Classification of Mutations in TUBB4A: A New Spectrum of Disease (P1.6-031)

Objective: To conduct a subtype analysis of children with mutations in the β-tubulin gene, TUBB4A, including canonical Hypomyelination with Atrophy of the Basal Ganglia (H-ABC). Background: TUBB4A associated leukodystrophy is now known to encompass a spectrum of presentations, but limited data is available on genotype-phenotype correlations or distinct cohorts within this disorder. Design/Methods: We retrospectively extracted clinical data from individuals with TUBB4A mutations including genotype, age at onset, clinical signs at presentation, maximum motor milestone, GMFCS score (Gross Motor Functional Classification), and evaluated time to specific clinical milestones, including gastrostomy placement. Kaplan Meier was used for survival analysis. Wilcoxon rank sum test distinguished differences between subtypes. Results: Three clinically distinct subtypes emerged amongst 125 individuals. Type I is a rare, milder presentation with onset between 6–24 months and preservation of walking into the fifth decade. Type II (70% of total) presents between birth and 4 years with a median age of onset at 9.5 months. The best achieved motor milestone is at least supported (95%) or independent walking (63%). Independent ambulation was lost by 25 years, with a median age of 8. The canonical H-ABC p.Asp249Asn mutation (32% of total) was closely associated with Type II. Individuals carrying p.Asp249Asn were more likely to reach independent ambulation, but lost ambulation and needed gastrostomy placement sooner within the Type II cohort (p Conclusions: We expand upon the known phenotypic spectrum of TUBB4A mutations, highlighting three distinct clinical subsets in a spectrum of disease with limited phenotype correlation to regionally clustered locations of TUBB4A mutations. Disclosure: Dr. Charsar has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Cross has nothing to disclose. Dr. Sherbini has nothing to disclose. Dr. Kramer-Golinkoff has nothing to disclose. Dr. Simons has nothing to disclose. Dr. Van Der Knaap has nothing to disclose. Dr. Vanderver has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Shire. Dr. Vanderver holds stock and/or stock options in Aetna. Dr. Vanderver has received research support from Illumina, Shire, Gilead, Eli Lilly.