the cell-type drivers of pathology and characterization of modifying variables that influence clinical outcomes and achievement of timely diagnosis.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries.

BACKGROUND: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. METHODS: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. RESULTS: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1-3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1-5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. CONCLUSION: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians' struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.

Biochemical signatures of disease severity in multiple sulfatase deficiency.

Sulfatases catalyze essential cellular reactions, including degradation of glycosaminoglycans (GAGs). All sulfatases are post-translationally activated by the formylglycine generating enzyme (FGE) which is deficient in multiple sulfatase deficiency (MSD), a neurodegenerative lysosomal storage disease. Historically, patients were presumed to be deficient of all sulfatase activities; however, a more nuanced relationship is emerging. Each sulfatase may differ in their degree of post-translational modification by FGE, which may influence the phenotypic spectrum of MSD. Here, we evaluate if residual sulfatase activity and accumulating GAG patterns distinguish cases from controls and stratify clinical severity groups in MSD. We quantify sulfatase activities and GAG accumulation using three complementary methods in MSD participants. Sulfatases differed greatly in their tolerance of reduction in FGE-mediated activation. Enzymes that degrade heparan sulfate (HS) demonstrated lower residual activities than those that act on other GAGs. Similarly, HS-derived urinary GAG subspecies preferentially accumulated, distinguished cases from controls, and correlated with disease severity. Accumulation patterns of specific sulfatase substrates in MSD provide fundamental insights into sulfatase regulation and will serve as much-needed biomakers for upcoming clinical trials. This work highlights that biomarker investigation of an ultra-rare disease can simultaneously inform our understanding of fundamental biology and advance clinical trial readiness efforts.

TREX1 is required for microglial cholesterol homeostasis and oligodendrocyte terminal differentiation in human neural assembloids.

Three Prime Repair Exonuclease 1 (TREX1) gene mutations have been associated with Aicardi-Goutières Syndrome (AGS) - a rare, severe pediatric autoimmune disorder that primarily affects the brain and has a poorly understood etiology. Microglia are brain-resident macrophages indispensable for brain development and implicated in multiple neuroinflammatory diseases. However, the role of TREX1 - a DNase that cleaves cytosolic nucleic acids, preventing viral- and autoimmune-related inflammatory responses - in microglia biology remains to be elucidated. Here, we leverage a model of human embryonic stem cell (hESC)-derived engineered microglia-like cells, bulk, and single-cell transcriptomics, optical and transmission electron microscopy, and three-month-old assembloids composed of microglia and oligodendrocyte-containing organoids to interrogate TREX1 functions in human microglia. Our analyses suggest that TREX1 influences cholesterol metabolism, leading to an active microglial morphology with increased phagocytosis in the absence of TREX1. Notably, regulating cholesterol metabolism with an HMG-CoA reductase inhibitor, FDA-approved atorvastatin, rescues these microglial phenotypes. Functionally, TREX1 in microglia is necessary for the transition from gliogenic intermediate progenitors known as pre-oligodendrocyte precursor cells (pre-OPCs) to precursors of the oligodendrocyte lineage known as OPCs, impairing oligodendrogenesis in favor of astrogliogenesis in human assembloids. Together, these results suggest routes for therapeutic intervention in pathologies such as AGS based on microglia-specific molecular and cellular mechanisms.

Hematologic abnormalities in Aicardi Goutières Syndrome.

BACKGROUND: Because of the broad clinical spectrum, heritable autoinflammatory diseases present a management and therapeutic challenge. The most common genetic interferonopathy, Aicardi Goutières Syndrome (AGS), is associated with early onset neurologic disability and systemic inflammation. The chronic inflammation of AGS is the result of dysregulation of interferon (IFN) expression by one of nine genes within converging pathways. While each AGS subtype shares common features, distinct patterns of severity and potential for systemic complications amongst the genotypes are emerging. Multilineage cytopenias are a potentially serious, but poorly understood, complication of AGS. As immunomodulatory treatment options are developed, it is important to characterize the role of the disease versus treatment in hematologic abnormalities. This will allow for better understanding and management of cytopenia. METHODS: In total, 142 individuals with molecularly-confirmed AGS were included. Information on genotype, demographics, and all available hematologic laboratory values were collected from existing medical records. As part of a clinical trial, a subset of this cohort (n = 52) were treated with a janus kinase inhibitor (baricitinib), and both pre- and post-treatment values were included. Abnormal values were graded based on Common Terminology Criteria for Adverse Events (CTCAE v5.0), supplemented with grading definitions for thrombocytosis, and were compared across genotypes and baricitinib exposure. RESULTS: In total, 11,184 laboratory values were collected over a median of 2.54 years per subject (range 0-22.68 years). To reduce bias from repeated sampling within a limited timeframe, laboratory results were restricted to the most abnormal value within a month (n = 8485). The most common abnormalities were anemia (noted in 24% of subjects prior to baricitinib exposure), thrombocytopenia (9%), and neutropenia (30%). Neutropenia was most common in the SAMHD1 cohort and increased with baricitinib exposure (38/69 measurements on baricitinib versus 14/121 while not on baricitinib). Having an abnormality prior to treatment was associated with having an abnormality on treatment for neutropenia and thrombocytopenia. CONCLUSION: By collecting available laboratory data throughout the lifespan, we were able to identify novel patterns of hematologic abnormalities in AGS. We found that AGS results in multilineage cytopenias not limited to the neonatal period. Neutropenia, anemia, and thrombocytopenia were common. Moderate-severe graded events of neutropenia, anemia, and leukopenia were more common on baricitinib, but rarely of clinical consequence. Based on these results, we would recommend careful monitoring of hematologic parameters of children affected by AGS throughout the lifespan, especially while on therapy, and consideration of AGS as a potential differential diagnosis in children with neurologic impairment of unclear etiology with hematologic abnormalities. Trial registration ClinicalTrials.gov Identifier: NCT01724580 ClinicalTrials.gov Identifier: NCT03921554.

Psychometric outcome measures in beta-propeller protein-associated neurodegeneration (BPAN).

BACKGROUND: Beta-propeller protein-associated neurodegeneration (BPAN) is a rare neurodegenerative disorder characterized by iron accumulation in the brain with spectrum of neurodevelopmental and movement phenotypes. In anticipation of future clinical trials and to inform clinical care, there is an unmet need to capture the phenotypic diversity of this rare disorder and better define disease subtypes. METHODS: A total of 27 individuals with BPAN were included in our natural history study, from which traditional outcome measures were obtained in 18 subjects. Demographic and diagnostic information, along with acquisition of basic developmental skills and overall neurologic severity were extracted from the medical records. Functional outcome measures were administered at the time of the evaluation or applied retrospectively at the last clinical encounter for patients who were not able to travel for in person. Based on age and functional level, the following assessments were administered: Leiter-3, Gross Motor Function Measure (GMFM)-66 Item Sets, Vineland-3, and Peabody-2. RESULTS: Overall, cognitive function was more impaired compared to gross motor function. Onset of symptoms of BPAN within the first 6 months of life was associated with decreased gain of ambulation and gain of spoken language (ambulation: log-rank test p = 0.0015; gain of first word: p = 0.0015). There was no difference in age at seizure onset by age at initial symptom onset (p = 0.8823). Collection of prospective outcome measures was limited by attention and behavior in our patient population, reinforcing the complexity of phenotype assessment and inadequacy of available standardized tests. Overall, gross motor and adaptive behavior assessments were better able to capture the dynamic range of function across the BPAN population than the fine motor and non-verbal cognitive tests. Floor effects were noted across outcome measures in a subset of individuals for cognitive and adaptive behavior tests. CONCLUSION: Our data suggest the distinct phenotypes of BPAN: a severe, early onset form and an attenuated form with higher cognitive capabilities. Early age at onset was a key factor in predicting future neurologic impairment.

Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It results from pathogenic variants in ABCD1, which encodes the peroxisomal very-long-chain fatty acid transporter, causing a spectrum of neurodegenerative phenotypes. The childhood cerebral form of the disease is particularly devastating. Early diagnosis and intervention improve outcomes. Because newborn screening facilitates identification of at-risk individuals during their asymptomatic period, X-ALD was added to the Pennsylvania newborn screening program in 2017. We analyzed outcomes from the first four years of X-ALD newborn screening, which employed a two-tier approach and reflexive ABCD1 sequencing. There were 51 positive screens with elevated C26:0-lysophosphatidylcholine on second-tier screening. ABCD1 sequencing identified 21 hemizygous males and 24 heterozygous females, and clinical follow up identified four patients with peroxisomal biogenesis disorders. There were two false-positive cases and one false-negative case. Three unscreened individuals, two of whom were symptomatic, were diagnosed following their young siblings' newborn screening results. Combined with experiences from six other states, this suggests a U.S. incidence of roughly 1 in 10,500, higher than had been previously reported. Many of these infants lack a known family history of X-ALD. Together, these data highlight both the achievements and challenges of newborn screening for X-ALD.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology Points to Consider for Diagnosis and Management of Autoinflammatory Type I Interferonopathies: CANDLE/PRAAS, SAVI, and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI), and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of "points to consider" to improve diagnosis, treatment, and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates, and an allied health care professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires, and consensus methodology, "points to consider" to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment, and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI, and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment, and management of patients with CANDLE/PRAAS, SAVI, and AGS and aim to standardize and improve care, quality of life, and disease outcomes.

The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS.

OBJECTIVE: Autoinflammatory type I interferonopathies, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS), stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) and Aicardi-Goutières syndrome (AGS) are rare and clinically complex immunodysregulatory diseases. With emerging knowledge of genetic causes and targeted treatments, a Task Force was charged with the development of 'points to consider' to improve diagnosis, treatment and long-term monitoring of patients with these rare diseases. METHODS: Members of a Task Force consisting of rheumatologists, neurologists, an immunologist, geneticists, patient advocates and an allied healthcare professional formulated research questions for a systematic literature review. Then, based on literature, Delphi questionnaires and consensus methodology, 'points to consider' to guide patient management were developed. RESULTS: The Task Force devised consensus and evidence-based guidance of 4 overarching principles and 17 points to consider regarding the diagnosis, treatment and long-term monitoring of patients with the autoinflammatory interferonopathies, CANDLE/PRAAS, SAVI and AGS. CONCLUSION: These points to consider represent state-of-the-art knowledge to guide diagnostic evaluation, treatment and management of patients with CANDLE/PRAAS, SAVI and AGS and aim to standardise and improve care, quality of life and disease outcomes.