Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) and other TUBB4A-associated leukoencephalopathies have clinical features including hypomyelination, delayed motor development, truncal hypotonia, spasticity and dystonia. Although a spectrum of clinical presentations is known to exist, no studies exist on the use of COA in this disorder.

Individuals were enrolled in an IRB approved natural history study of TUBB4A-associated leukoencephalopathies. The Gross Motor Function Measure 88 (GMFM-88) tool was used to analyze the gross motor function of thirteen patients. The GMFM-88 evaluates five dimensions including (A) laying and rolling, (B) sitting, (C) crawling and kneeling, (D) standing and (E) walking, running and jumping. Results of GMFM-88 were compared to the Gross Motor Functional Classification Score (GMFCS), a five-point score that can be assigned from review of medical records. Genotype was noted in all participating individuals. Scores were compared to normative data. Spearman correlation was performed between GMFM-88 and GMFCS

Gross motor abilities in TUBB4A-associated leukoencephalopathies ranged from GMFM-88 of 2.5-97%. 85% of individuals (11/13) had baseline scores above the tenth percentile on the first dimension (laying and rolling), however, only 54% (7/13) achieved this in the second dimension (sitting), and only 69% achieved a total score of higher than the 10^th percentile. Two recurrent mutations were seen: c.763G>A (p.V255I) (n=3) was associated with preserved gross motor function, including independent ambulation (2/3); c.785G>A (p.R262H) (n=3) was associated with severe neurologic outcomes. GMFM-88 was highly correlated with an independently assigned GMFCS (r=-0.83, p=0.0001).

TUBB4A-associated hypomyelinating leukodystrophies are clinically variable, and encompass different subtypes. Novel tools are needed in order to accurately capture the heterogenous gross motor function of patients with H-ABC and other TUBB4A-associated leukoencephalopathies. GMFCS, a simple five point scale, accurately captures motor function in this disorder.