Top Caregiver Concerns in Rett syndrome and related disorders: data from the US Natural History Study

Objective: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) has enabled development of novel therapeutic approaches that are currently undergoing clinical evaluation or are proposed to move into clinical development. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top clinical concerns in order to gain information to guide the development and selection of outcome measures for future clinical trials. Methods: Caregivers of participants enrolled in the US Natural History Study of RTT and related disorders were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for Classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2. Results: The top caregiver concerns for Classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The rank order of the frequency of the top caregiver concerns for Classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. The frequency of caregiver concern for seizures, hand use, and spoken language increased in relation to clinician assessed severity in these clinical domains, showing consistency between clinician assessments and caregiver concerns. Comparison across disorders found commonalities in the top caregiver concerns between Classic RTT, Atypical RTT, MECP2 Duplication Syndrome, CDKL5 Deficiency Disorder, and FOXG1 Syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features. Conclusion: The top caregiver concerns for individuals with RTT and the RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

[1]  J. Neul,et al.  Rett Syndrome and MECP2 Duplication Syndrome: Disorders of MeCP2 Dosage , 2022, Neuropsychiatric disease and treatment.

[2]  S. Peters,et al.  Design and outcome measures of LAVENDER, a phase 3 study of trofinetide for Rett syndrome. , 2022, Contemporary clinical trials.

[3]  E. Mercuri,et al.  Cortical Visual Impairment in CDKL5 Deficiency Disorder , 2022, Frontiers in Neurology.

[4]  H. Doll,et al.  Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale , 2021, Orphanet Journal of Rare Diseases.

[5]  Joni N. Saby,et al.  Multisite Study of Evoked Potentials in Rett Syndrome , 2021, Annals of neurology.

[6]  S. Skinner,et al.  Phenotypic features in MECP2 duplication syndrome: Effects of age , 2020, American journal of medical genetics. Part A.

[7]  W. Kaufmann,et al.  A Psychometric Evaluation of the Motor-Behavioral Assessment Scale for Use as an Outcome Measure in Rett Syndrome Clinical Trials. , 2020, American journal on intellectual and developmental disabilities.

[8]  Cary Fu,et al.  Detection of neurophysiological features in female R255X MeCP2 mutation mice , 2020, Neurobiology of Disease.

[9]  Meghan T. Miller,et al.  Measuring What Matters to Individuals with Angelman Syndrome and Their Families: Development of a Patient-Centered Disease Concept Model , 2020, Child psychiatry and human development.

[10]  E. Marsh,et al.  Consensus guidelines on managing Rett syndrome across the lifespan , 2020, BMJ paediatrics open.

[11]  E. Marsh,et al.  Multisystem comorbidities in classic Rett syndrome: a scoping review , 2020, BMJ paediatrics open.

[12]  J. Neul,et al.  Pharmacological readthrough of R294X Mecp2 in a novel mouse model of Rett Syndrome. , 2020, Human molecular genetics.

[13]  W. Kaufmann,et al.  Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings , 2020, Frontiers in Integrative Neuroscience.

[14]  W. Kaufmann,et al.  Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome , 2019, Neurology.

[15]  D. Hessl,et al.  Voice of People with Fragile X Syndrome and Their Families: Reports from a Survey on Treatment Priorities , 2019, Brain sciences.

[16]  M. D. Del Bigio,et al.  MECP2 Mutation Interrupts Nucleolin–mTOR–P70S6K Signaling in Rett Syndrome Patients , 2018, Front. Genet..

[17]  W. Kaufmann,et al.  The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2 , 2018, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[18]  W. Kaufmann,et al.  The course of awake breathing disturbances across the lifespan in Rett syndrome , 2018, Brain and Development.

[19]  S. Julia,et al.  Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features , 2018, Journal of Medical Genetics.

[20]  Hye-Seung Lee,et al.  Scoliosis in Rett Syndrome: Progression, Comorbidities, and Predictors. , 2017, Pediatric neurology.

[21]  W. Kaufmann,et al.  Longitudinal course of epilepsy in Rett syndrome and related disorders , 2017, Brain : a journal of neurology.

[22]  E. Strettoi,et al.  Visual impairment in FOXG1-mutated individuals and mice , 2016, Neuroscience.

[23]  N. C. Schanen,et al.  Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. , 2015, Human molecular genetics.

[24]  Hye-Seung Lee,et al.  Developmental delay in Rett syndrome: data from the natural history study , 2014, Journal of Neurodevelopmental Disorders.

[25]  W. Kaufmann,et al.  Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome , 2014, Journal of Medical Genetics.

[26]  Rodney C. Samaco,et al.  Preclinical research in Rett syndrome: setting the foundation for translational success , 2012, Disease Models & Mechanisms.

[27]  Hye-Seung Lee,et al.  Gastrointestinal and Nutritional Problems Occur Frequently Throughout Life in Girls and Women With Rett Syndrome , 2012, Journal of pediatric gastroenterology and nutrition.

[28]  W. Kaufmann,et al.  Social impairments in Rett syndrome: characteristics and relationship with clinical severity. , 2012, Journal of intellectual disability research : JIDR.

[29]  W. Kaufmann,et al.  Rett syndrome: Revised diagnostic criteria and nomenclature , 2010, Annals of neurology.

[30]  H. Leonard,et al.  InterRett, a model for international data collection in a rare genetic disorder. , 2009, Research in autism spectrum disorders.

[31]  H. Zoghbi,et al.  Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome , 2008, Neurology.

[32]  A. Bird,et al.  Reversal of Neurological Defects in a Mouse Model of Rett Syndrome , 2007, Science.

[33]  A. Yaroshinsky,et al.  A Double-Blind, Randomized, Placebo-Controlled Clinical Study of Trofinetide in the Treatment of Rett Syndrome. , 2017, Pediatric neurology.

[34]  E. Anagnostou,et al.  Improving Treatment Trial Outcomes for Rett Syndrome: The Development of Rett-specific Anchors for the Clinical Global Impression Scale , 2015 .