ABSTRACT
Aicardi Goutières Syndrome (AGS) is an autoinflammatory disorder resulting in sustained interferon activation through defects in nucleic acid modification and sensing pathways. Thus, mRNA-based vaccination used against SARS-CoV-2, raise disease-specific safety concerns. To assess interferon signaling, we tested mRNA SARS-CoV-2 vaccines in AGS whole blood samples. Interferon activation is measured through quantitation of interferon signaling gene (ISG) expression and is increased in AGS patients. There was no increase in ISG scores from baseline following treatment with the nucleoside modified mRNA formulation compared to an increase with unmodified. A patient-family survey reported that the vaccines were well tolerated. These findings suggest that COVID vaccination using nucleoside-modified forms of mRNA vaccines are unlikely to directly stimulate ISG expression in response to mRNA internalization in AGS tissues. With continued community spread, we recommend vaccination using nucleoside-modified mRNA vaccines in this rare disease group in individuals for whom vaccines were previously well tolerated.
ABSTRACT
-To characterize the performance of the TUBB4A-related disorder population at traditional gross motor evaluations and adaptive behavior questionnaires. -To determine the functional performance of the population and confirm the existence of a functional genotype/phenotype correlation. Prospective study. Children were evaluated by providers trained in the administration of Gross Motor Function Measure-88 (GMFM-88), and Vineland Adaptive Behavior Scale 3rd edition (VABS-3) Parent/Caregiver Form. Motor function and adaptive behavior abilities were assessed with hybrid in-person/remote evaluations, due to COVID-19 pandemic constrains in travel. Fifty individuals with a clinical and molecular diagnosis of TUBB4A-related disorders. None. GMFM-88, VABS-3. Patients showed severe gross motor impairment, with floor effect performance at the GMFM-88. Impaired performance of motor abilities and daily living skills was observed at the VABS-3, while social and communicative abilities were relatively spared. A genotype-phenotype correlation was observed, with a lower overall functional level observed in the non-p.Asp249Asn subcohort. The severe motor impairment observed in this population makes challenging the administration of commonly administered gross motor assessments such as the GMFM-88, while the VABS-3 appears to describe better this population, being able to highlight functional differences associated with specific genotypes. The identification of outcome measures tailored on populations with rare disorders has the potential to be helpful in clinical prognostication as well as cohort selection for future clinical trials. None.
ABSTRACT
Research Objectives -To characterize the performance of the TUBB4A-related disorder population at traditional gross motor evaluations and adaptive behavior questionnaires. -To determine the functional performance of the population and confirm the existence of a functional genotype/phenotype correlation. Design Prospective study. Setting Children were evaluated by providers trained in the administration of Gross Motor Function Measure-88 (GMFM-88), and Vineland Adaptive Behavior Scale 3rd edition (VABS-3) Parent/Caregiver Form. Motor function and adaptive behavior abilities were assessed with hybrid in-person/remote evaluations, due to COVID-19 pandemic constrains in travel. Participants Fifty individuals with a clinical and molecular diagnosis of TUBB4A-related disorders. Interventions None. Main Outcome Measures GMFM-88, VABS-3. Results Patients showed severe gross motor impairment, with floor effect performance at the GMFM-88. Impaired performance of motor abilities and daily living skills was observed at the VABS-3, while social and communicative abilities were relatively spared. A genotype-phenotype correlation was observed, with a lower overall functional level observed in the non-p.Asp249Asn subcohort. Conclusions The severe motor impairment observed in this population makes challenging the administration of commonly administered gross motor assessments such as the GMFM-88, while the VABS-3 appears to describe better this population, being able to highlight functional differences associated with specific genotypes. The identification of outcome measures tailored on populations with rare disorders has the potential to be helpful in clinical prognostication as well as cohort selection for future clinical trials. Author(s) Disclosures None.
ABSTRACT
Research Objectives To characterize the feasibility of mainstream outcome measures in a cohort of children with clinical and genetic diagnosis of AGS. To determine the performance and existence of possible floor effect with mainstream outcomes in children with AGS. To evaluation the cognitive abilities of children with AGS and determine how this influences motor performance. Design Prospective study- Francesco will need to add. Setting Children were evaluated by providers trained in the administration of Gross Motor Function Measure-88 (GMFM-88), Leiter International Scales 3rd edition, and parent-reported measure (Vineland Adaptive Behavior Scale 3rd edition, VABS-3). All cognitive evaluations occurred in person, while motor function and adaptive behavior abilities were assessed with hybrid in-person/remote evaluations, due to COVID-19 pandemic constrains in travel. Participants Eighty individuals with a clinical and molecular diagnosis of AGS Interventions None. Main Outcome Measures GMFM-88, Leiter International Scales 3rd edition, VABS-3. Results Patients showed severe gross motor impairment, with floor effect performance at the GMFM-88. Impaired performance of motor abilities and daily living skills was observed at the VABS-3, while social abilities were relatively spared. The evaluation of the non-verbal cognitive abilities bypassed the limited verbal expression of our population and showed a less striking floor effect when compared pure motor evaluations. Conclusions Non-verbal cognitive evaluations and adaptive behavior evaluations appeared to be able to describe the performance of children with AGS while the severe motor impairment makes challenging the administration of commonly used gross motor assessments such as the GMFM-88. The identification of outcome measures tailored on populations with rare disorders has the potential to be helpful in clinical prognostication as well as cohort selection for future clinical trials. Author(s) Disclosures None.
ABSTRACT
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.
Subject(s)
Autoimmune Diseases of the Nervous System , Nervous System Malformations , Rheumatology , Skin Diseases , Autoimmune Diseases of the Nervous System/genetics , Erythema Nodosum , Fingers/abnormalities , Humans , Quality of LifeABSTRACT
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.