Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8)

Abstract: Background and objectives: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials. Methods: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software. Results: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence. Discussion: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials.

Parent Summary: This study examines the clinical features of creatine transporter deficiency (CTD) and its impact on caregivers to identify meaningful outcome measures for future clinical trials. Thirty-one patients with confirmed SLC6A8 mutations, mostly male and under 18, were assessed through physical exams, neuropsychological testing, and caregiver burden surveys. Most showed symptoms before age two, but diagnosis was delayed to an average of 6.5 years. Common findings included developmental delays, early behavioral issues, seizures in nearly half, low muscle tone, problems with speech, and movement difficulties. Most patients required daily nursing support, and adaptive testing confirmed moderate-to-severe intellectual disability in male patients. Importantly, caregiver burden was high, with 79% at risk of burnout, significantly more than in families affected by Fragile X syndrome. The study highlights the need for early diagnosis and recommends tools like the Vineland scale, Peabody Picture Vocabulary Test (PPVT5), and Caregiver Burden Inventory (CBI) as valuable endpoints in future CTD therapeutic trials.

Link to article: https://www.neurology.org/doi/10.1212/WNL.0000000000209243?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

PubMed: https://pubmed.ncbi.nlm.nih.gov/38531017/

Authors: Aurore Curie, MD, PhD, Laurence Lion-François, MD, Vassili Valayannopoulos, MD, PhD, Nathalie Perreton, MSc, Marie Gavanon, MSc, Nathalie Touil, MSc, Amandine Brun-Laurisse, MSc, Fahra Gheurbi, MSc, Marion Buchy, MSc, Hulya Halep, MSc, David Cheillan, PharmD, PhD, Catherine Mercier, PhD, Anaïs Brassier, MD, Béatrice Desnous, MD, PhD, Behrouz Kassai, MD, PhD, Pascale De Lonlay, MD, PhD, and Vincent Des Portes, MD, PhD

Key Terms: CTD, Clinical Study, Diagnostic, Mutation Study, Pediatric Patient, Adult Patient, Male + Female Patients