The natural history of variable subtypes in pediatric-onset TUBB4A-related leukodystrophy.
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Gavazzi Francesco, Charsar Brittany, Hamilton Eline, Erler Jacqueline A, Patel Virali, Woidill Sarah, Sevagamoorthy Anjana, Helman Guy, Schmidt Johanna, Pizzino Amy, Muirhead Kayla, Takanohashi Asako, Bonkowsky Joshua L, Meyerhoffer Kelsee, Simons Cas, Doi Hiroshi, Satoko Miyatake, Matsumoto Naomichi, Delgado Mauricio R, Sanchez-Castillo Meredith, Wang Jingming, de Carvalho Daniel Rocha, Tournev Ivailo, Chamova Teodora, Jordanova Albena, Clegg Nancy J, Nicita Francesco, Bertini Enrico, Teng Michelle, Williams Dan, Tonduti Davide, Houlden Henry, Stellingwerff Menno, Wassmer Evangeline, Garcia-Cazorla Angeles, Bernard Geneviève, Mirchi Amytice, Toutounchi Helia, Wolf Nicole I, van der Knaap Marjo S, Shults Justine, Adang Laura A, Vanderver Adeline L
Аннотация
We establish the natural history of pediatric-onset TUBB4A-related leukodystrophy to improve clinical trial readiness through a medical record-based longitudinal study. An international cohort of 216 individuals with pediatric-onset TUBB4A-related leukodystrophy was included. Demographic information and medical events were extracted from medical records or publications. Retrospective scores (Gross Motor Function - Metachromatic Leukodystrophy [GMFC-MLD] and Communication Function Classification System [CFCS]) were applied to assess function. Survival analysis distinguished differences in longitudinal neurocognitive function and time to event outcomes between subtypes. A decision tree predicted independent ambulation from early motor milestones. Genotype (p.Asp249Asn vs non-p.Asp249Asn) and independent sitting by age 9 months predicted ambulation by 3 years, and stratification into three subgroups: early-infantile (non- sitting by 9 months), late-infantile (normal early milestones without the common p.Asp249Asn mutation), and a cohort of p.Asp249Asn late-infantile onset individuals. Median age at symptom onset was 0.71 years (interquartile range: [0.33, 1.50]). Common symptoms at onset include delayed development and tone abnormalities (n = 125, 66.5 % and n = 77, 43.0 %). The most common medical complications included scoliosis (N = 51/142), hip dislocation (N = 30/101), and seizures (N = 51/163). The early-infantile more severely affected cohort had a greater prevalence of G-tube placement, scoliosis, and seizure compared to the late-infantile form (p < 0.01). Peak motor and communication abilities were comparable between the p.Asp249Asn and the late infantile cohorts. Despite the acquisition of early milestones, individuals with p.Asp249Asn showed a more rapid decline of functional abilities compared to other late infantile forms (log-rank p = 0.0002). Better understanding of TUBB4A-related leukodystrophy subtypes will improve clinical care, allow targeted preventive interventions, and permit disease stratification for future disease-modifying clinical trials.