Clinical Characteristics of Creatine Transporter Deficiency (CTD): Final Results of the Vigilan Observational Study
Melanie Brandabur1, Simona Bianconi2, Irina Anselm4, Bruce A. Barshop5, Elizabeth Berry-Kravis6, Dwight D Koeberl7, Kim M Cecil8, Fady Hannah-Shmouni3, Nicola Longo9, Saadet Mercimek-Andrews10, Forbes D Porter2, Samar Rahhal11, Reid Sutton12, Susan Blair1, Tricia Cimms1, Lin Zhang1, Cristan Farmer PhD13, Audrey Thurm13, Judith Miller14
1Ultragenyx Pharmaceutical Inc, 2Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 3National Institutes of Health, 4Boston Children's Hospital, 5University of California San Diego, 6Rush University Medical Center, 7Duke University, 8Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 9University of Utah, 10, University of Toronto, The Hospital for Sick Children, 11Eunice Kennedy Shriver National Institute of Child Health and Human Development, 12Baylor College of Medicine, 13National Institute of Mental Health, 14The Children’s Hospital of Philadelphia
Objective:
To enhance understanding of symptoms and developmental course of people living with CTD, contribute to development of therapeutic intervention programs, and identify potential study endpoints relevant to CTD.
Background:
Little is known about the natural history of CTD, an X-linked disorder of disrupted creatine transport into cells.
Design/Methods:
This study (NCT02931682) used parent questionnaires and clinical assessments to characterize clinical features of males with confirmed CTD (SLC6A8 pathogenic variant) for up to 4 years.
Results:
Fifty patients (mean baseline age, 8.8 years; range, 1.5-24.4 years) were enrolled. Mean age at first symptom was 9.0 months, mean time from initial evaluation to diagnosis was 3.2 years, and mean CTD diagnosis age was 4.9 years. In addition to global developmental delay, medical history included seizures (68%), hypotonia (decreased muscle tone; 50%), aggressive behavior (46%), self-injurious behavior (40%), autism spectrum disorder features (32%), attention deficit disorder (32%), anxiety disorder (20%), and cardiac arrhythmia (8%). Baseline language levels were single words (42%), sentences (33%), babbling (15%), no speech (4%), and unknown (4%). Behaviorally, based on the ABC-2 questionnaire, patients with CTD often exhibited irritability and hyperactivity. Baseline gastrointestinal symptoms included constipation (44%), choking/gagging (32%), vomiting (16%), and gastroesophageal reflux disease (12%). Across measures, little change or improvement was seen over time.
Conclusions:
In patients with CTD, symptoms occurred early in life, with a prolonged delay before CTD diagnosis. Further, patients with CTD experienced a range of neurologic, cardiac, and gastrointestinal symptoms and had meaningful and persistent delays and impairments in language and cognitive ability, with very limited skill development over the four-year study. Significant and persistent impairments suggest therapeutic intervention would be needed at a young age to improve outcomes.